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Sample records for atherogenesis

  1. Platelets: pleiotropic roles in atherogenesis and atherothrombosis.

    Science.gov (United States)

    Linden, Matthew D; Jackson, Denise E

    2010-11-01

    Platelets are small, anucleate blood elements of critical importance in cardiovascular disease. The ability of platelets to activate and aggregate to form blood clots in response to endothelial injury, such as plaque rupture, is well established. These cells are therefore important contributors to ischaemia in atherothrombosis, and antiplatelet therapy is effective for this reason. However, growing evidence suggests that platelets are also important mediators of inflammation and play a central role in atherogenesis itself. Interactions between activated platelets, leukocytes and endothelial cells trigger autocrine and paracrine activation signals, resulting in leukocyte recruitment at and into the vascular wall. Direct physical interaction may contribute also, through platelet adhesion molecules assisting localization of monocytes to the site of atherogenesis and platelet granule release contributing to the chronic inflammatory milieu which leads to foam cell development and accelerated atherogenesis. Recent studies have shown that antiplatelet therapy in animal models of accelerated atherogenesis can lead to decreased plaque size and improve plaque stability. This review examines the complexity of platelet function and the nature of interactions between activated platelets, leukocytes and endothelial cells. We focus on the growing body of evidence that platelets play a critical role in atherogenesis and contribute to progression of atherosclerosis. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis

    NARCIS (Netherlands)

    Shantsila, E.; Kamphuisen, P. W.; Lip, G. Y. H.

    2010-01-01

    The complex and multifactorial nature of atherogenesis and development of atherothrombotic complications involves numerous interactions between various cell types inside the vascular wall (e.g. macrophages and smooth muscle cells) and in the blood (e.g. leukocytes and platelets). One relatively

  3. Involvement of multiple cell lineages in atherogenesis | Ogeng'o ...

    African Journals Online (AJOL)

    Atherogenesis is a multicellular event. Early reports concentrated on the role of endotheliocytes, monocyte - macrophages and smooth muscle cells. Recognition of the immuno-inflammatory nature of the process, however, expanded the scope of cellular involvement and more recent reviews emphasize the role of immune ...

  4. Targeted deletions of cyclooxygenase-2 and atherogenesis in mice

    DEFF Research Database (Denmark)

    Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene

    2010-01-01

    low-density lipoprotein receptor knockouts. Deletion of Mac-COX-2 appeared to remove a restraint on COX-2 expression in lesional nonleukocyte (CD45- and CD11b-negative) vascular cells that express vascular cell adhesion molecule and variably alpha-smooth muscle actin and vimentin, portending a shift...... in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts depressed its modest upregulation by anti-CD3epsilon. However, biosynthesis of PGs, TC composition in lymphatic organs, and atherogenesis in low-density lipoprotein...... receptor knockouts were unaltered in TC knockouts. CONCLUSIONS: Macrophage-COX-2, primarily a source of thromboxane A(2) and prostaglandin (PG)E(2), promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source...

  5. Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice.

    Directory of Open Access Journals (Sweden)

    Florian Willecke

    Full Text Available BACKGROUND: Strong evidence supports a protective role of the cannabinoid receptor 2 (CB(2 in inflammation and atherosclerosis. However, direct proof of its involvement in lesion formation is lacking. Therefore, the present study aimed to characterize the role of the CB(2 receptor in Murine atherogenesis. METHODS AND FINDINGS: Low density lipoprotein receptor-deficient (LDLR(-/- mice subjected to intraperitoneal injections of the selective CB(2 receptor agonist JWH-133 or vehicle three times per week consumed high cholesterol diet (HCD for 16 weeks. Surprisingly, intimal lesion size did not differ between both groups in sections of the aortic roots and arches, suggesting that CB(2 activation does not modulate atherogenesis in vivo. Plaque content of lipids, macrophages, smooth muscle cells, T cells, and collagen were also similar between both groups. Moreover, CB(2 (-/-/LDLR(-/- mice developed lesions of similar size containing more macrophages and lipids but similar amounts of smooth muscle cells and collagen fibers compared with CB(2 (+/+/LDLR(-/- controls. While JWH-133 treatment reduced intraperitoneal macrophage accumulation in thioglycollate-elicited peritonitis, neither genetic deficiency nor pharmacologic activation of the CB(2 receptor altered inflammatory cytokine expression in vivo or inflammatory cell adhesion in the flow chamber in vitro. CONCLUSION: Our study demonstrates that both activation and deletion of the CB(2 receptor do not relevantly modulate atherogenesis in mice. Our data do not challenge the multiple reports involving CB(2 in other inflammatory processes. However, in the context of atherosclerosis, CB(2 does not appear to be a suitable therapeutic target for reduction of the atherosclerotic plaque.

  6. Stability Analysis of a Reaction-Diffusion System Modeling Atherogenesis

    KAUST Repository

    Ibragimov, Akif

    2010-01-01

    This paper presents a linear, asymptotic stability analysis for a reaction-diffusionconvection system modeling atherogenesis, the initiation of atherosclerosis, as an inflammatory instability. Motivated by the disease paradigm articulated by Ross, atherogenesis is viewed as an inflammatory spiral with a positive feedback loop involving key cellular and chemical species interacting and reacting within the intimal layer of muscular arteries. The inflammatory spiral is initiated as an instability from a healthy state which is defined to be an equilibrium state devoid of certain key inflammatory markers. Disease initiation is studied through a linear, asymptotic stability analysis of a healthy equilibrium state. Various theorems are proved, giving conditions on system parameters guaranteeing stability of the health state, and a general framework is developed for constructing perturbations from a healthy state that exhibit blow-up, which are interpreted as corresponding to disease initiation. The analysis reveals key features that arterial geometry, antioxidant levels, and the source of inflammatory components (through coupled third-kind boundary conditions or through body sources) play in disease initiation. © 2010 Society for Industrial and Applied Mathematics.

  7. Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats.

    Science.gov (United States)

    Sithu, Srinivas D; Malovichko, Marina V; Riggs, Krista A; Wickramasinghe, Nalinie S; Winner, Millicent G; Agarwal, Abhinav; Hamed-Berair, Rihab E; Kalani, Anuradha; Riggs, Daniel W; Bhatnagar, Aruni; Srivastava, Sanjay

    2017-05-04

    Mechanisms of atherogenesis have been studied extensively in genetically engineered mice with disturbed cholesterol metabolism such as those lacking either the LDL receptor (Ldlr) or apolipoprotein E (apoe). Few other animal models of atherosclerosis are available. WT rabbits or rats, even on high-fat or high-cholesterol diets, develop sparse atherosclerotic lesions. We examined the effects of Ldlr deletion on lipoprotein metabolism and atherosclerotic lesion formation in Sprague-Dawley rats. Deletion of Ldlr resulted in the loss of the LDLR protein and caused a significant increase in plasma total cholesterol and triglycerides. On normal chow, Ldlr-KO rats gained more weight and were more glucose intolerant than WT rats. Plasma proprotein convertase subtilisin kexin 9 (PCSK9) and leptin levels were higher and adiponectin levels were lower in KO than WT rats. On the Western diet, the KO rats displayed exaggerated obesity and age-dependent increases in glucose intolerance. No appreciable aortic lesions were observed in KO rats fed normal chow for 64 weeks or Western diet for 16 weeks; however, after 34-52 weeks of Western diet, the KO rats developed exuberant atherosclerotic lesions in the aortic arch and throughout the abdominal aorta. The Ldlr-KO rat may be a useful model for studying obesity, insulin resistance, and early-stage atherosclerosis.

  8. AVE 0991-angiotensin-(1-7) receptor agonist, inhibits atherogenesis in apoE-knockout mice.

    Science.gov (United States)

    Toton-Zuranska, J; Gajda, M; Pyka-Fosciak, G; Kus, K; Pawlowska, M; Niepsuj, A; Wolkow, P; Olszanecki, R; Jawien, J; Korbut, R

    2010-04-01

    Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. It was also proved that Ang II promotes atherogenesis. Angiotensin-(1-7) [Ang-(1-7)] opposites Ang II action. Therefore, we would like to find out whether Ang-(1-7) receptor agonist: AVE 0991, could ameliorate atherosclerosis progression in an experimental model of atherosclerosis: apolipoprotein E (apoE) - knockout mice. AVE 0991 inhibited atherogenesis, measured both by "en face" method (7.63+/-1.6% vs. 14.6+/-2.1%) and "cross-section" method (47 235+/-7 546 microm(2) vs. 91 416+/-8 357 microm(2)). This is the first report showing the effect of AVE 0991 on atherogenesis in gene-targeted mice.

  9. Effects of Atorvastatin on Oxidative Stress Biomarkers and Mitochondrial Morphofunctionality in Hyperfibrinogenemia-Induced Atherogenesis

    Directory of Open Access Journals (Sweden)

    María de la Paz Scribano

    2014-01-01

    Full Text Available Relationship between hyperfibrinogenemia (HF, oxidative stress, and atherogenesis was established. Effect of atorvastatin (Ator was assessed. Wistar male (6 months rats were studied: Ctr, control, without HF induction; Ctr-Ator, without HF treated with atorvastatin; AI, atherogenesis induced, and AI-Ator, atherogenesis induced and treated with atorvastatin. Atherogenesis was induced by daily adrenaline injection (0.1 mL/day/rat for 90 days; treatment started 15 days after induction. Fibrinogen (mg/dL and nitric oxide (NO were measured in plasma (mM and superoxide dismutase (SOD (U/mL in red cell lysate by spectrophotometry. Slices of aorta were analyzed by electron microscopy (EM. ANOVA and chi-square test were used; P<0.05 was established. There were no significant differences between Ctr and Ctr-Atorv in fibrinogen, NO, and SOD values. Comparing Ctr with AI an increase of fibrinogen is observed (P<0.001, but it decreased after administration of atorvastatin in AI-Ator (P<0.001. NO diminished in AI relative to Ctr and increased in AI-Ator (P<0.001. SOD showed an increase in AI and AI-Ator compared to Ctr (P<0.001. EM revealed expansion of intermembrane space and disorganization of crests in AI. In AI-Ator mitochondrial areas and diameters were similar to control. Atorvastatin normalizes HF, stabilizes NO, increases SOD, and produces a partial regression of mitochondrial lesions.

  10. Myeloid I kappa B alpha Deficiency Promotes Atherogenesis by Enhancing Leukocyte Recruitment to the Plaques

    NARCIS (Netherlands)

    Goossens, Pieter; Vergouwe, Monique N.; Gijbels, Marion J. J.; Curfs, Danielle M. J.; van Woezik, Johannes H. G.; Hoeksema, Marten A.; Xanthoulea, Sofia; Leenen, Pieter J. M.; Rupec, Rudolf A.; Hofker, Marten H.; de Winther, Menno P. J.

    2011-01-01

    Activation of the transcription factor NF-kappa B appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-kappa B inhibitor I kappa B alpha in atherosclerosis. Myeloid-specific deletion of I kappa B alpha results in larger and more advanced lesions in

  11. Myeloid IκBα deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques

    NARCIS (Netherlands)

    P. Goossens (Pieter); Y. Vergouwe (Yvonne); M. Gijbels (Marion); D.M.J. Curfs (Danielle M.); J.H.G. van Woezik (Johannes H.); M.A. Hoeksema (Marten); S. Xanthoulea (Sofia); P.J. Leenen (Pieter); R.A. Rupec (Rudolf); M.A. Hofker (Marten); M.P.J. de Winther (Menno P.)

    2011-01-01

    textabstractActivation of the transcription factor NF-κB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-κB inhibitor IκBα in atherosclerosis. Myeloid-specific deletion of IκBα results in larger and more advanced lesions in LDL-R-deficient

  12. Myeloid IκBα deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques

    NARCIS (Netherlands)

    Goossens, Pieter; Vergouwe, Monique N.; Gijbels, Marion J. J.; Curfs, Danielle M. J.; van Woezik, Johannes H. G.; Hoeksema, Marten A.; Xanthoulea, Sofia; Leenen, Pieter J. M.; Rupec, Rudolf A.; Hofker, Marten H.; de Winther, Menno P. J.

    2011-01-01

    Activation of the transcription factor NF-κB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-κB inhibitor IκBα in atherosclerosis. Myeloid-specific deletion of IκBα results in larger and more advanced lesions in LDL-R-deficient mice without

  13. Early Signs of Atherogenesis in Adolescents in a Havana Family Medicine Catchment Area.

    Science.gov (United States)

    Valdés, Wendy; Díaz-Perera, Georgia; Espinosa, Tania M

    2015-10-01

    INTRODUCTION Atherosclerosis is the common underlying cause of cardiovascular diseases; the leading cause of morbidity and mortality globally. It is a major contributor to disability and poorer quality of life and is costly to health systems, individuals, families and society. Early signs of atherogenesis are manifestations of atherosclerosis and known atherogenic risk factors occurring at young ages and detectable by health professionals. Early detection of such signs in children and adolescents enables actions to prevent short- and long-term complications. OBJECTIVE Detect early signs of atherogenesis in adolescents in Family Doctor-and-Nurse Office No. 13 of the Raúl Gómez García Polyclinic in Havana's 10 de Octubre Municipality. METHODS An observational, cross-sectional descriptive study was conducted: the universe consisted of 110 adolescents and, once exclusion criteria were applied, the sample was made up of 96 adolescents in the office's geographical catchment area. Variables included sociodemographic data; measurements from physical and anthropometric examinations (weight, height, body mass index, waist circumference, blood pressure, presence of acanthosis nigricans); maternal history of diabetes mellitus and hypertension, smoking during pregnancy; birth weight and duration of exclusive breastfeeding; lifestyle (physical activity, dietary habits by frequency of consumption of fruits and vegetables, salt intake, and smoking); and a history of atherogenic risk factors and atherosclerotic diseases (hypertension, diabetes mellitus, heart disease, cerebrovascular disease, peripheral arterial disease and chronic kidney disease) in adolescents and their families. The number of early signs of atherogenesis was determined. Descriptive statistics and a chi-square test, with significance threshold set at p = 0.05, were used to examine differences by sex and age. RESULTS A total of 62.5% of participating adolescents were female and the same percent of the total

  14. Stability Analysis of a Model of Atherogenesis: An Energy Estimate Approach II

    KAUST Repository

    Ibragimov, A. I.

    2010-01-01

    This paper considers modelling atherogenesis, the initiation of atherosclerosis, as an inflammatory instability. Motivated by the disease paradigm articulated by Russell Ross, atherogenesis is viewed as an inflammatory spiral with positive feedback loop involving key cellular and chemical species interacting and reacting within the intimal layer of muscular arteries. The inflammation is modelled through a system of non-linear reaction-diffusion-convection partial differential equations. The inflammatory spiral is initiated as an instability from a healthy state which is defined to be an equilibrium state devoid of certain key inflammatory markers. Disease initiation is studied through a linear, asymptotic stability analysis of a healthy equilibrium state. Various theorems are proved giving conditions on system parameters guaranteeing stability of the health state and conditions on system parameters leading to instability. Among the questions addressed in the analysis is the possible mitigating effect of anti-oxidants upon transition to the inflammatory spiral. © 2010 Taylor & Francis.

  15. The emerging role of cardiovascular risk factor-induced mitochondrial dysfunction in atherogenesis

    Directory of Open Access Journals (Sweden)

    De Pascalis Susanna

    2009-12-01

    Full Text Available Abstract An important role in atherogenesis is played by oxidative stress, which may be induced by common risk factors. Mitochondria are both sources and targets of reactive oxygen species, and there is growing evidence that mitochondrial dysfunction may be a relevant intermediate mechanism by which cardiovascular risk factors lead to the formation of vascular lesions. Mitochondrial DNA is probably the most sensitive cellular target of reactive oxygen species. Damage to mitochondrial DNA correlates with the extent of atherosclerosis. Several cardiovascular risk factors are demonstrated causes of mitochondrial damage. Oxidized low density lipoprotein and hyperglycemia may induce the production of reactive oxygen species in mitochondria of macrophages and endothelial cells. Conversely, reactive oxygen species may favor the development of type 2 diabetes mellitus, mainly through the induction of insulin resistance. Similarly - in addition to being a cause of endothelial dysfunction, reactive oxygen species and subsequent mitochondrial dysfunction - hypertension may develop in the presence of mitochondrial DNA mutations. Finally, other risk factors, such as aging, hyperhomocysteinemia and cigarette smoking, are also associated with mitochondrial damage and an increased production of free radicals. So far clinical studies have been unable to demonstrate that antioxidants have any effect on human atherogenesis. Mitochondrial targeted antioxidants might provide more significant results.

  16. The Counter-Regulation of Atherogenesis: a Role for Interleukin-33

    Directory of Open Access Journals (Sweden)

    Pavel Kuneš

    2010-01-01

    Full Text Available The recently recognized cytokine interleukin-33 and its receptor ST2 play a favorable role during atherogenesis by inducing a Th1→Th2 shift of the immune response. IL-33 also protects the failing human heart from harmful biomechanical forces which lead to cardiomyocyte hypertrophy and exaggerated interstitial fibrosis. IL-33 inevitably displays side effects common to other Th2 cytokines, the most grave of which is a predisposition to allergic reactions. IL-33 is a nuclear transcription factor of endothelial cells. As such, it is abundant in nonproliferating vessels. Its down-regulation is required for angiogenesis, which may be profitable in wound healing or deleterious in tumor growth.

  17. Low-sodium diet induces atherogenesis regardless of lowering blood pressure in hypertensive hyperlipidemic mice.

    Directory of Open Access Journals (Sweden)

    Fernanda B Fusco

    Full Text Available This study investigated the influence of sodium restriction and antihypertensive drugs on atherogenesis utilizing hypertensive (H low-density lipoprotein-receptor knockout mice treated or not with losartan (Los or hydralazine (Hyd and fed low-sodium (LS or normal-sodium (NS chow. Despite reducing the blood pressure (BP of H-LS mice, the LS diet caused arterial lipid infiltration due to increased plasma total cholesterol (TC and triglycerides (TG. Los and Hyd reduced the BP of H-LS mice, and Los effectively prevented arterial injury, likely by reducing plasma TG and nonesterified fatty acids. Aortic lipid infiltration was lower in Los-treated H-LS mice (H-LS+Los than in normotensive (N-LS and H-LS mice. Aortic angiotensin II type 1 (AT1 receptor content was greater in H-NS than H-LS mice and in H-LS+Hyd than H-LS+Los mice. Carboxymethyl-lysine (CML and receptor for advanced glycation end products (RAGE immunostaining was greater in H-LS than H-NS mice. CML and RAGE levels were lower in LS animals treated with antihypertensive drugs, and Hyd enhanced the AT1 receptor level. Hyd also increased the gene expression of F4/80 but not tumor necrosis factor-α, interleukin (IL-1β, IL-6, IL-10, intercellular adhesion molecule-1 or cluster of differentiation 66. The novelty of the current study is that in a murine model of simultaneous hypertension and hyperlipidemia, the pleiotropic effect of chronic, severe sodium restriction elicited aortic damage even with reduced BP. These negative effects on the arterial wall were reduced by AT1 receptor antagonism, demonstrating the influence of angiotensin II in atherogenesis induced by a severely LS diet.

  18. Resolvin E1 Attenuates Atherosclerotic Plaque Formation in Diet and Inflammation Induced Atherogenesis

    Science.gov (United States)

    Hasturk, Hatice; Abdallah, Rima; Kantarci, Alpdogan; Nguyen, Daniel; Giordano, Nicholas; Hamilton, James; Van Dyke, Thomas E.

    2015-01-01

    Objective Epidemiological and recent clinical studies implicate periodontitis as an independent risk factor for cardiovascular disease. Previously, we demonstrated that rabbits with experimental periodontitis and cholesterol diet exhibit more aortic plaque compared to diet alone. We also showed that a proresolution mediator, Resolvin E1 (RvE1), reverses the experimental periodontitis. Here, we determined whether oral/topical application of RvE1 attenuates aortic atherosclerosis induced by both diet and periodontal inflammation. Approach and Results Thirty-nine rabbits on a 13-week regimen of 0.5% cholesterol diet were included. Periodontitis was induced by P. gingivalis in 24 rabbits and 15 rabbits were placed in no-periodontitis groups. Interventions were no-treatment, vehicle, and RvE1 treatment (4μg/site or 0.4 μg/site) topically applied 3-times/ week. At 13 weeks, both periodontitis and atherosclerosis were quantified. Atherosclerotic plaques were assessed by Sudan IV staining, histology and ex vivo MRI. Serum levels of C-reactive protein (CRP) were evaluated as a measure of systemic inflammation.RvE1, used as an oral/topical agent, significantly diminished atherogenesis and prevented periodontitis (pperiodontal inflammation, oral/topical application of RvE1 resulted in significantly less arterial plaque, a lower intima/media ratio, and decreased inflammatory cell infiltration compared to no-treatment (pperiodontitis and prevents vascular inflammation and atherogenesis in the absence of periodontitis. The inhibition of vascular inflammation with endogenous mediators of resolution of inflammation provides a novel approach in the prevention of atherogenic events. PMID:25792445

  19. Genetic Evidence Supports a Major Role for Akt1 in VSMCs During Atherogenesis

    Science.gov (United States)

    Rotllan, Noemi; Wanschel, Amarylis C.; Fernandez-Hernando, Ana; Salerno, Alessandro G.; Offermanns, Stefan; Sessa, William C.; Fernández-Hernando, Carlos

    2015-01-01

    Rationale Coronary artery disease (CAD), the direct result of atherosclerosis, is the most common cause of death in Western societies. Vascular smooth muscle cell (VSMC) apoptosis occurs during the progression of atherosclerosis and in advanced lesions, promotes plaque necrosis, a common feature of high-risk/vulnerable atherosclerotic plaques. Akt1, a serine-threonine protein kinase, regulates several key endothelial cell (EC) and VSMC functions including cell growth, migration, survival and vascular tone. While global deficiency of Akt1 results in impaired angiogenesis and massive atherosclerosis, the specific contribution of VSMC Akt1 remains poorly characterized. Objective To investigate the contribution of VSMC Akt1 during atherogenesis and in established atherosclerotic plaques. Methods and Results We generated two mouse models in which Akt1 expression can be suppressed specifically in VSCMs before (Apoe−/−Akt1fl/flSm22αCRE) and after (Apoe−/−Akt1fl/flSM-MHC-CreERT2E) the formation of atherosclerotic plaques. This approach allows us to interrogate the role of Akt1 during the initial and late steps of atherogenesis. Absence of Akt1 in VSMCs during the progression of atherosclerosis results in larger atherosclerotic plaques characterized by bigger necrotic core areas, enhanced VSMC apoptosis and reduced fibrous cap and collagen content. In contrast, VSMC Akt1 inhibition in established atherosclerotic plaques does not influence lesion size but markedly reduces the relative fibrous cap area in plaques and increases VSMC apoptosis. Conclusions Akt1 expression in VSMCs influences early and late stages of atherosclerosis. Absence of Akt1 in VSMCs induces features of plaque vulnerability including fibrous cap thinning and extensive necrotic core areas. These observations suggest that interventions enhancing Akt1 expression specifically in VSMCs may lessen plaque progression. PMID:25868464

  20. Oats (Avena sativa) reduce atherogenesis in LDL-receptor-deficient mice.

    Science.gov (United States)

    Andersson, K E; Svedberg, K A; Lindholm, M W; Oste, R; Hellstrand, P

    2010-09-01

    The cholesterol-lowering properties of oats, largely ascribed to its contents of soluble fibers, beta-glucans, are well established, whereas effects on atherogenesis are less well elucidated. Oats also contains components with reported antioxidant and anti-inflammatory effects that may affect atherogenesis. In this work we examined effects of oat bran on plasma cholesterol, markers of inflammation, eNOS expression and development of atherosclerosis in LDL-receptor-deficient (LDLr(-/-)) mice. Female LDLr(-/-) mice were fed Western diet+/-oat bran. Two concentrations of oat bran (40 and 27%) were compared regarding effects on plasma lipids. There was a dose-dependent reduction of plasma cholesterol by 42 and 20% with 40 and 27% oat bran, respectively. Both concentrations also lowered plasma triglycerides (by 45 and 33%) and relative levels of plasma LDL+VLDL. The reduction of plasma lipids was accompanied by increased faecal excretion of cholesterol and bile acids. Oat bran (40%) efficiently reduced atherosclerotic lesion area in the descending aorta (-77%) and aortic root (-33%). Plasma levels of fibrinogen and soluble vascular cell adhesion molecule-1 (VCAM-1) were significantly lower, and immunofluorescence of aortic sections revealed a 75% lower expression of VCAM-1 in oat-fed mice. The expression of eNOS protein in the aortic wall was increased in mice fed oat bran. Oat bran supplemented to a Western diet lowers plasma cholesterol, reduces levels of some inflammatory markers, increases eNOS expression and inhibits atherosclerotic lesion development in LDLr(-/-) mice. It remains to be investigated which components in oats contribute to these effects. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  1. Citreoviridin Enhances Atherogenesis in Hypercholesterolemic ApoE-Deficient Mice via Upregulating Inflammation and Endothelial Dysfunction.

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    Hai-Feng Hou

    Full Text Available Vascular endothelial dysfunction and inflammatory response are early events during initiation and progression of atherosclerosis. In vitro studies have described that CIT markedly upregulates expressions of ICAM-1 and VCAM-1 of endothelial cells, which result from NF-κB activation induced by CIT. In order to determine whether it plays a role in atherogenesis in vivo, we conducted the study to investigate the effects of CIT on atherosclerotic plaque development and inflammatory response in apolipoprotein E deficient (apoE-/- mice. Five-week-old apoE-/- mice were fed high-fat diets and treated with CIT for 15 weeks, followed by assay of atherosclerotic lesions. Nitric oxide (NO, vascular endothelial growth factor (VEGF and endothelin-1 (ET-1 were detected in serum. Levels of intercellular adhesion molecule-1 (ICAM-1, vascular cell adhesion molecule-1 (VCAM-1, VEGF, and ET-1 in plaque areas of artery walls were examined. NF-κB p65 expression and NF-κB activation in aorta also were assessed. CIT treatment significantly augmented atherosclerotic plaques and increased expressions of ICAM-1, VCAM-1, VEGF and ET-1 in aorta. Mechanistic studies showed that activation of NF-κB was significantly elevated by CIT treatment, indicating the effect of CIT on atherosclerosis may be regulated by activation of NF-κB.

  2. Increased proliferation of explanted vascular smooth muscle cells: a marker presaging atherogenesis.

    Science.gov (United States)

    Absher, P M; Schneider, D J; Baldor, L C; Russell, J C; Sobel, B E

    1997-06-01

    The JCR:LA-cp homozygous cp/cp corpulent rat is genetically predisposed to develop atherosclerosis evident after 9 and 18 months of age in males and females and to manifest metabolic derangements resembling those seen in type II diabetes in humans (hyperinsulinemia, insulin resistance, hyperglycemia and hypertriglyceridemia). The present study was undertaken to determine whether vascular smooth muscle cells (SMCs) explanted from vessels destined to become atherosclerotic later in life exhibit intrinsic properties ex vivo that presage atherogenesis to provide a means for evaluating promptly intervention designed to modify it. SMCs were cultured from aortic explants of JCR:LA-cp corpulent (cp/cp) and lean control (+/+) rats of 4, 5, 6, and 9 months of age. Compared with SMCs from controls, SMCs from cp/cp rats exhibited increased proliferation, higher saturation density, increased augmentation of proliferation in response to selected mitogens and greater adherence to extracellular matrix proteins. The increased proliferative activity ex vivo anteceded by several months the development of atherosclerotic lesions in vivo. Thus, it is a promising marker in assessments of the efficacy of interventions designed to retard or prevent atherosclerosis.

  3. Impaired endothelial nitric oxide bioavailability: a common link between aging, hypertension, and atherogenesis?

    LENUS (Irish Health Repository)

    Walsh, Thomas

    2012-01-31

    Endothelial-derived nitric oxide (NO) is responsible for maintaining continuous vasodilator tone and for regulating local perfusion and systemic blood pressure. It also has significant antiproliferative effects on vascular smooth muscle and platelet anti-aggregatory effects. Impaired endothelial-dependent (NO mediated) vasorelaxation is observed in most animal and human models of healthy aging. It also occurs in age-associated conditions such as atherosclerosis and hypertension. Such "endotheliopathy" increases vascular risk in older adults. Studies have indicated that pharmacotherapeutic intervention with angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methyl-glutaryl coenzyme-A reductase inhibitors may improve NO-mediated vasomotor function. This review, evaluates the association between impaired endothelial NO bioavailability, accelerated vascular aging, and the age-associated conditions hypertension and atherogenesis. This is important, because pharmacotherapy aimed at improving endothelial NO bioavailability could modify age-related vascular disease and transform age into a potentially modifiable vascular risk factor, at least in a subpopulation of older adults.

  4. Hypertrophic Mesenteric Adipose Tissue May Play a Role in Atherogenesis in Inflammatory Bowel Diseases.

    Science.gov (United States)

    Theocharidou, Eleni; Balaska, Aikaterini; Vogiatzis, Konstantinos; Tellis, Constantinos C; Gossios, Thomas D; Athyros, Vasilios G; Tselepis, Alexandros D; Karagiannis, Asterios

    2016-09-01

    Adipokines released by the adipose tissue are known to play a role in atherogenesis. The hypertrophic mesenteric fat in patients with inflammatory bowel diseases (IBD) also produces adipokines that are considered to play a role in intestinal inflammation. Whether they also contribute to accelerated atherosclerosis in IBD is unknown. The aim of this study was to assess the role of 2 adipokines, resistin and adiponectin, in IBD. We previously published data on 3 markers of cardiovascular risk, carotid intima-media thickness, carotid-femoral pulse wave velocity, and lipoprotein-associated phospholipase A2, in 44 patients with IBD and 44 controls matched for established cardiovascular risk factors. In this study, we measured resistin and adiponectin levels, and assessed their correlations with carotid intima-media thickness, pulse wave velocity, and lipoprotein-associated phospholipase A2. Resistin levels were significantly higher in patients with IBD (13.7 versus 10 ng/mL; P = 0.022), but there was no difference in adiponectin levels. Resistin levels were significantly higher in patients with active disease compared with those in remission (18.9 versus 11.3 ng/mL; P = 0.014). Adiponectin levels were significantly lower in Crohn's disease compared with ulcerative colitis (6736.3 ± 3105 versus 10,476.1 ± 5575.7 ng/mL; P = 0.026). Adiponectin correlated inversely with pulse wave velocity (rho = -0.434; P effect.

  5. A plant-based diet, atherogenesis, and coronary artery disease prevention.

    Science.gov (United States)

    Tuso, Phillip; Stoll, Scott R; Li, William W

    2015-01-01

    A plant-based diet is increasingly becoming recognized as a healthier alternative to a diet laden with meat. Atherosclerosis associated with high dietary intake of meat, fat, and carbohydrates remains the leading cause of mortality in the US. This condition results from progressive damage to the endothelial cells lining the vascular system, including the heart, leading to endothelial dysfunction. In addition to genetic factors associated with endothelial dysfunction, many dietary and other lifestyle factors, such as tobacco use, high meat and fat intake, and oxidative stress, are implicated in atherogenesis. Polyphenols derived from dietary plant intake have protective effects on vascular endothelial cells, possibly as antioxidants that prevent the oxidation of low-density lipoprotein. Recently, metabolites of L-carnitine, such as trimethylamine-N-oxide, that result from ingestion of red meat have been identified as a potential predictive marker of coronary artery disease (CAD). Metabolism of L-carnitine by the intestinal microbiome is associated with atherosclerosis in omnivores but not in vegetarians, supporting CAD benefits of a plant-based diet. Trimethylamine-N-oxide may cause atherosclerosis via macrophage activation. We suggest that a shift toward a plant-based diet may confer protective effects against atherosclerotic CAD by increasing endothelial protective factors in the circulation while reducing factors that are injurious to endothelial cells. The relative ratio of protective factors to injurious endothelial exposure may be a novel approach to assessing an objective dietary benefit from a plant-based diet. This review provides a mechanistic perspective of the evidence for protection by a plant-based diet against atherosclerotic CAD.

  6. Arrest functions of the MIF ligand/receptor axes in atherogenesis

    Directory of Open Access Journals (Sweden)

    Sabine eTillmann

    2013-05-01

    Full Text Available Macrophage migration inhibitory factor (MIF has been defined as an important chemokine-like function (CLF chemokine with an essential role in monocyte recruitment and arrest. Adhesion of monocytes to the vessel wall and their transendothelial migration are critical in atherogenesis and many other inflammatory diseases. Chemokines carefully control all steps of the monocyte recruitment process. Those chemokines specialized in controlling arrest are typically immobilized on the endothelial surface, mediating the arrest of rolling monocytes by chemokine receptor-triggered pathways. The chemokine receptor CXCR2 functions as an important arrest receptor on monocytes. An arrest function has been revealed for the bona fide CXCR2 ligands CXCL1 and CXCL8, but genetic studies also suggested that additional arrest chemokines are likely to be involved in atherogenic leukocyte recruitment. While CXCR2 is known to interact with numerous CXC chemokine ligands, the CLF-chemokine MIF, which structurally does not belong to the CXC chemokine sub-family, was surprisingly identified as a non-cognate ligand of CXCR2, responsible for critical arrest functions during the atherogenic process. MIF was originally identified as macrophage migration inhibitory factor, but is now known as a potent inflammatory cytokine with chemokine-like functions including chemotaxis and leukocyte arrest. This review will cover the mechanisms underlying these functions, including MIF’s effects on LFA1 integrin activity and signal transduction, and will discuss the structural similarities between MIF and the bona fide CXCR2 ligand CXCL8 while emphasizing the structural differences. As MIF also interacts with CXCR4, a chemokine receptor implicated in CXCL12-elicited lymphocyte arrest, the arrest potential of the MIF/CXCR4 axis will also be scrutinized as well as the recently identified role of pericyte MIF in attracting leukocytes exiting through venules as part of the pericyte 'motility

  7. Subclinical atherogenesis in patients with mild psoriasis: A role for IL-6?

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    Michelle Larissa Zini Lise

    Full Text Available Summary Introduction: A link of psoriasis with subclinical atherosclerosis has been postulated and cytokine network might intermediate this association. Few data are available in patients with mild psoriasis. We evaluated carotid intima-media thickness (cIMT in drug-free psoriatic individuals and controls. In parallel, we searched for associations of cIMT with disease activity indexes and serum interleukins (IL in psoriatic patients. Method: An experienced radiologist performed the cIMT analyses. Cytokine concentrations were assessed by flow cytometry. Disease activity was evaluated based on psoriasis area and severity index (PASI as well as body surface area (BSA. Results: Sixty-five (65 patients and 64 controls were studied. Mean age of patients (50.9 years did not differ from controls (p=0.362. A low PASI and BSA (0.05. Smoking habit and diabetes mellitus predominated in cases (p=0.002. An altered cIMT (≥ 0.9 mm was more frequent in cases than in controls (23.8% versus 8.5%, adjusted p=0.045. Mean cIMT was higher in cases with a borderline significance (p=0.057. cIMT scores did not correlate to PASI (rs=0.066; p=0.250 or BSA (rs=0.175; p=0.185, but did correlate significantly with serum IL-6 (rs=0.26; p=0.005. Conclusion: Subclinical atherosclerosis was more frequent in patients with mild psoriasis than controls. cIMT in psoriatic individuals correlated with serum IL-6, pointing to an eventual proatherogenic role of IL-6 in these patients. Newer studies should clarify the connection of atherogenesis with cytokines in psoriasis.

  8. Study of the inhibition effect of ethanolic extract of mangosteen pericarp on atherogenesis in hypercholesterolemic rat

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    Titin Andri Wihastuti

    2015-10-01

    Full Text Available Objective: To investigate the effect of ethanolic extract of mangosteen pericarp (EEMP through lipid profile, H2O2, nuclear factor-kappa B (NF-κB, inducible nitric oxide synthase (iNOS and endothelial nitric oxide synthase (eNOS measurement in hypercholesterolemic rat. Methods: A total of 20 rats were used in true laboratory experiment which were divided into 5 groups (n = 4 using posttest-only design. There were a normal diet group, a hypercholesterol diet (HCD group, a group that was given HCD with EEMP 200 mg/kg body weight, a group that was given HCD with 400 mg/kg body weight and a group that was given HCD with 800 mg/kg body weight. The lipid profile was measured using Cobas Mira. On the other hand, H2O2 was analysed using colorimetric hydrogen peroxide kit. Double staining immunofluorescence was given to observe NF-κB, iNOS and eNOS by using confocal laser scanning microscopy. The result was analyzed quantitatively using Olymphus Fluoview software (version 1.7a. Results: Lipid profile was significantly worsened in HCD and H2O2 level and expressions of NF-κB, iNOS and eNOS were also increased in HCD. EEMP 200 mg/kg body weight generally did not show significant results. However, high density lipoprotein level was affected by EEMP 400 mg/kg body weight, but not for other lipid profiles which reduced H2O2 level and NF-κB, iNOS and eNOS expressions significantly. EEMP 800 mg/kg body weight had been shown to be the most effective dose to improve lipid profile, decrease level of H2O2 and the expression of NF-κB and iNOS and maintain expression of eNOS. Conclusions: EEMP is an anti-inflammatory and antioxidant agent to inhibit atherogenesis in hypercholesterolemic rat.

  9. The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?

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    Dimitar Divchev

    2008-06-01

    Full Text Available Dimitar Divchev, Bernhard SchiefferDepartment of Cardiology and Angiology, Medizinische Hochschule Hannover, GermanyAbstract: Inflammation, lipid peroxidation and chronic activation of the renin–angiotensin system (RAS are hallmarks of the development of atherosclerosis. Recent studies have suggested the involvement of the pro-inflammatory secretory phospholipase A2 (sPLA2-IIA in atherogenesis. This enzyme is produced by different cell types through stimulation by proinflammatory cytokines. It is detectable in the intima and in media smooth muscle cells, not only in atherosclerotic lesions but also in the very early stages of atherogenesis. sPLA2-IIA can hydrolyse the phospholipid monolayers of low density lipoproteins (LDL. Such modified LDL show increased affinity to proteoglycans. The modified particles have a greater tendency to aggregate and an enhanced ability to insert cholesterol into cells. This modification may promote macrophage LDL uptake leading to the formation of foam cells. Furthermore, sPLA2-IIA is not only a mediator for localized inflammation but may be also used as an independent predictor of adverse outcomes in patients with stable coronary artery disease or acute coronary syndromes. An interaction between activated RAS and phospholipases has been indicated by observations showing that inhibitors of sPLA2 decrease angiotensin (Ang II-induced macrophage lipid peroxidation. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated suggesting a central role of sPLA2-IIA in these processes and offering a possible target for treatment. The role of sPLA2-IIA in the perpetuation of atherosclerosis appears to be the missing link between inflammation, activated RAS and lipidperoxidation.Keywords: secretory phospholipase A2, lipoproteins, renin-angiotensin system, inflammation, atherosclerosis

  10. Association of dietary sodium intake with atherogenesis in experimental diabetes and with cardiovascular disease in patients with Type 1 diabetes.

    Science.gov (United States)

    Tikellis, Chris; Pickering, Raelene J; Tsorotes, Despina; Harjutsalo, Valma; Thorn, Lena; Ahola, Aila; Wadén, Johan; Tolonen, Nina; Saraheimo, Markku; Gordin, Daniel; Forsblom, Carol; Groop, Per-Henrik; Cooper, Mark E; Moran, John; Thomas, Merlin C

    2013-05-01

    It is recommended that individuals with diabetes restrict their dietary sodium intake. However, although salt intake is correlated with BP (blood pressure), it also partly determines the activation state of the RAAS (renin-angiotensin-aldosterone system), a key mediator of diabetes-associated atherosclerosis. apoE KO (apolipoprotein E knockout) mice were allocated for the induction of diabetes with streptozotocin or citrate buffer (controls) and further randomized to isocaloric diets containing 0.05%, 0.3% or 3.1% sodium with or without the ACEi [ACE (angiotensin-converting enzyme) inhibitor] perindopril. After 6 weeks of study, plaque accumulation was quantified and markers of atherogenesis were assessed using RT-PCR (reverse transcription-PCR) and ELISA. The association of sodium intake and adverse cardiovascular and mortality outcomes were explored in 2648 adults with Type 1 diabetes without prior CVD (cardiovascular disease) from the FinnDiane study. A 0.05% sodium diet was associated with increased plaque accumulation in diabetic apoE KO mice, associated with activation of the RAAS. By contrast, a diet containing 3.1% sodium suppressed atherogenesis associated with suppression of the RAAS, with an efficacy comparable with ACE inhibition. In adults with Type 1 diabetes, low sodium intake was also associated with an increased risk of all-cause mortality and new-onset cardiovascular events. However, high sodium intake was also associated with adverse outcomes, leading to a J-shaped relationship overall. Although BP lowering is an important goal for the management of diabetes, off-target actions to activate the RAAS may contribute to an observed lack of protection from cardiovascular complications in patients with Type 1 diabetes with low sodium intake.

  11. Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

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    Shan, Qiuli [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Wang, Jing, E-mail: avaecn@gmail.com [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Huang, Fengchen [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Lv, Xiaowen [Feed Safety Reference Laboratory of Ministry of Agriculture, Feed Research Institute, Chinese Academy of Agricultural Sciences, Zhongguancun South Street 12, Beijing 100081 (China); Ma, Min [Laboratory of Biotechnology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Du, Yuguo [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China)

    2014-04-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE{sup −/−} mice were exposed to TCDD (15 μg/kg) and Aroclor1254 (55 mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several pro-atherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE{sup −/−} mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies. - Highlights: • Augmented atherogenesis was found in ApoE{sup −/−} mice co-exposed to Aroclor1254 and TCDD. • Enhanced expression of PF4, MCP-1 and RIG-I correlated with augmented lesions. • POPs combination may be a greater cardiovascular health risk than individual POPs.

  12. NG2 Proteoglycan Ablation Reduces Foam Cell Formation and Atherogenesis via Decreased Low-Density Lipoprotein Retention by Synthetic Smooth Muscle Cells.

    Science.gov (United States)

    She, Zhi-Gang; Chang, Yunchao; Pang, Hong-Bo; Han, Wenlong; Chen, Hou-Zao; Smith, Jeffrey W; Stallcup, William B

    2016-01-01

    Obesity and hyperlipidemia are critical risk factors for atherosclerosis. Because ablation of NG2 proteoglycan in mice leads to hyperlipidemia and obesity, we investigated the impact of NG2 ablation on atherosclerosis in apoE null mice. Immunostaining indicates that NG2 expression in plaque, primarily by synthetic smooth muscle cells, increases during atherogenesis. NG2 ablation unexpectedly results in decreased (30%) plaque development, despite aggravated obesity and hyperlipidemia. Mechanistic studies reveal that NG2-positive plaque synthetic smooth muscle cells in culture can sequester low-density lipoprotein to enhance foam-cell formation, processes in which NG2 itself plays direct roles. In agreement with these observations, low-density lipoprotein retention and lipid accumulation in the NG2/ApoE knockout aorta is 30% less than that seen in the control aorta. These results indicate that synthetic smooth muscle cell-dependent low-density lipoprotein retention and foam cell formation outweigh obesity and hyperlipidemia in promoting mouse atherogenesis. Our study sheds new light on the role of synthetic smooth muscle cells during atherogenesis. Blocking plaque NG2 or altering synthetic smooth muscle cells function may be promising therapeutic strategies for atherosclerosis. © 2015 American Heart Association, Inc.

  13. Dysfunctional lipoproteins from young smokers exacerbate cellular senescence and atherogenesis with smaller particle size and severe oxidation and glycation.

    Science.gov (United States)

    Park, Ki-Hoon; Shin, Dong-Gu; Cho, Kyung-Hyun

    2014-07-01

    Until now, there has been limited information on the effects of smoking on atherogenesis and senescence in the context of lipoprotein parameters, particularly in young smokers who have smoked fewer than 10 cigarettes per day for 3 years. In this study, lipoprotein profiles and functions were compared between smoker (n = 21) and control groups (n = 20). In the smoking group, ferric ion reduction abilities of serum and high-density lipoprotein (HDL) fractions were significantly reduced, and low-density lipoprotein (LDL) was severely oxidized. All lipoprotein particles from the smoker group showed higher advanced glycated end products with more triglyceride (TG) content compared with the control group. Lipoproteins from smokers showed faster agarose gel electromobility as well as greater smear band intensity in SDS-PAGE due to oxidation and glycation. LDL from smokers was more sensitive to oxidation and promoted foam cell forma-tion in macrophages. Gel filtration column chromatography revealed that the protein and cholesterol peaks of VLDL and LDL were elevated in the smoker group, whereas those of HDL were reduced. Human dermal fibroblast cells from the smoker group showed severe senescence following treatment with HDL2 and HDL3. Although HDL from young smokers showed impaired antioxidant ability, smaller particle size, and increased TG content, cholesteryl ester transfer protein activities were greatly enhanced in the serum and HDL fractions of the smoker group. In conclusion, smoking can cause production of dysfunctional lipoproteins having a smaller particle size that exacerbate senescence and atherogenic progress due to oxidation and glycation. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  14. Loss of p27 phosphorylation at Ser10 accelerates early atherogenesis by promoting leukocyte recruitment via RhoA/ROCK.

    Science.gov (United States)

    Molina-Sánchez, P; Chèvre, R; Rius, C; Fuster, J J; Andrés, V

    2015-07-01

    Reduced phosphorylation of the tumor suppressor p27(Kip1) (p27) at serine 10 (Ser10) is a hallmark of advanced human and mouse atherosclerosis. Apolipoprotein E-null mice defective for this posttranslational modification (apoE(-/-)p27Ser10Ala) exhibited increased atherosclerosis burden at late disease states. Here, we investigated the regulation of p27 phosphorylation in Ser10 at the very initial stages of atherosclerosis and its impact on endothelial-leukocyte interaction and early plaque formation. Hypercholesterolemia in fat-fed apoE(-/-) mice is associated with a rapid downregulation of p27-phospho-Ser10 in primary endothelial cells (ECs) and in aorta prior to the development of macroscopically-visible lesions. We find that lack of p27 phosphorylation at Ser10 enhances the expression of adhesion molecules in aorta of apoE(-/-) mice and ECs, and augments endothelial-leukocyte interactions and leukocyte recruitment in vivo. These effects correlated with increased RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signaling in ECs, and inhibition of this pathway with fasudil reduced leukocyte-EC interactions to control levels in the microvasculature of p27Ser10Ala mice. Moreover, apoE(-/-)p27Ser10Ala mice displayed increased leukocyte recruitment and homing to atherosusceptible arteries and augmented early plaque development, which could be blunted with fasudil. In conclusion, our studies demonstrate a very rapid reduction in p27-phospho-Ser10 levels at the onset of atherogenesis, which contributes to early plaque build-up through RhoA/ROCK-induced integrin expression in ECs and enhanced leukocyte recruitment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Sphingosine signaling and atherogenesis

    DEFF Research Database (Denmark)

    Xu, Cang-bao; Hansen-Schwartz, Jacob; Edvinsson, Lars

    2004-01-01

    Sphingosine-1-phosphate (S1P) has diverse biological functions acting inside cells as a second messenger to regulate cell proliferation and survival, and extracellularly, as a ligand for a group of G protein-coupled receptors (GPCRs) named the endothelial differentiation gene (EDG) family. Five...

  16. Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2

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    Ping Zeng

    2015-01-01

    Full Text Available Macrophage survival is believed to be a contributing factor in the development of early atherosclerotic lesions. Dysregulated apoptosis of macrophages is involved in the inflammatory process of atherogenesis. Apigenin is a flavonoid that possesses various clinically relevant properties such as anti-inflammatory, antiplatelet, and antitumor activities. Here we showed that apigenin attenuated atherogenesis in apoE-/- mice in an in vivo test. In vitro experiments suggested that apigenin induced apoptosis of oxidized low density lipoprotein- (OxLDL- loaded murine peritoneal macrophages (MPMs. Proteomic analysis showed that apigenin reduced the expression of plasminogen activator inhibitor 2 (PAI-2. PAI-2 has antiapoptotic effects in OxLDL-loaded MPMs. Enhancing PAI-2 expression significantly reduced the proapoptosis effects of apigenin. Molecular docking assay with AutoDock software predicted that residue Ser473 of Akt1 is a potential binding site for apigenin. Lentiviral-mediated overexpression of Akt1 wild type weakened the proapoptosis effect of apigenin in OxLDL-loaded MPMs. Collectively, apigenin executes its anti-atherogenic effects through inducing OxLDL-loaded MPMs apoptosis. The proapoptotic effects of apigenin were at least partly attributed to downregulation of PAI-2 through suppressing phosphorylation of AKT at Ser473.

  17. C-Peptide and Atherogenesis: C-Peptide as a Mediator of Lesion Development in Patients with Type 2 Diabetes Mellitus?

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    Nikolaus Marx

    2008-01-01

    Full Text Available Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show increased levels of C-peptide and over the last years various groups examined the effect of C-peptide in vascular cells as well as its potential role in lesion development. While some studies demonstrated beneficial effects of C-peptide, for example, by showing an inhibition of smooth muscle cell proliferation, others suggested proatherogenic mechanisms in patients with type 2 diabetes. Among them, C-peptide may facilitate the recruitment of inflammatory cells into early lesions and promote lesion progression by inducing smooth muscle cell proliferation. The following review will summarize the effects of C-peptide in vascular cells and discuss the potential role of C-peptide in atherogenesis in patients with type 2 diabetes.

  18. Genetic polymorphism of glutathion S-transferase P1 (GSTP1 Ile105Val and susceptibility to atherogenesis in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Grubiša Ivana

    2013-01-01

    Full Text Available One of the characteristics of type 2 diabetes mellitus (T2DM is the state of persistent oxidative stress (OS that has been implicated in the pathogenesis of diseases such is atherosclerosis mainly through chronic hyperglycemia that stimulates production of reactive oxygen species (ROS and increases OS. Glutathione S-transferase P1 (GSTP1 is a member of the cytosolic GST superfamily. It plays an important role in neutralizing OS as an enzyme. Also, it participates in regulation of stress signaling and protects cells against apoptosis via its noncatalytic ligand-binding activity. GSTP1 Ile105Val functional polymorphism influences protein catalytic activity and stability and the aim of this study was to determine whether this gene variation influences susceptibility to atherogenesis in T2DM patients. A total of 240 individuals (140 patients with T2DM, accompanied with clinical manifestations of atherosclerosis, and 100 healthy controls were included in this study. Genomic DNA was isolated from peripheral blood cells and genotyping was performed using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP analysis. We obtained no statistically significant differences in the distribution of alleles and genotypes between cases and controls (P>0.05 but association between Ile/Val (OR=0.6, 95%CI=0.35-1.05, P=0.08 and Val/Val (OR=0.45, 95%CI=0.18-1.11, P=0.08 genotypes and disease approached significance (P=0.08. Our results indicated that a larger study group is needed to establish the true relationship between potentialiy protective allele Val and the disease, and to determine the influence of other GSTP1 polymorphisms on atherogenesis in T2DM patients. [Projekat Ministarstva nauke Republike Srbije, br. 175075

  19. Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice.

    Directory of Open Access Journals (Sweden)

    Clément Cochain

    Full Text Available T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3(+ regulatory T cell (Treg responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1 in T cell activation and CD4(+ T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr(-/-Pd1(-/- displayed striking increases in systemic CD4(+ and CD8(+ T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr(-/-Pd1(-/- mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr(-/- mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis.

  20. Effects of a pomegranate fruit extract rich in punicalagin on oxidation-sensitive genes and eNOS activity at sites of perturbed shear stress and atherogenesis.

    Science.gov (United States)

    de Nigris, Filomena; Williams-Ignarro, Sharon; Sica, Vincenzo; Lerman, Lilach O; D'Armiento, Francesco P; Byrns, Russell E; Casamassimi, Amelia; Carpentiero, Daniela; Schiano, Concetta; Sumi, Daigo; Fiorito, Carmela; Ignarro, Louis J; Napoli, Claudio

    2007-01-15

    Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p-CREB). Polyphenolic antioxidants contained in the juice derived from the pomegranate contribute to the reduction of oxidative stress and atherogenesis during disturbed shear stress. To evaluate the effects of intervention with the Pomegranate Fruit Extract (PFE) rich in polyphones (punicalagin, which is a potent antioxidant) on ELK-1, p-CREB, and endothelial nitric oxide synthase (eNOS) expression induced by high shear stress in vitro and in vivo. At the doses used in the study, both the PFE and the regular pomegranate juice concentrate reduced the activation of ELK-1 and p-CREB and increased eNOS expression (which was decreased by perturbed shear stress) in cultured human endothelial cells and in atherosclerosis-prone areas of hypercholesterolemic mice. PFE and pomegranate juice increased cyclic GMP levels while there was no significant effect of both compounds on the conversion of L-arginine to L-citrulline. Administration of these compounds to hypercholesterolemic mice significantly reduced the progression of atherosclerosis and isoprostane levels and increased nitrates. This protective effect was relevant with PFE. Vasomotor reactivity was improved and EC(25) values in response to Ach and NONOate were significantly increased in treated mice in comparison to controls. This study indicates that the proatherogenic effects induced by perturbed shear stress can be also reversed by chronic administration of PFE.

  1. Heat shock protein-27 attenuates foam cell formation and atherogenesis by down-regulating scavenger receptor-A expression via NF-κB signaling.

    Science.gov (United States)

    Raizman, Joshua E; Chen, Yong-Xiang; Seibert, Tara; Hibbert, Benjamin; Cuerrier, Charles M; Salari, Samira; Zhao, Xiaoling; Hu, Tieqiang; Shi, Chunhua; Ma, Xiaoli; Simard, Trevor; Caravaggio, Justin; Rayner, Katey; Bowdish, Dawn; Moore, Kathryn; O'Brien, Edward R

    2013-12-01

    Previously, we showed an inverse correlation between HSP27 serum levels and experimental atherogenesis in ApoE(-/-) mice that over-express HSP27 and speculated that the apparent binding of HSP27 to scavenger receptor-A (SR-A) was of mechanistic importance in attenuating foam cell formation. However, the nature and importance of the interplay between HSP27 and SR-A in atheroprotection remained unclear. Treatment of THP-1 macrophages with recombinant HSP27 (rHSP27) inhibited acLDL binding (-34%; p<0.005) and uptake (-38%, p<0.05). rHSP27 reduced SR-A mRNA (-39%, p=0.02), total protein (-56%, p=0.01) and cell surface (-53%, p<0.001) expression. The reduction in SR-A expression by rHSP27 was associated with a 4-fold increase in nuclear factor-kappa B (NF-κB) signaling (p<0.001 versus control), while an inhibitor of NF-κB signaling, BAY11-7082, attenuated the negative effects of rHSP27 on both SR-A expression and lipid uptake. To determine if SR-A is required for HSP27 mediated atheroprotection in vivo, ApoE(-/-) and ApoE(-/-) SR-A(-/-) mice fed with a high fat diet were treated for 3weeks with rHSP25. Compared to controls, rHSP25 therapy reduced aortic en face and aortic sinus atherosclerotic lesion size in ApoE(-/-) mice by 39% and 36% (p<0.05), respectively, but not in ApoE(-/-)SR-A(-/-) mice. In conclusion, rHSP27 diminishes SR-A expression, resulting in attenuated foam cell formation in vitro. Regulation of SR-A by HSP27 may involve the participation of NF-κB signaling. Lastly, SR-A is required for HSP27-mediated atheroprotection in vivo. © 2013.

  2. [Modulation by some fatty acids of protein kinase C-dependent NADPH oxidase in human adherent monocyte: mechanism of action, possible implication in atherogenesis].

    Science.gov (United States)

    Léger, C L; Kadri-Hassani, N

    1995-01-01

    It is largely admitted nowadays that the early stage of the atherosclerotic lesion involves formation of oxidized (and minimally oxidized) low-density lipoprotein. Their properties are briefly reviewed. It is recalled that a lipolytic process also takes place both at the lumenal surface and in the subendothelial space of the vessels implying lipoprotein lipase (LpL) activity. Recent studies emphasize the role of LpL in accumulating LDL in the vascular tissue (Rutledge & Golberg, J. Lipid Res., 1994, 35, 1152-1160), but the role of LpL-generated unesterified fatty acids (UEFA) in these two locations and their possible implication in atherogenesis are largely neglected. Physiological and pathophysiological significance of UEFA in the human adherent monocyte modulation of the superoxide anion (O2.-) production has been examined by our group, leading to a possible mechanism of modulation of LDL oxidative modification. The O2.- production-modulating effect of a 30-min UEFA preincubation has been studied in intact human adherent monocytes (HAM) after stimulation by a direct effector of protein kinase C (PKC). It has been established that UEFA alone (in the absence of PKC effectors) were not able to modulate the O2.- production of HAM whereas they had such a capacity in the presence of PKC effectors, phorbol myristate acetate (PMA) or diacylglycerol (DAG). In this case inhibitors of PKC such as GF 109203 X suppressed the modulating effect. UEFA have also been shown to possess a bimodal action in the presence of PKC effectors: they depressed or enhanced O2.- production at micromolar or nanomolar concentrations, respectively. All these results contrasted with others obtained in neutrophils or nonadherent monocytes, suggesting an absolute requirement of PKC for the phagocyte-NADPH oxydase (PHOX) activation especially in the case of HAM. In HAM, the maximal enhancing effects were obtained with monomethyl ramified saturated (MMRS) and linear unsaturated (LU) FAs such as

  3. Plaque of atherosclerosis in aorta: review on atherogenesis, formation of plaque, clinical significance, methods of imaging and treatment; Placa de aterosclerose em aorta: revisao sobre aterogenese, formacao de placa, significado clinco, metodos de imagens e tratamento

    Energy Technology Data Exchange (ETDEWEB)

    Furtado, Rogerio Gomes; Nunes, Colandy G. de Oliveira; Rassi Junior, Luis; Melato, Luciano Henrique; Turco, Fabio de Paula; Borges, Moises Marcos, E-mail: rogerinhofurtado@gmail.com [Centro de Diagnostico por Imagem (CDI), Goiania, GO (Brazil); Sara, Leonardo [Instituto do Coracao (InCor/FM/USP), Sao Paulo, SP (Brazil)

    2009-04-15

    There is a certain consensus in the literature that the earliest stage of atherogenesis is characterized by the accumulation of spongy cells in the region of the intimal artery. Risk factors such as arterial hypertension, smoking, diabetes mellitus, hypercholesterolemia, male gender and advanced age predispose a person to the formation of plaques in the coronaries and aorta. A greater number of acute coronary events as well as strokes have been observed in people with these risk factors. Strokes are the third cause of death in the USA, with about 40% of the cases being of cryptogenic origin. Since 1989 the atheroma plaques which develop in the thoracic aorta have been considered to be responsible for cerebral and peripheral strokes which were previously considered cryptogenic because imaging techniques such as electrocardiogram transesophageal, computerized tomogram, nuclear magnetic angio-resonance have visualized and characterized the lesions with plaques of arteriosclerosis in the thoracic aorta. The authors of this article made a systematic review in the PUBMED about arteriosclerosis in the aorta and its diagnostic methods. This review includes the physiopathology of the formation of atheroma to the aorta and its consequences, diagnostic methods such as echo transesophageal, computerized tomogram and angio resonance, as well as the advantages and disadvantages of each method of identification of the lesions. An analysis of the clinical significance of the size, form and location of the atheroma plaques in the thoracic aorta were made based on clinical studies, as well as their treatment with anticoagulants, antiplatelet and drugs to reduce cholesterol. (author)

  4. Aggravated restenosis and atherogenesis in ApoCIII transgenic mice but lack of protection in ApoCIII knockouts: the effect of authentic triglyceride-rich lipoproteins with and without ApoCIII.

    Science.gov (United States)

    Li, Haibo; Han, Yingchun; Qi, Rong; Wang, Yuhui; Zhang, Xiaohong; Yu, Maomao; Tang, Yin; Wang, Mengyu; Shu, Ya-Nan; Huang, Wei; Liu, Xinfeng; Rodrigues, Brian; Han, Mei; Liu, George

    2015-09-01

    Previously, our group and others have demonstrated a causative relationship between severe hypertriglyceridaemia and atherogenesis in mice. Furthermore, clinical investigations have shown high levels of plasma Apolipoprotein C-III (ApoCIII) associated with hypertriglyceridaemia and even cardiovascular disease. However, it remains unclear whether ApoCIII affects restenosis in vivo, and whether such an effect is mediated by ApoCIII alone, or in combination with hypertriglyceridaemia. We sought to investigate ApoCIII in restenosis and clarify how smooth muscle cells (SMCs) respond to authentic triglyceride-rich lipoproteins (TRLs) with or without ApoCIII (TRLs ± ApoCIII). ApoCIII transgenic (ApoCIIItg) and knockout (ApoCIII-/-) mice underwent endothelial denudation to model restenosis. Here, ApoCIIItg mice displayed severe hypertriglyceridaemia and increased neointimal formation compared with wild-type (WT) or ApoCIII-/- mice. Furthermore, increased proliferating cell nuclear antigen (PCNA)-positive cells, Mac-3, and vascular cell adhesion protein-1 (VCAM-1) expression, and 4-hydroxynonenal (4HNE) production were found in lesion sites. ApoCIIItg and ApoCIII-/- mice were then crossed to low-density lipoprotein receptor-deficient (Ldlr-/-) mice and fed an atherogenic diet. ApoCIIItg/Ldlr-/- mice had significantly increased atherosclerotic lesions. However, there was no statistical difference in restenosis between ApoCIII-/- and WT mice, and in atherosclerosis between ApoCIII/Ldlr double knockout and Ldlr-/- mice. SMCs were then incubated in vitro with authentic TRLs ± ApoCIII isolated from extreme hypertriglyceridaemia glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1-deficient (GPIHBP1-/-) mice crossed with ApoCIIItg or ApoCIII-/- mice. It was shown that TRLs + ApoCIII promoted SMC proliferation, VCAM-1 expression, and reactive oxygen species (ROS) production, and activated the Akt pathway. Scavenging ROS significantly reduced SMC

  5. The Dynamics of Oxidized LDL during Atherogenesis

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    Hiroyuki Itabe

    2011-01-01

    Full Text Available Accumulating evidence indicates that oxidized low-density lipoprotein (OxLDL is a useful marker for cardiovascular disease. The uptake of OxLDL by scavenger receptors leads to the accumulation of cholesterol within the foam cells of atherosclerotic lesions. OxLDL has many stimulatory effects on vascular cells, and the presence of OxLDL in circulating blood has been established. According to the classical hypothesis, OxLDL accumulates in the atherosclerotic lesions over a long duration, leading to advanced lesions. However, recent studies on time-course changes of OxLDL in vivo raised a possibility that OxLDL can be transferred between the lesions and the circulation. In this paper, the in vivo dynamics of OxLDL are discussed.

  6. Methotrexate in Atherogenesis and Cholesterol Metabolism

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    Eric Coomes

    2011-01-01

    Full Text Available Methotrexate is a disease-modifying antirheumatic drug commonly used to treat inflammatory conditions such as rheumatoid arthritis which itself is linked to increased cardiovascular risk. Treatments that target inflammation may also impact the cardiovascular system. While methotrexate improves cardiovascular risk, inhibition of the cyclooxygenase (COX-2 enzyme promotes atherosclerosis. These opposing cardiovascular influences may arise from differing effects on the expression of proteins involved in cholesterol homeostasis. These proteins, ATP-binding cassette transporter (ABC A1 and cholesterol 27-hydroxylase, facilitate cellular cholesterol efflux and defend against cholesterol overload. Methotrexate upregulates expression of cholesterol 27-hydroxylase and ABCA1 via adenosine release, while COX-2 inhibition downregulates these proteins. Adenosine, acting through the A2A and A3 receptors, may upregulate proteins involved in reverse cholesterol transport by cAMP-PKA-CREB activation and STAT inhibition, respectively. Elucidating underlying cardiovascular mechanisms of these drugs provides a framework for developing novel cardioprotective anti-inflammatory medications, such as selective A2A receptor agonists.

  7. Aterogênese em artéria ilíaca comum de suínos submetidos à homocisteinemia induzida pela ingestão de metionina Atherogenesis in swine iliac artery with homocystinemia induced by methionine ingestion

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    Luís Henrique Gil França

    2006-03-01

    . Blood samples were collected for analyses of total cholesterol, triglycerides, HDL and homocysteine concentrations. The animals were submitted to arteriography to evaluate the patency of iliac arteries and then sacrificed. The iliac artery segment was removed for histological analysis. RESULTS: All animals survived the procedure, and there were no significant changes in total cholesterol, triglycerides and HDL concentrations in both groups. Microscopic examinations of the control group did not show pathological changes and was similar in all analyses. In the group receiving the methionine diet, the plaques were formed by foamy macrophages, but smooth muscle cells, cholesterol crystals or inflammatory cells were not seen. The tunica media had the internal elastic lamina intact. In the control group, there was no change in homocysteine levels during the experiment. In the methionine group, there was an increase in plasma homocysteine levels, with an average value of 59.80 µmol/l after 30 days with a methionine-rich diet. CONCLUSION: Homocystinemia induced by methionine causes atherogenesis in the swine iliac artery.

  8. Modulation of growth control mechanisms critical to atherogenesis

    NARCIS (Netherlands)

    Zwijsen, R.M.L.

    1992-01-01

    The principal lesion characteristic of atherosclerosis is the plaque. This lesion mainly consists of smooth muscle cells, connective matrix and large amounts of extracellular lipids. Smooth muscle cell hyperplasia is an integral event in atherosclerotic plaque formation and the resultant

  9. Role of marginal vitamin C deficiency in atherogenesis

    DEFF Research Database (Denmark)

    Frikke-Schmidt, Henriette Rønne; Lykkesfeldt, Jens

    2009-01-01

    Vitamin C is a pivotal redox modulater in many biological reactions of which several remain poorly understood. Naturally, vitamin C has been subject of many investigations over the past decades in relation to its possible beneficial effects on cardiovascular disease primarily based on its powerful...... yet general antioxidant properties. However, growing epidemiological, clinical and experimental evidence now suggests a more specific role of ascorbate in vasomotion and in the prevention of atherosclerosis. For example, in contrast to most other biological antioxidants, administration of vitamin C...... can apparently induce vasodilation. Millions of people worldwide can be diagnosed with vitamin C deficiency according to accepted definitions. In this perspective, the present review examines the evidence for a specific link between vitamin C deficiency and increased risk of atherosclerosis as well...

  10. Isoliquiritigenin Attenuates Atherogenesis in Apolipoprotein E-Deficient Mice

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    Fen Du

    2016-11-01

    Full Text Available Isoliquiritigenin (ISL exhibits antioxidation and anti-inflammation activity. We sought to investigate the effects and mechanism of ISL on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE−/− mice. Firstly, we determined that ISL reduced the mRNA levels of inflammatory factors interleukin 6 (IL-6, tumor necrosis factor α (TNF-α, and monocyte chemotactic protein-1 (MCP-1, while it increased the expression of several lipoprotein-related genes in peritoneal macrophages treated with lipopolysaccharide (LPS. ISL also enhanced peroxisome proliferator-activated receptor gamma (PPARγ protein levels and reversed the changes of ATP-binding cassette transporter A (ABCA1 and cluster of differentiation 36 (CD36 in macrophages treated with oxidative low-density lipoprotein (ox-LDL. Then, in an in vivo study, female apoE−/− mice were fed a Western diet with ISL (0, 20, 100 mg/kg/day added for 12 weeks. We found that ISL decreased the plasma cholesterol levels of very low-density lipoprotein (VLDL/LDL, promoted plasma superoxide dismutase (SOD and paraoxonase-1 (PON1 activities, and decreased plasma IL-6, TNF-α, and MCP-1 levels. Moreover, ISL significantly reduced the atherosclerotic lesions and hepatic steatosis in apoE−/− mice. In the liver, ISL altered the expression of several key genes (such as SRBI, ABCA1, ABCG8, PPARγ, and FASN involving cholesterol-selective uptake and excretion into bile, triglyceride (TG biosynthesis, and inflammation. These results suggest that the atheroprotective effects of ISL are due to the improvement of lipid metabolism, antioxidation, and anti-inflammation, which involve PPARγ-dependent signaling.

  11. Stability Analysis of a Model of Atherogenesis: An Energy Estimate Approach

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    A. I. Ibragimov

    2008-01-01

    Full Text Available Atherosclerosis is a disease of the vasculature that is characterized by chronic inflammation and the accumulation of lipids and apoptotic cells in the walls of large arteries. This disease results in plaque growth in an infected artery typically leading to occlusion of the artery. Atherosclerosis is the leading cause of human mortality in the US, much of Europe, and parts of Asia. In a previous work, we introduced a mathematical model of the biochemical aspects of the disease, in particular the inflammatory response of macrophages in the presence of chemoattractants and modified low density lipoproteins. Herein, we consider the onset of a lesion as resulting from an instability in an equilibrium configuration of cells and chemical species. We derive an appropriate norm by taking an energy estimate approach and present stability criteria. A bio-physical analysis of the mathematical results is presented.

  12. Shear stress-induced collagen XII expression is associated with atherogenesis.

    Science.gov (United States)

    Jin, Xin; Iwasa, Satoshi; Okada, Kyoko; Ooi, Akishi; Mitsui, Kazuhiro; Mitsumata, Masako

    2003-08-15

    Fluid shear stress has been shown to modulate various endothelial functions. We selected a shear stress-specific clone, identified as collagen XII, from a bovine aortic endothelial cell (BAEC) cDNA library. We confirmed that shear stress induces collagen XII expression at both the mRNA and protein levels in cultured BAECs and human umbilical vein ECs (HUVECs) by stimulating transcription. When HUVECs were exposed to shear stress, they secreted collagen XII protein and it was deposited underneath them. Strong expression of collagen XII was found in the intima of human aortic wall lacking atherosclerotic lesions, whereas weak expression was seen in the intima of atherosclerotic plagues. Furthermore, the downstream portion of atherosclerotic plaques showed apparently weak collagen XII expression compared with the upstream portion. These results suggest that collagen XII expression induced by fluid shear stress may play a role in stabilizing the vascular structure and preventing the formation of atherosclerotic lesions.

  13. Preferential pharmacological inhibition of macrophage ACAT increases plaque formation in mouse and rabbit models of atherogenesis.

    Science.gov (United States)

    Perrey, S; Legendre, C; Matsuura, A; Guffroy, C; Binet, J; Ohbayashi, S; Tanaka, T; Ortuno, J C; Matsukura, T; Laugel, T; Padovani, P; Bellamy, F; Edgar, A D

    2001-04-01

    The cholesteryl ester, foam cell-enriched vulnerable plaque is a principle pharmacological target for reducing athero-thrombosis. Acyl CoA:cholesterol Acyl Transferase (ACAT) catalyzes the esterification of free cholesterol in intestine, liver, adrenal and macrophages, leading in the latter cells to intracellular cholesteryl ester accumulation and foam cell formation in the arterial intima. Previous studies suggested the existence of several isoforms of ACAT with different tissue distribution and this has largely been confirmed by molecular cloning of ACAT-1 and ACAT-2. We developed a series of ACAT inhibitors that preferentially inhibited macrophage ACAT relative to hepatic or intestinal ACAT based on in vitro assays and ex vivo bioavailability studies. Four of these compounds were tested in three models of atherosclerosis at oral doses shown to give sufficient bioavailable monocyte/macrophage ACAT inhibitory activity. In fat-fed C57BL/6 mice, chow fed apo E-/- mice and KHC rabbits, the various ACAT inhibitors had either no effect or increased indices of atherosclerotic foam cell formation. Direct and indirect measurements suggest that the increase in plaque formation may have been related to inhibition of macrophage ACAT possibly leading to cytotoxic effects due to augmented free cholesterol. These results suggest that pharmacological inhibition of macrophage ACAT may not reduce, but actually aggravate, foam cell formation and progression.

  14. Circulating levels of human salusin-β, a potent hemodynamic and atherogenesis regulator.

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    Kazumi Fujimoto

    Full Text Available Using bioinformatics analysis, we previously identified salusin-β, an endogenous bioactive peptide with diverse physiological activities. Salusin-β is abundantly expressed in the neuroendocrine system and in systemic endocrine cells/macrophages. Salusin-β acutely regulates hemodynamics and chronically induces atherosclerosis, but its unique physicochemical characteristics to tightly adhere to all types of plastic and glassware have prevented elucidation of its precise pathophysiological role. To quantitate plasma total salusin-β concentrations, we produced rabbit and chicken polyclonal antibodies against the C- and N-terminal end sequences, circumvented its sticky nature, and successfully established a sandwich enzyme-linked immunosorbent assay (ELISA. Salusin-β was abundantly present in the plasma of healthy volunteers, ranging from 1.9 to 6.6 nmol/L. Reverse phase-high performance liquid chromatography analysis showed that a single immunoreactive salusin-β peak coincided with synthetic authentic salusin-β. Plasma salusin-β concentrations were unaffected by postural changes and by potent vasopressin release stimuli, such as hypertonic saline infusion or smoking. However, salusin-β concentrations showed significant circadian variation; concentrations were high during the daytime and reached the lowest concentrations in the early morning. Plasma salusin-β levels in subjects with diabetes mellitus, coronary artery disease, and cerebrovascular disease showed distinctly higher levels than healthy controls. Patients with panhypopituitarism combined with complete central diabetes insipidus also showed significantly higher plasma salusin-β levels. Therefore, the ELISA system developed in this study will be useful for evaluating circulating total salusin-β levels and for confirming the presence of authentic salusin-β in human plasma. The obtained results suggest a limited contribution of the neuroendocrine system to peripheral total salusin-β concentrations and a role for plasma total salusin-β concentrations as an indicator of systemic vascular diseases.

  15. Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice.

    Science.gov (United States)

    Nuotio-Antar, Alli M; Hachey, David L; Hasty, Alyssa H

    2007-12-01

    Glucocorticoids, which are well established to regulate body fat mass distribution, adipocyte lipolysis, hepatic gluconeogenesis, and hepatocyte VLDL secretion, are speculated to play a role in the pathology of metabolic syndrome. Recent focus has been on the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which is capable of regenerating, and thus amplifying, glucocorticoids in key metabolic tissues such as liver and adipose tissue. To determine the effects of global 11beta-HSD1 inhibition on metabolic syndrome risk factors, we subcutaneously injected "Western"-type diet-fed hyperlipidemic mice displaying moderate or severe obesity [LDL receptor (LDLR)-deficient (LDLR(-/-)) mice and mice derived from heterozygous agouti (A(y)/a) and homozygous LDLR(-/-) breeding pairs (A(y)/a;LDLR(-/-) mice)] with the nonselective 11beta-HSD inhibitor carbenoxolone for 4 wk. Body composition throughout the study, end-point fasting plasma, and extent of hepatic steatosis and atherosclerosis were assessed. This route of treatment led to detection of high levels of carbenoxolone in liver and fat and resulted in decreased weight gain due to reduced body fat mass in both mouse models. However, only A(y)/a;LDLR(-/-) mice showed an effect of 11beta-HSD1 inhibition on fasting insulin and plasma lipids, coincident with a reduction in VLDL due to mildly increased VLDL clearance and dramatically decreased hepatic triglyceride production. A(y)/a;LDLR(-/-) mice also showed a greater effect of the drug on reducing atherosclerotic lesion formation. These findings indicate that subcutaneous injection of an 11beta-HSD1 inhibitor allows for the targeting of the enzyme in not only liver, but also adipose tissue, and attenuates many metabolic syndrome risk factors, with more pronounced effects in cases of severe obesity and hyperlipidemia.

  16. Laser-induced fluorescence in atherogenesis: assessment of endothelium and macrophages

    Science.gov (United States)

    Oraevsky, Alexander A.; Fink, Tami N.; Jacques, Steven L.; Tittel, Frank K.; Henry, Philip D.

    1995-01-01

    Fluorescence spectroscopy experiments were focused on circulating monocytes and endothelial cells, two cell types that play a central role in the development and progression of atheromatous lesions. Our aim was to gain new insights into the cellular physiology of atherosclerosis and allow the development of diagnostic tests for the evaluation of atherosclerosis risk.

  17. Circulating Levels of Human salusin-β,a Potent Hemodynamic and Atherogenesis Regulator

    Science.gov (United States)

    Fujimoto, Kazumi; Hayashi, Akinori; Kamata, Yuji; Ogawa, Akifumi; Watanabe, Takuya; Ichikawa, Raishi; Iso, Yoshitaka; Koba, Shinji; Kobayashi, Youichi; Koyama, Takatoshi; Shichiri, Masayoshi

    2013-01-01

    Using bioinformatics analysis, we previously identified salusin-β, an endogenous bioactive peptide with diverse physiological activities. Salusin-β is abundantly expressed in the neuroendocrine system and in systemic endocrine cells/macrophages. Salusin-β acutely regulates hemodynamics and chronically induces atherosclerosis, but its unique physicochemical characteristics to tightly adhere to all types of plastic and glassware have prevented elucidation of its precise pathophysiological role. To quantitate plasma total salusin-β concentrations, we produced rabbit and chicken polyclonal antibodies against the C- and N-terminal end sequences, circumvented its sticky nature, and successfully established a sandwich enzyme-linked immunosorbent assay (ELISA). Salusin-β was abundantly present in the plasma of healthy volunteers, ranging from 1.9 to 6.6 nmol/L. Reverse phase-high performance liquid chromatography analysis showed that a single immunoreactive salusin-β peak coincided with synthetic authentic salusin-β. Plasma salusin-β concentrations were unaffected by postural changes and by potent vasopressin release stimuli, such as hypertonic saline infusion or smoking. However, salusin-β concentrations showed significant circadian variation; concentrations were high during the daytime and reached the lowest concentrations in the early morning. Plasma salusin-β levels in subjects with diabetes mellitus, coronary artery disease, and cerebrovascular disease showed distinctly higher levels than healthy controls. Patients with panhypopituitarism combined with complete central diabetes insipidus also showed significantly higher plasma salusin-β levels. Therefore, the ELISA system developed in this study will be useful for evaluating circulating total salusin-β levels and for confirming the presence of authentic salusin-β in human plasma. The obtained results suggest a limited contribution of the neuroendocrine system to peripheral total salusin-β concentrations and a role for plasma total salusin-β concentrations as an indicator of systemic vascular diseases. PMID:24098553

  18. Geraniol attenuates fibrosis and exerts anti-inflammatory effects on diet induced atherogenesis by NF-κB signaling pathway.

    Science.gov (United States)

    Jayachandran, Muthukumaran; Chandrasekaran, Balaji; Namasivayam, Nalini

    2015-09-05

    Atherosclerosis is now generally accepted as a chronic inflammatory condition. The transcription factor nuclear factor kappa B (NF-κB) is a key regulator of inflammation, immune responses, cell survival and cell proliferation. Tissue remodeling plays a significant role during the phase of inflammation and oxidative stress. In our study we have evaluated the effect of geraniol (GOH), a natural terpenoid on oxidative stress, inflammation and tissue remodeling in experimental animals. Experimental animals (hamsters) were divided into four groups; group 1 were control animals; group 2 were animals fed GOH alone (100mg/kg b.w. p.o); group 3 were animals fed atherogenic diet (standard pellet diet+10% coconut oil+0.25% cholesterol); group 4 animals were fed atherogenic diet as in group 3+GOH (100mg/kg b.w). At the end of the experimental period animals were killed and liver, heart and aorta tissues were analyzed for lipid peroxidation markers, non enzymic antioxidants and collagen distribution using histological studies like Milligan's trichrome and Picrosirius red staining. As inflammation plays a key role in tissue remodeling we also targeted the key inflammatory cytokine, NF-κB. GOH supplementation greatly prevented the remodeling of tissues by enhancing the free radical scavenging and anti-inflammatory effects. Thus in conclusion it can be suggested that GOH (100mg/kg b.w) prevents the atherogenic diet induced fibrosis in experimental hamsters. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Analysis of in situ and ex vivo αVβ3 integrin expression during experimental carotid atherogenesis.

    Science.gov (United States)

    Yao, Yuyu; Jiang, Yibo; Sheng, Zulong; Zhang, Yi; An, Yanli; Yan, Fengdi; Ma, Genshan; Liu, Naifeng; Teng, Gaojun; Cheng, Zhen

    2012-01-01

    Mural inflammation has been shown to contribute to the development of plaque, with the α(V)β(3) integrin highly expressed in atherosclerotic plaques. We herein examined α(V)β(3) integrin expression as a function of carotid atherosclerosis formation in the apolipoprotein E-deficient (apoE(-/-)) mouse. Constrictive collars were placed around the left common carotid arteries of apo E(-/-) mice maintained on a high-fat diet (n = 14). Before and 21 days following collar placement, in vivo serial magnetic resonance imaging (MRI) measurements of the carotid aortic diameter were performed using a 7T magnetic resonance (MR) scanner. Near- infrared fluorescence (NIRF) imaging was performed (n = 6) using an in vivo imaging system 0-24 hours following administration of 1.0 nmol c(RGDyK)-Cy5.5 via the tail vein. A competition experiment was performed by the co-injection of a saturating dose of bicyclic RGD peptide H-Glu[cyclo(Arg-Gly-Asp-D-Tyr-Lys)]2 (n = 3). Following image acquisition and sacrifice at 24 hours after injection, carotid arteries were harvested for histological analyses. Neointima formation and arterial remodeling in the carotid arteries of apoE(-/-) mice were induced by the placement of a constrictive collar. Significantly greater fluorescent signals were obtained from constrictive collar left common carotid arteries as compared to uninvolved aortic segments in constrictive collar mice. Binding to stenotic lesions was efficiently blocked in competition experiments. Immunostaining confirmed the presence of mural α(V)β(3) integrin expression in macrophages in the neointima. Signal intensity increased in a macrophage density-dependent fashion in the stenotic segments. Mural α(V)β(3) integrin expression, as determined using RGD-Cy5.5 near-infrared optical imaging, was increased in carotid arteries with constrictive collars in experimental mice. This expression can estimate the macrophage-bound inflammatory activity of atherosclerotic lesions.

  20. The prolactin receptor is expressed in macrophages within human carotid atherosclerotic plaques: a role for prolactin in atherogenesis?

    NARCIS (Netherlands)

    Reuwer, Anne; van Eijk, Marco; Houttuijn-Bloemendaal, Felicia; van der Loos, Chris; Claessen, Nike; Teeling, Peter; Kastelein, J. J.; Hamann, Jörg; Goffin, Vincent; von der Thüsen, Jan; Twickler, Marcel; Aten, Jan

    2011-01-01

    Atherosclerotic vascular disease is the consequence of a chronic inflammatory process, and prolactin has been shown to be a component of the inflammatory response. Additionally, recent studies indicate that prolactin contributes to an atherogenic phenotype. We hypothesized that this may be the

  1. Molecular etiology of atherogenesis--in vitro induction of lipidosis in macrophages with a new LDL model.

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    Luis M B B Estronca

    Full Text Available BACKGROUND: Atherosclerosis starts by lipid accumulation in the arterial intima and progresses into a chronic vascular inflammatory disease. A major atherogenic process is the formation of lipid-loaded macrophages in which a breakdown of the endolysomal pathway results in irreversible accumulation of cargo in the late endocytic compartments with a phenotype similar to several forms of lipidosis. Macrophages exposed to oxidized LDL exihibit this phenomenon in vitro and manifest an impaired degradation of internalized lipids and enhanced inflammatory stimulation. Identification of the specific chemical component(s causing this phenotype has been elusive because of the chemical complexity of oxidized LDL. METHODOLOGY/PRINCIPAL FINDINGS: Lipid "core aldehydes" are formed in oxidized LDL and exist in atherosclerotic plaques. These aldehydes are slowly oxidized in situ and (much faster by intracellular aldehyde oxidizing systems to cholesteryl hemiesters. We show that a single cholesteryl hemiester incorporated into native, non-oxidized LDL induces a lipidosis phenotype with subsequent cell death in macrophages. Internalization of the cholesteryl hemiester via the native LDL vehicle induced lipid accumulation in a time- and concentration-dependent manner in "frozen" endolysosomes. Quantitative shotgun lipidomics analysis showed that internalized lipid in cholesteryl hemiester-intoxicated cells remained largely unprocessed in those lipid-rich organelles. CONCLUSIONS/SIGNIFICANCE: The principle elucidated with the present cholesteryl hemiester-containing native-LDL model, extended to other molecular components of oxidized LDL, will help in defining the molecular etiology and etiological hierarchy of atherogenic agents.

  2. Circulating early biomarkers of atherogenesis in participants of the Longitudinal Study of Adult Health (ELSA-Brasil) without diabetes or cardiovascular disease.

    Science.gov (United States)

    Almeida-Pititto, Bianca de; Ribeiro-Filho, Fernando Flexa; Barreto, Sandhi; Duncan, Bruce B; Schmidt, Maria Inês; Lotufo, Paulo A; Bensenor, Isabela M; Ferreira, Sandra R G

    2016-01-01

    Our aim was to describe the distribution of selected biomarkers according to age and sex, adjusted for HOMA-IR and adiposity, in a subset of middle-aged individuals of Brazilian Longitudinal Study of Adult Health-ELSA without diabetes mellitus or CVD. This cross-sectional study was conducted in 998 participants of the ELSA-Brasil without diabetes and/or cardiovascular disease. In addition to the traditional risk factors, several biomarkers concentrations were compared according to sex, age groups (35-44; 45-54 yrs) and HOMA-IR tertiles. Linear regression was used to examine independent associations of sex and age with selected novel biomarkers, adjusted for body adiposity and HOMA-IR. Fifty-five percent were women. Men had higher mean values of body mass index, waist circumference, blood pressure, plasma glucose, HOMA-IR, worse lipid profile and higher E-selectin and lower leptin concentrations than women; while women had higher levels of HDL-cholesterol and leptin than men. Mean values of waist circumference, systolic BP, plasma glucose and apolipoprotein B (Apo B) increased with age in both sexes. Leptin and E-selectin concentrations increased across HOMA-IR tertiles. Independent associations of Apo B with age were found only in male sex, while of leptin with body mass index and HOMA-IR, and of E-selectin with HOMA-IR in both sexes. In conclusion, our data indicate age, sex, adiposity and, consequently, insulin resistance, influence circulating levels of Apo B, leptin and E-selectin, suggesting that those aspects should be taken into consideration when assessing these parameters for research or clinical purposes in individuals at relatively low cardiometabolic risk.

  3. Protective effects of ginger-turmeric rhizomes mixture on joint inflammation, atherogenesis, kidney dysfunction and other complications in a rat model of human rheumatoid arthritis.

    Science.gov (United States)

    Ramadan, Gamal; El-Menshawy, Omar

    2013-04-01

    Besides joint destruction, extra-articular complications (outside the locomotor system) are frequent in rheumatoid arthritis (RA) patients, especially cardiovascular, hematological and metabolic disorders. Here, we evaluated and compared the protective activity of two different doses of mixture of ginger and turmeric rhizomes powder (1 : 1) suspended in distilled water (GTaq) in alleviating both articular and extra-articular manifestations in rat adjuvant-induced arthritis (AIA). Arthritis was induced by a single intra-dermal injection of 0.1 mL of Complete Freund's adjuvant (containing heat-killed Mycobacterium tuberculosis) into the palmar surface of the left hind paw after the rats were subjected to light diethyl ether anesthesia. Arthritic rats received orally and daily (for 28 consecutive days) distilled water as vehicle, indomethacin (1.0 mg/kg body weight), or GTaq (200 or 400 mg/kg body weight) from the day of arthritis induction. The present study showed that GTaq (especially the high dose) was more effective (4.2-38.4% higher, P loss in body weight gain, the histopathological changes observed in ankle joints, blood leukocytosis and thrombocytosis, iron deficiency anemia, serum hypoalbuminemia and globulinemia, the impairment of kidney functions, and the risks for cardiovascular disease in arthritic rats. These protective effects of GTaq were mediated through increasing the food intake and decreasing the systemic inflammation that occur at the appearance of polyarthritis, oxidative stress and dyslipidemia. Ginger-turmeric rhizomes mixture may be effective against RA severity and complications as shown in an AIA rat model. © 2013 The Authors International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  4. Tiaozhi Tongmai Granules reduce atherogenesis and promote the expression of ATP-binding cassette transporter A1 in rabbit atherosclerotic plaque macrophages and the liver

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    Qing Sun

    2014-07-01

    Conclusions: Tiaozhi Tongmai Granules appear to have an anti-atherogenic effect that is most likely mediated by simultaneously upregulating the protein expression of ABCA1 in rabbit atherosclerotic plaque macrophages and in the liver.

  5. Modulation of gap junctional intercellular communication between human smooth muscle cells by leukocyte-derived growth factors and cytokines in relation to atherogenesis

    NARCIS (Netherlands)

    Mensink, A.

    1997-01-01


    In this thesis, the effect of leukocyte-derived growth factors and cytokines on GJIC between SMC was investigated. GJIC is regarded as an important mechanism in the control of cell growth, cell differentiation and tissue homeostasis. Disturbance of SMC growth control is regarded to be a

  6. Composition evaluation of the tallow and meat fatty acids of the cattle and determining their atherogenesis and thrombogenesisindexes in South Khorasan Province

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    Mohammad Malekaneh

    2015-01-01

    Conclusion: It was found that the sum of trans and stearic fatty acids was more in tallow. The hypocholesterolemic fatty acids levels were higher in the meat in the whole province. The cattle’s meat had lower atherogenetic and thrombogenetic properties compared with the animals’ fat.The consumed cattle’s meat and fat in the province appear to have a proper condition.

  7. Efeito da goma guar parcialmente hidrolisada no metabolismo de lipídeos e na aterogênese de camundongos Effect of partially hydrolyzed guar gum on lipid metabolism and atherogenesis of mice

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    Luciana Rodrigues Fernandes

    2006-10-01

    Full Text Available OBJETIVO: Observar os efeitos da goma guar parcialmente hidrolisada no metabolismo de colesterol e na formação de placa aterosclerótica em aorta de camundongos deficientes no receptor LDL, euglicêmicos ou com hiperglicemia induzida por estreptozotocina. MÉTODOS: Trinta e seis camundongos deficientes para o receptor de LDL foram divididos em quatro grupos de nove animais: grupos euglicêmicos, alimentados com dieta aterogênica padrão (controle euglicêmico ou suplementada com 7,5% de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada euglicêmico e grupos hiperglicêmicos alimentados com dieta aterogênica padrão (controle hiperglicêmico ou suplementada com 7,5% de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada hiperglicêmico. Após quatro semanas de experimento foram medidos: ingestão alimentar, ganho de peso, glicemia, colesterol plasmático e hepático, assim como lesão aterosclerótica na aorta torácica e abdominal. RESULTADOS: Os resultados mostram que a suplementação de goma guar parcialmente hidrolisada levou ao aumento do colesterol hepático e plasmático em animais euglicêmicos, mas sem aumento na área de lesão aterosclerótica na aorta. Em animais hiperglicêmicos, a redução no colesterol plasmático não foi estatisticamente significante, mas no que se refere à lesão da aorta, observou-se redução significante. CONCLUSÃO: Os resultados sugerem que a goma guar parcialmente hidrolisada pode reduzir a aterosclerose associada ao Diabetes Mellitus tipo 1.OBJECTIVE: The objective of this study was to observe the effects of partially hydrolyzed guar gum on cholesterol metabolism and atherosclerosis in the aorta of euglycemic and streptozotocin-induced hyperglycemic LDL receptor deficient mice. METHODS: Thirty six LDL receptor deficient mice were divided into 4 groups of 9 animals: euglycemic groups fed on hypercholesterolemic diet without or supplemented with 7.5% of partially hydrolyzed guar gum and streptozotocin-induced hyperglycemic groups also fed an atherogenic diet without or supplemented with 7.5% of partially hydrolyzed guar gum. After 4 weeks of experiment, food intake, body weight, glycemia, blood and liver cholesterol and atherosclerotic lesion in the aorta were determined. RESULTS: The results showed that partially hydrolyzed guar gum induced an increase in blood and liver cholesterol in euglycemic mice when compared with euglycemic control groups at the end of the experiment. On the other hand, although not affecting plasma cholesterol, hyperglycemic mice supplemented with partially hydrolyzed guar gum had the lesion area in the aorta significantly reduced. In hyperglycemic animals, plasma cholesterol did not decrease significantly but the lesion area in the aorta did. CONCLUSION: The present study suggests that partially hydrolyzed guar gum can reduce the development of atherosclerosis associated with type 1 diabetes mellitus.

  8. Silencing of CD40 in vivo reduces progression of experimental atherogenesis through an NF-κB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis.

    Science.gov (United States)

    Hueso, Miguel; De Ramon, Laura; Navarro, Estanislao; Ripoll, Elia; Cruzado, Josep M; Grinyo, Josep M; Torras, Joan

    2016-12-01

    CD40/CD40L signaling exerts a critical role in the development of atherosclerosis, and microRNAs (miRNAs) are key regulators in vascular inflammation and plaque formation. In this work, we investigated mRNA/miRNA expression during progression of atherosclerotic lesions through CD40 silencing. We silenced CD40 with a specific siRNA in ApoE(-/-) mice and compared expression of mRNA/miRNA in ascending aorta with scrambled treated mice. siRNA-CD40 treated mice significantly reduced the extension and severity of atherosclerotic lesions, as well as the number of F4/80(+), galectin-3(+) macrophages and NF-κB(+) cells in the intima. Genome-wide mRNA/miRNA profiling allowed the identification of transcripts, which were significantly upregulated during atherosclerosis; among them, miR-125b and miR-30a, Xpr1, a regulator of macrophage differentiation, Taf3, a core transcription factor and the NF-κB activator Ikkβ, whereas, the NF-κB inhibitor Ikbα was downregulated during disease progression. All those changes were reversed upon CD40 silencing. Interestingly, TAF3, XPR1 and miR-125b were also overexpressed in human atherosclerotic plaques. Murine Taf3 and Xpr1 were detected in the perivascular adipose tissue (PVAT), and Taf3 also in intimal foam cells. Finally, expression of miR-125b was regulated by the CD40-NF-κB signaling axis in RAW264.7 macrophages. CD40 silencing with a specific siRNA ameliorates progression of experimental atherosclerosis in ApoE(-/-) mice, and evidences a role for NF-κB, Taf3, Xpr1, and miR-125b in the pathogenesis of atherosclerosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Clinical chemistry of atherosclerosis : Contribution to apolipoprotein-E analysis, public Health and nutricion

    NARCIS (Netherlands)

    Brouwer, Dineke Aletta Johanna

    1999-01-01

    Chapter 1 is meant as a general introduction to atherosclerosis and the ensuing coronary artery disease (CAD). It gives special attention to atherogenesis, lipoprotein metabolism and nutritional factors. The chapter opens with the presentation of an integrated model of atherogenesis with a central

  10. Atherosclerosis – A Review | Amballi | Nigerian Medical Practitioner

    African Journals Online (AJOL)

    ... are present in smaller amounts. Past studies have also indicated that essential fatty acid (EFA) and Vitamin E prevent atherogenesis. This review emphasizes the biochemical events of atherogenesis as well as the role of Chlamydia pneumoniae in atherosclerosis. Nigerian Medical Practitioner Vol. 48 (1), 2005: 22 - 28 ...

  11. LDL particle size and reactive oxygen metabolites in dyslipidemic patients

    Directory of Open Access Journals (Sweden)

    Kazuhiko Kotani

    2012-01-01

    Conclusions: These findings of the co-existence of both markers suggest that sdLDL and oxidative stress can be cooperative in atherogenesis, possibly leading to the incidence of CVD, in dyslipidemic patients.

  12. Macrovascular disease and atherosclerosis in SSc

    NARCIS (Netherlands)

    Hettema, M. E.; Bootsma, H.; Kallenberg, C. G. M.

    Atherosclerosis is considered to be a chronic inflammatory disorder. Several autoimmune rheumatic diseases are characterized by premature and accelerated atherosclerosis in which both classical and non-classical risk factors contribute to atherogenesis. SSc is characterized by vasculopathy, and

  13. Cardiovascular disease in systemic lupus erythematosus: has the time for action come?

    NARCIS (Netherlands)

    van Leuven, Sander I.; Kastelein, John J. P.; Hayden, Michael R.; d'Cruz, David; Hughes, Graham R.; Stroes, Erik S.

    2005-01-01

    PURPOSE OF REVIEW: The recognition that inflammation is a hallmark of atherosclerotic disease has led to a series of studies reporting accelerated atherogenesis in chronic inflammatory diseases. Indeed, systemic lupus erythematosus is associated with an increased incidence of cardiovascular disease

  14. (18)F-FDG PET imaging of murine atherosclerosis

    DEFF Research Database (Denmark)

    Hag, Anne Mette Fisker; Pedersen, Sune Folke; Christoffersen, Christina

    2012-01-01

    To study whether (18)F-FDG can be used for in vivo imaging of atherogenesis by examining the correlation between (18)F-FDG uptake and gene expression of key molecular markers of atherosclerosis in apoE(-/-) mice....

  15. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus

    NARCIS (Netherlands)

    Diamant, Michaela; Nieuwland, Rienk; Pablo, Renée F.; Sturk, Augueste; Smit, Jan W. A.; Radder, Jasper K.

    2002-01-01

    Background-Type 2 diabetes is associated with accelerated atherosclerosis. Because cell-derived microparticles support coagulation and inflammation, they may be involved in atherogenesis. We characterized circulating microparticles both in patients with uncomplicated, well-regulated type 2 diabetes

  16. The effect of prolonged dietary nitrate supplementation on atherosclerosis development

    NARCIS (Netherlands)

    Marsch, Elke; Theelen, Thomas L.; Janssen, Ben J. A.; Briede, Jacco J.; Haenen, Guido R.; Senden, Joan M. G.; van Loon, Lucas J. C.; Poeze, Martijn; Bierau, Jörgen; Gijbels, Marion J.; Daemen, Mat J. A. P.; Sluimer, Judith C.

    2016-01-01

    Short term dietary nitrate or nitrite supplementation has nitric oxide (NO)-mediated beneficial effects on blood pressure and inflammation and reduces mitochondrial oxygen consumption, possibly preventing hypoxia. As these processes are implicated in atherogenesis, dietary nitrate was hypothesized

  17. Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts

    DEFF Research Database (Denmark)

    Gonen, Ayelet; Hansen, Lotte; Turner, William W

    2014-01-01

    Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use...... not target relevant antigens. These data demonstrate the feasibility of development of a small-molecule immunogen that could stimulate MAA-specific immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis....

  18. Evidence for roles of radicals in protein oxidation in advanced human atherosclerotic plaque

    DEFF Research Database (Denmark)

    Fu, S; Davies, Michael Jonathan; Stocker, R

    1998-01-01

    Oxidative damage might be important in atherogenesis. Oxidized lipids are present at significant concentrations in advanced human plaque, although tissue antioxidants are mostly present at normal concentrations. Indirect evidence of protein modification (notably derivatization of lysine) or oxida......Oxidative damage might be important in atherogenesis. Oxidized lipids are present at significant concentrations in advanced human plaque, although tissue antioxidants are mostly present at normal concentrations. Indirect evidence of protein modification (notably derivatization of lysine...

  19. Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite

    DEFF Research Database (Denmark)

    Thomas, S R; Davies, Michael Jonathan; Stocker, R

    1998-01-01

    As peroxynitrite is implicated as an oxidant for low-density lipoprotein (LDL) in atherogenesis, we investigated this process using reagent peroxynitrite (ONOO-) and 3-morpholinosydnonimine (SIN-1, which produces peroxynitrite via generation of NO. and O2.-). LDL oxidation was assessed by the con......As peroxynitrite is implicated as an oxidant for low-density lipoprotein (LDL) in atherogenesis, we investigated this process using reagent peroxynitrite (ONOO-) and 3-morpholinosydnonimine (SIN-1, which produces peroxynitrite via generation of NO. and O2.-). LDL oxidation was assessed...

  20. Albumin to creatinine ratio as a predictor to the severity of coronary ...

    African Journals Online (AJOL)

    Mohamed Sadaka

    2013-02-28

    Feb 28, 2013 ... Abstract Introduction: Microalbuminuria (MA) is a well-known risk factor for coronary artery disease (CAD). It is associated with higher cardiovascular mortality, especially in ... Coronary artery disease (CAD) is a major cause of death and ... which is gaining recognition as a marker of an atherogenesis,.

  1. Increased YKL-40 expression in patients with carotid atherosclerosis

    DEFF Research Database (Denmark)

    Michelsen, Axel Gottlieb; Rathcke, C.N.; Skjelland, M.

    2010-01-01

    Objective: We hypothesized a role for the inflammatory protein YKL-40 in atherogenesis and plaque destabilization based on its role in macrophage activation, tissue remodeling, and angiogenesis. Methods: Serum YKL-40 levels were measured by enzyme immunoassay in 89 patients with carotid atheroscl...

  2. Stroke in a Patient With HIV Infection

    Directory of Open Access Journals (Sweden)

    Buse Rahime Hasırcı

    2015-08-01

    Full Text Available Stroke which is a common complication in Human immumodeficiency virus type 1 positive patients is seen between 1% and 5% in clinical series. Vasculopathy and atherogenesis in HIV are the main pathologic mechanisms of stroke. We report a 63 year old man with sudden onset of a right hemiplegia and who was diagnosed as HIV-related stroke.

  3. Plasma Lipid Peroxidation and Total Antioxidant Status among ...

    African Journals Online (AJOL)

    BACKGROUND: The oxidative modification hypothesis of atherosclerosis predicts that low density lipoprotein-cholesterol (LDL-C) oxidation is an early event in atherosclerosis and that oxidized LDL-C contributes to atherogenesis. OBJECTIVE: To determine a link, if any, between the plasma lipid peroxidation and total ...

  4. Sex steroids and lipoprotein metabolism

    NARCIS (Netherlands)

    Gevers Leuven, J.A.

    1994-01-01

    Lipoprotein metabolism is involved in atherogenesis. Female sex-hormones have substantial effects on both lipoprotein metabolism and the vessel wall. Cholesterol, one of the major lipids in lipoproteins, is both the substrate for, and the target of, the steroidal sex hormones.

  5. Acyl-CoA:cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-Leiden mice

    NARCIS (Netherlands)

    Delsing, D. J.; Offerman, E. H.; van Duyvenvoorde, W.; van der Boom, H.; de Wit, E. C.; Gijbels, M. J.; van der Laarse, A.; Jukema, J. W.; Havekes, L. M.; Princen, H. M.

    2001-01-01

    The present study investigated whether the ACAT inhibitor avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect in ApoE*3-Leiden mice. Two groups of 15 female ApoE*3-Leiden mice were put on a high-cholesterol (HC) diet; 1 group received 0.01% (wt/wt) avasimibe mixed

  6. Progress in structural analysis of glycosaminoglycans and their ...

    African Journals Online (AJOL)

    Recent research data on GAGs have suggested that they have many new biological functions such as anti-atherogenesis, anticoagulation, prevention and cure of arthritis, morphogenesis and cell division. They are widely applied in functional food, clinical medicine, cosmetics and biomaterial. Especially, in the biomaterials ...

  7. Growth hormone therapy influences endothelial function in children with renal failure.

    NARCIS (Netherlands)

    Lilien, M.R.; Schröder, C.H.; Levtchenko, E.N.; Koomans, H.A.

    2004-01-01

    Endothelial dysfunction, an early step in atherogenesis, is prevalent in children with renal insufficiency. Endothelial dysfunction in growth hormone deficiency is reversed by growth hormone (rhGH) therapy. Renal failure induces growth hormone resistance at the receptor and post-receptor level,

  8. The effect of storage temperature on the quality of eggs from ...

    African Journals Online (AJOL)

    rahim

    or change of egg yolk pH during cold storage (Ahn et al., 1999). ..... showed that the t-10, c-12 CLA inhibited liver stearoyl-CoA desaturase enzyme activity, an enzyme .... acid reduces plasma lipoproteins and early aortic atherogenesis in ...

  9. No effect of consumption of green and black tea on plasma lipid and antioxidant levels and on LDL Oxidation in smokers

    NARCIS (Netherlands)

    Princen, H.M.G.; Duyvenvoorde, W. van; Buytenhek, R.; Blonk, C.; Tijburg, L.B.M.; Langius, J.A.E.; Meinders, A.E.; Pijl, H.

    1998-01-01

    Intake of flavonoids is associated with a reduced cardiovascular risk. Oxidation of LDL is a major step in atherogenesis, and antioxidants may protect LDL from oxidation. Because tea is an important source of flavonoids which are strong antioxidants, we have assessed in a randomized,

  10. Coronary artery calcification in hemophilia A: No evidence for a protective effect of factor VIII deficiency on atherosclerosis

    NARCIS (Netherlands)

    Tuinenburg, A.; Rutten, A.; Kavousi, M.; Leebeek, F.W.G.; Ypma, P.F.; Laros-Van Gorkom, B.A.P.; Nijziel, M.R.; Kamphuisen, P.W.; Mauser-Bunschoten, E.P.; Roosendaal, G.; Biesma, D.H.; Van Der Lugt A., [No Value; Hofman, A.; Witteman, J.C.M.; Bots, M.L.; Schutgens, R.E.G.

    2011-01-01

    Mortality due to ischemic heart disease is lower in hemophilia patients when compared to the general male population. As coagulation plays a role in the inflammatory pathways involved in atherogenesis, we investigated whether the clotting factor deficiency protects hemophilia patients from

  11. Identification and quantification of diadenosine polyphosphate concentrations in human plasma

    DEFF Research Database (Denmark)

    Jankowski, Joachim; Jankowski, Vera; Laufer, Udo

    2003-01-01

    Diadenosine polyphosphates have been demonstrated to be involved in the control of vascular tone as well as the growth of vascular smooth muscle cells and hence, possibly, in atherogenesis. In this study we investigated the question of whether diadenosine polyphosphates are present in human plasma...... and whether a potential source can be identified that may release diadenosine polyphosphates into the circulation....

  12. Clinical, functional and neurohormonal aspects to implement the concept to prevent subclinical atherosclerosis in a short-term and long-term prognosis

    OpenAIRE

    Hinhuliak, Alexander

    2014-01-01

    In order to assess the prevention of subclinical atherosclerosis in a short-term (3 months) and long-term (1 year) prognosis according to functional and neurohormonal markers of atherogenesis 164 patients have been examined with clinical signs of subclinical atherosclerosis and atypical clinical.

  13. Continuous reduction of plasma paraoxonase activity with increasing dialysis vintage in hemodialysis patients

    DEFF Research Database (Denmark)

    Henning, Bernhard F; Holzhausen, Helge; Tepel, Martin

    2010-01-01

    Plasma paraoxonase (PON) is an enzyme that hydrolyzes organic phosphate and aromatic carboxylic acid esters. Reduced activity is associated with early events of atherogenesis. The relevance of PON phenotypes is not well characterized in hemodialysis patients. In a cross-sectional study we measure...... dialysis vintage (P...

  14. Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: a crucial role for Kruppel-like factor 2

    NARCIS (Netherlands)

    Tits, L.J.H. van; Stienstra, R.; Lent, P.L.E.M. van; Netea, M.G.; Joosten, L.A.B.; Stalenhoef, A.F.H.

    2011-01-01

    OBJECTIVE: Macrophages are key players in atherogenesis because of their properties to form foam cells that produce a large variety of pro-inflammatory mediators. We addressed the potency of phenotypic different macrophages to accumulate oxidized LDL. METHODS AND RESULTS: Surprisingly,

  15. Effect of Darapladib on Major Coronary Events After an Acute Coronary Syndrome The SOLID-TIMI 52 Randomized Clinical Trial

    NARCIS (Netherlands)

    O'Donoghue, Michelle L.; Braunwald, Eugene; White, Harvey D.; Steen, Dylan P.; Lukas, Mary Ann; Tarka, Elizabeth; Steg, P. Gabriel; Hochman, Judith S.; Bode, Christoph; Maggioni, Aldo P.; Im, KyungAh; Shannon, Jennifer B.; Davies, Richard Y.; Murphy, Sabina A.; Crugnale, Sharon E.; Wiviott, Stephen D.; Bonaca, Marc P.; Watson, David F.; Weaver, W. Douglas; Serruys, Patrick W.; Cannon, Christopher P.; Hochman, Judith; Steg, Ph Gabriel; Serruys, Patrick; Weaver, Douglas; Lamp, Jessica M.; McCourt, Alexandra; Barakat, Deana; Mezzetti, Jessica; Morrison, C. Andrew; Stevens, Matthew; Ward, Chelsea; Ardissino, Diego; Aylward, Philip E.; Babilonia, Noe; Britto, Frank; Budaj, Andrzej; Chen, Shih-Ann; Corbalán, Ramón; Dalby, Anthony J.; Dellborg, Mikael; deWinter, R. J.; Dorobantu, Maria; Duris, Tibor; Gao, Runlin; Goudev, Assen R.; Grande, Peer; Gratsiansky, Nikolay; Guneri, Sema; Hamm, Christian; Husted, Steen; Isaza, Daniel; Kimura, Takeshi; Kiss, Robert; Lewis, Basil; López-Sendón, José; Mancini, G. B. John; Mathur, Atul; Mittal, Sanjay; Montalescot, Gilles; Nicolau, José C.; Oude Ophuis, Ton; Paolasso, Ernesto; Parkhomenko, Alexander; Ray, Kausik; Reddy, Krishna; Seung, Ki-Bae; Somaraju, Bhoopathiraju; Spinar, Jindrich; Sritara, Piyamitr; Theroux, Pierre; Wijns, William; Collins, Rory; Anderson, Jeffrey; DeMets, David; Ganz, Peter; Sandercock, Peter; Weber, Michael; Fisher, Marian; Buhr, Kevin; Diegel, Scott; Schultz, Melissa; Lowe, Cheryl; Mills, Kristen; Ruvido, Jessica; Alkhalil, Maria; Rehman, Mian Qasim; Stebletsova, Irina; Shimmer, Margarita; Forni, Danielle; Awtry, Eric; Berger, Clifford J.; Croce, Kevin; Desai, Akshay; Gelfand, Eli; Ho, Carolyn; Leeman, David E.; Link, Mark S.; Pande, Ashvin; Ruberg, Frederick; Vita, Joseph A.; Gignac, Gretchen; Hochberg, Ephraim; Lane, Andrew; Rosenberg, Carol; Wagner, Andrew; Wolpin, Brian M.; Goessling, Wolfram; Acquilano, Dayle E.; Waltemyer, Rachel; Kunder, Sharon; Syed, Asif; Aigbogun, Joy; Taylor, Michelle; Daga, Shruti; Cicconetti, Greg; Nandy, Indrani; Shannon, Jennifer; Deenadayalu, Naveen; Koduru, Suresh; Murphy, Sabina; Zhou, Jing; Abraham, Liliana; Beloscar, Juan; Bettinotti, Marcelo; Dumont, Carlos; Fernandez, Ricardo; Fuentealba, Victorino José; Covelli, Guillermo; García Durán, Rubén; Hominal, Miguel Angel; Jure, Horacio; Litvak, Marcos; Luciardi, Hector; Macin, Stella; MacKinnon, Ignacio; Milesi, Rodolfo; Montaña, Oscar; Olavegogeascoechea, Pablo; Prado, Aldo; Sala, Jorgelina; Gorosito, Vanina; Sassone, Sonia; Maffei, Laura; Schmuck, Raul; Vico, Marisa; Vita, Nestor; Arstall, Margaret; Ashby, Dale; Colquhoun, David; Cross, David; Farshid, Ahmad; Freeman, Melanie; New, Gishel; Hammett, Christopher; Kanna, Rajesh; Lehman, Ron; Roberts-Thomson, Philip; William, Maged; Yamen, Eric; Beauloye, Christophe; Beunk, Jan; Boland, Jean; Charlier, Filip; Claeys, Marc; Dujardin, Karl; Friart, Alain; Legrand, Victor; Schoors, Danny; Sinnaeve, Peter; Vandenbossche, Jean-Luc; Abrantes, José; Alves da Costa, Fernando; Ardito, Wilma; Bodanese, Luiz; Braga, Joao Carlos; Carvalho, Antonio; Dutra, Oscar; Feitosa, Gilson; Guimarães, Artur Eduardo; Hernandes, Mauro; Leães, Paulo; Lima, Felipe; Lotufo, Paulo; Maia, Lilia; Manenti, Euler; Mattos, Marco Antônio; Michalaros, Yorghos; Paiva, Maria Sanali; Piegas, Leopoldo; Pimentel Filho, Pedro; Precoma, Dalton; Rabelo Alves Junior, Álvaro; Rassi, Salvador; Reis, Gilmar; Resende, Elmiro; Rossi, Paulo; Saraiva, José Francisco; Silva Júnior, Delcio; Silva, Frederico Augusto; Souza, Juliana; Wainstein, Marco; Ribeiro, Jorge; Benov, Haralambi; Chompalova, Boryana; Goshev, Evgeniy; Raev, Dimitar; Goudev, Assen; Grigorov, Mladen; Grigorova, Valentina; Mihov, Atanas; Nikolov, Fedya; Petrov, Ivo; Postadzhiyan, Arman; Ramshev, Konstantin; Tisheva, Snezhanka; Tzekova, Maria; Bhargava, Rakesh; Cha, James; Constance, Christian; Davies, Richard; Della Siega, Anthony; Klinke, Peter; Dong, Raymond; Dupuis, Robert; Gyenes, Gabor; Huynh, Thao; Labonte, Roger; Lai, Christopher; Leader, Rolland; Leiter, Lawrence; Lonn, Eva; Nguyen, Michel; Pandey, Amritanshu; Polasek, Petr; Ramanathan, Krishnan; Rose, Barry; Rupka, Dennis; Sabbah, Eric; Syan, Gurcharan; Tishler, Steven; Vizel, Saul; Zeman, Peter; Albornoz Alarcon, Francisco Javier; Castro Galvez, Pablo; Florenzano Urzua, Fernando; Pedemonte Villablanca, Oneglio Antonio; Pérez Pino, Luis; Pincetti, Christian; Rodriguez Venegas, Manuel; Romero Castro, Carlos; Lamich, Ruben; Sepulveda Varela, Pablo Andres; Stockins, Benjamin; Chen, Yundai; Dong, Yugang; Fu, Guosheng; Hao, Yuming; Huang, Dejia; Jiao, Yang; Ke, Yuannan; Li, Chunjian; Li, Hongwei; Li, Tianfa; Li, Xiaodong; Li, Zhanquan; Liao, Dening; Liu, Ling; Lu, Qinghua; Qu, Peng; Shen, Zhujun; Shi, Haiming; Wu, Shulin; Xiang, Meixiang; Xu, Jiahong; Chen, Yihan; Yang, Xinchun; Yu, Jing; Yuan, Zuyi; Zhang, Yun; Zhou, Shuxian; Accini Mendoza, Jose Luis; Bohorquez, Ricardo; Botero, Rodrigo; Cano Lopez, Nelson; Hernandez, Hector; Jaramillo, Carlos; Jaramillo, Monica; Jaramillo, Nicolas; Manzur, Fernando; Mendoza, Fernan; Reynales, Humberto; Sanchez Vallejo, Gregorio; Ternera, Alfonso; Urina, Miguel; Cermak, Ondrej; Coufal, Zdenek; Dedek, Vratislav; Francek, Lumir; Grunfeldova, Hana; Gregor, Pavel; Kellnerova, Ivana; Klimsa, Zdenek; Kuchar, Ladislav; Linhart, Ales; Mayer, Otto; Taborsky, Milos; Vitovec, Jiri; Andersen, Ulla; Kristensen, Kjeld; Bang, Lia; Brønnum-Schou, Jens; Egstrup, Kenneth; Frost, Lars; Galatius, Soeren; Jeppesen, Jørgen; Rokkedal, Jens; Klarlund, Kim; Laursen, Rikke; Nielsen, Tonny; Melchior, Thomas; Mickley, Hans; Nielsen, Henrik; Nielsen, Walter; Schmidt, Erik; Sjøl, Anette; Skagen, Knud; Sykulski, Roman; Zeuthen, Elisabeth; Nyvad, Ole; Agraou, Benaissa; Bayet, Gilles; Caussin, Christophe; Coisne, Damien; Cottin, Yves; Decoulx, Eric; Delahaye, François; Delarche, Nicolas; D'Houdain, Fabrice; Dourmap-Collas, Caroline; Dubois-Rande, Jean-Luc; Elbaz, Meyer; Martelet, Michel; Nallet, Olivier; Cattan, Simon; Ohlmann, Patrick; Schiele, François; Steg, Gabriel; Traisnel, Gilles; Tricot, Olivier; Berrouschot, Joerg; Duengen, Hans-Dirk; Elsaesser, Albrecht; Erbel, Raimund; Moehlenkamp, Stefan; Franz, Norbert; Frey, Norbert; Hambrecht, Rainer; Haude, Michael; Janssens, Uwe; Joost, Alexander; Schunkert, Heribert; Kadel, Christoph; Katus, Hugo; Koenig, Wolfgang; Laufs, Ulrich; Loew, Anja; Klauss, Volker; Koenig, Andreas; Sohn, Hae-Young; Mudra, Harald; Neumann, Franz-Josef; Olbrich, Hans-Georg; Plehn, Alexander; Buerke, Michael; Ebelt, Henning; Schaefer, Andreas; Fischer, Dieter; Schaeufele, Tim; Steiner, Stephan; Kreuzer, Joerg; Tsoy, Irina; Stellbrink, Christoph; Sydow, Karsten; Baldus, Stephan; Tiroch, Klaus; Guelker, Hartmut; Haltern, Georg; Voehringer, Hans-Friedrich; Weber, Dirk; Werner, Gerald; Zeiher, Andreas Michael; Zeymer, Uwe; Zirlik, Andreas; Csapó, Kálmán; Herczeg, Béla; Katona, András; Keltai, Katalin; Kiss, Róbert Gábor; László, Zoltán; Lupkovics, Géza; Medvegy, Mihály; Merkely, Béla; Müller, Gábor; Nagy, András; Nagy, Lajos; Pálinkás, Attila; Sziliczei-Németh, N. N.; Sereg, Mátyás; Valcó, József; Vértes, András; Zámolyi, Károly; Arora, Parneesh; Bali, Harminder; Banker, Darshan; Chaganti, Venkateswara Rao; Chandra, Praveen Kumar; Chopra, Arun; Christopher, Johann; Dani, Sameer; Gupta, Sanjay; Shah, Shrenik; Hiremath, Shirish; Kaul, Upendra; Koduganti, Sarat; Kumar, Nirmal; Kumar, Sudeep; Mandala, Gokul; Naik, Sudhir; Oomman, Abraham; Padmanabhan, Tirumalai Nallan Chakravarthi; Parikh, Keyur; Reddy, Regalla Prasad; Roy, Sanjeeb; Sankardas, Mullasari; Sapra, Rakesh; Chopra, Vikas; Sathe, Shireesh; Sawhney, Jitendra; Atar, Shaul; Banai, Shmuel; Eldar, Michael; Elis, Avishay; Gavish, Dov; Goldhaber, Adiv; Gottlieb, Shmuel; Hayek, Tony; Hussein, Osamah; Katz, Amos; Klutstein, Marc; Kracoff, Oscar; Lishner, Michael; Lotan, Chaim; Meisel, Simcha; Mosseri, Morris; Qarawani, Dahud; Hasin, Yonathan; Rozenman, Yoseph; Schiff, Elad; Oliven, Arie; Weiss, Abraham; Baldin, Maria Grazia; Berni, Andrea; Biasucci, Luigi Marzio; Bongo, Angelo; Campo, Glanluca; Valgimigli, Marco; Colivicchi, Furio; de Servi, Stefano; Esposito, Giovanni; Gavazzi, Antonello; Marzilli, Mario; Merlini, Piera; Moretti, Luciano; Morocutti, Giorgio; Mos, Lucio; Patrizi, Giampiero; Rapezzi, Claudio; Branzi, Angelo; Terrosu, Pierfranco; Domae, Hiroshi; Fujii, Shigeru; Furukawa, Yutaka; Goto, Yoichi; Hirokami, Mitsugu; Ito, Hiroshi; Kawajiri, Kenji; Kimura, Kazuo; Kuramochi, Takehiko; Miyauchi, Katsumi; Muroya, Takahiro; Hata, Shiro; Yoshida, Takeo; Oku, Koji; Okutsu, Masaaki; Ooie, Tatsuhiko; Saito, Taro; Shimomura, Hideki; Shinozaki, Nobuaki; Shishido, Koki; Sugitatsu, Kazuya; Tanaka, Shinji; Suwa, Satoru; Takenaka, Takashi; Tamada, Atsushi; Tanabe, Kengo; Tanaka, Yutaka; Takahashi, Saeko; Yamazaki, Seiji; Chae, Shung-Chull; Hong, Taek-Jong; Jeong, Jin-Ok; Jeong, MyungHo; Kim, Hyo-Soo; Kim, Young-Hak; Ko, Young-Guk; Lee, Sang-Hoon; Yoon, Junghan; Bartels, Louis; Basart, Dick; de Nooijer, Cornelis; Dijkgraaf, René; de Graaf, Jacob J.; Groutars, Reginald; Visser, J.; Hamer, Barnabas J. B.; Hamraoui, Karim; Heijmeriks, Jan; Huizenga, Aline; Herrman, Johannes P. R.; Knufman, Nicole M. J.; Frederiks, Joost; Kuijper, Adrianus F. M.; Lenderink, Timo; van der Meer, Peter; Milhous, Gert-Jan; Nierop, Pieter; Oude Ophuis, Anthonius J. M.; Peerenboom, Patrick; Peters, Rene; Plomp, Jacobus; Prins, Paco; Schaap, Aart; van der Sluis, Aize; Smeele, Franciscus J. J.; van Hal, Johannes M. C.; Swart, Hendrik P.; Tjeerdsma, Geert; Troquay, Roland; van Eck, Martijn; Viergever, Eric; de Weerd, Gerardus J.; van Daele, Marcus; de Winter, Robbert J.; Zoet-Nugteren, Stijntje Kleisje; van der Zwaan, Coenraad; Zwart, Peter; Devlin, Gerard; Elliott, John; Harrison, Nigel; Hart, Hamish; O'Meeghan, Timothy; Stewart, Ralph; Ternouth, Ian; Tisch, Jonathan; van Pelt, Nicolaas; Wilkins, Gerard; Chen, Victor; Alarco Leon, Walter; Rodriguez Chávez, Victor Elías; Rojas Cañamero, Rodolfo; Rotta Rotta, Aida; Toce, Luis; Añonuevo, John; Barcinas, Roy; Coching, Raul Martin; Matiga, Generoso; Sulit, Dennis Jose; Uy, Norbert; Bronisz, Marek; Buszman, Pawel; Dalkowski, Maciej; Derlaga, Boguslaw; Fijalkowski, Marcin; Rynkiewicz, Andrzej; Firek, Bohdan; Gil, Robert; Jaworska, Krystyna; Kasprzak, Jaroslaw; Krzeminska-Pakula, Maria; Kleinrok, Andrzej; Kopaczewski, Jerzy; Kuc, Krzysztof; Kusnierz, Barbara; Lewczuk, Jerzy; Lysek, Roman; Miekus, Pawel; Mirek-Bryniarska, Ewa; Mlodziankowski, Adam; Musial, Wlodzimierz; Mysiak, Andrzej; Napora, Piotr; Piepiorka, Marek; Pluta, Wladyslaw; Prochaczek, Fryderyk; Przewlocki, Tadeusz; Rekosz, Jerzy; Rusicka, Teresa; Galaj, Andrzej; Sciborski, Ryszard; Szelemej, Roman; Szpajer, Michal; Wojewoda, Pawel; Wrzosek, Bozena; Zurakowski, Aleksander; Arsenescu Georgescu, Catalina Marina; Benedek, Imre; Capalneanu, Radu; Cinteza, Mircea; Craiu, Elvira; Cristea, Madalina; Dimulescu, Doina; Fruntelata, Ana-Gabriela; Ginghina, Carmen; Minescu, Bogdan; Musetescu, Rodica; Ionescu, Dan; Pop, Calin; Radoi, Mariana; Sinescu, Crina; Vinereanu, Dragos; Arkhipov, Mikhail; Barbarash, Olga; Bessonova, Nina; Boldueva, Svetlana; Boyarkin, Mikhail; Demko, Arkady; Duplyakov, Dmitry; Ermoshkina, Lyudmila; Glezer, Maria; Goloshchekin, Boris; Gordeev, Ivan; Grinshtein, Yury; Karpov, Yuri; Kobalava, Zhanna; Konstantinov, Vladimir; Kostenko, Victor; Kuimov, Andrey; Kuznetsov, Vadim; Libis, Roman; Markov, Valentin; Motylev, Igor; Novikova, Nina; Orlikova, Olga; Panchenko, Elizaveta; Panov, Alexey; Ruda, Mikhail; Sementsov, Dmitry; Shalaev, Sergey; Shvarts, Yuri; Simanenkov, Vladimir; Skorichenko, Vadim; Sukmanova, Irina; Smolenskaya, Olga; Tsyba, Larisa; Vishnevsky, Alexander; Yakhontov, Davyd; Yakusevich, Vladimir; Zadionchenko, Vladimir; Zateyshchikov, Dmitry; Zateyshchikova, Anna; Zrazhevskiy, Konstantin; Fridrich, Viliam; Gaspar, Ludovit; Hasilla, Jozef; Hranai, Marian; Kokles, Martin; Pella, Daniel; Basson, Matthys; Bayat, Junaid; Blignaut, Suzanne; Burgess, Lesley; Corbett, Clive; Da Silva, Agostinho; Dalby, Anthony; de Jong, Douwe; Mabin, Thomas; Manga, Pravin; Oosthuysen, Wessels; Ranjith, Naresh; Roodt, Andre; Roux, Jacobus; Soma, Prashilla; Swanepoel, Nicolaas; Theron, Hendrik; van Zyl, Louis; Barrabes Riu, José Antonio; Figueras Bellot, Jaume; Bayón Fernández, Julián; Simarro Martin-Ambrosio, Eugenio; Benedicto Buendía, Amparo; Castro Conde, Almudena; Íñiguez Romo, Andrés; Jiménez Navarro, Manuel; López García-Aranda, Víctor; Mainar Tello, Vicente; Marco Garde, Pilar; Mayordomo López, Juan; Mollá Jimenez, Cristina; Antón Pascual, Jose Luis; Plaza Pérez, Ignacio; Ridocci Soriano, Francisco; Viles Beltrán, Dolors; Bandh, Stellan; Christensen, Kjeld; Herlitz, Johan; Karlsson, Jan-Erik; Mooe, Thomas; Persson, Birgitta; Timberg, Ingar; Witt, Nils; Cheng, Chen-Chuan; Hung, Huei-Hong; Lai, Wen-Ter; Tu, Chung-Ming; Li, Ai-Hsien; Wu, Ching-Fen; Wu, Chiung-Jen; Yin, Wei-Hsian; Buakhamsri, Adisai; Kaewsuwanna, Pinij; Kiatchoosakun, Songsak; Kuanprasert, Srun; Wongpraparut, Nattawut; Bayata, Serdar; Yavuzgil, Oguz; Amosova, Ekaterina; Batushkin, Valerii; Dyadyk, Oleksandr; Goloborodko, Borys; Karpenko, Oleksandr; Kononenko, Lyudmyla; Kopytsya, Mykola; Koval, Olena; Kovalskyy, Ihor; Legkonogov, Olexandr; Malynovsky, Yaroslav; Shershnyova, Oxana; Netiazhenko, Vasyl; Nikonov, Vadim; Parkhomenko, Oleksandr; Prokhorov, Oleksandr; Rebrov, Borys; Potapenko, Pavlo; Rudenko, Leonid; Shcherbak, Viktor; Stanislavchuk, Mykola; Tseluyko, Vira; Yagensky, Andriy; Ahsan, Arif; Been, Martin; Bethell, Hugh; Senior, Roxy; Cox, Dominic; Findlay, Iain; Fisher, Michael; Gandhi, Manish; Gorog, Diana; Jacques, Adam; Keeling, Philip; O'Rourke, Brian; Pell, Alastair; Spratt, James; Trouton, Thomas; Wong, Yuk-ki; Abadier, Rafik; Abrahams, Lisa; Afonso, Luis; Aggarwal, Atul; Aggarwal, Kul; Ahmed, Abdel; Ahmed, Syed; Albirini, Abdulhay; Anderson, Jay; Angiolillo, Dominick; Ansari, Saadat; Applegate, Robert; Arif, Imran; Leesar, Massoud; Aronow, Herbert; Asbill, Brian; Ashraf, Raashid; Atalay, Hasan; Atassi, Keith; Atieh, Mahmoud; Babayan, Zaruhi; Harjai, Kishore; Baker, Seth; Barr, Lawrence; Barringhaus, Kurt; Bayron, Carlos; Benjamin, Sabrina; Benton, Robert; Berglund, Robert; Conn, Eric; Bertolet, Barry; Bhagwat, Ravi; Biederman, Robert; Bisher, Edward; Blanchard, Arnoux; Brown, Christopher; Butman, Samuel; Campbell, Charles; Canaday, Donald; Carlson, Thomas; Casale, Paul; Cashion, William; Chandler, Arthur; Chandna, Harish; Chandrasekaran, Suresh; Chang, George; Chronos, Nicolas; Chang, Mark; Chhabra, Anil; Chin, John; Cochran, David; Cohen, Kenneth; Cucher, Fred; Dauber, Ira; de Gregorio, Michele; del Core, Michael; Dewhurst, Robert; Rodriguez, Rolando; Dionisopoulos, Peter; Donovan, Daniel; Doty, William; Drossner, Michael; East, Cara; Eaton, Gregory; Ebrahimi, Ramin; Effron, Barry; Elkhadra, Maan; Elsner, Gregory; Erickson, Bernard; Fehrenbacher, George; Feldman, Robert; Fernandes, Valerian; Fishberg, Robert; Flores, Angel; Foreman, Riley; Frankel, Robert; French, William; Fuentes, Francisco; Fujise, Kenichi; Fulmer, James; Gabry, Mark; Baig, Mirza; Curran, Patrick; Garcia Pulido, Jesus; Gatien, Lionel; Gazmuri, Raul; Gencheff, Nelson; Gilmore, Richard; Giugliano, Gregory; Goldberg, Ronald; Goldman, Steven; Movahed, M. Reza; Goldstein, Mark; Gonzalez, Domingo; Gottlieb, Daniel; Grabarczyk, Mark; Graham, Bruce; Gruberg, Luis; Gumm, Darrel; Gupta, Saurabh; Lee, David; Hage-Korban, Elie; Hakas, Joseph; Hamroff, Glenn; Harris, Barry; Hearne, Steven; Held, John; Henderson, David A.; Hermany, Paul; Herzog, William; Hinchman, David; Fry, Stefanie; Hockstad, Eric; Hodson, Robert; Hollenbaugh, Darren; Horwitz, Phillip; Hurst, Paul; Ibrahim, Hassan; Imburgia, Michael; Izzo, Mark; Jaffrani, Naseem; Jan, Mian; Janout, Marek; Ring, Michael; Jones, Steven; Kahn, Brian; Kakavas, Peter; Kates, Andrew; Bach, Richard; Katopodis, John; Kazimir, Michal; Kennett, Jerry; Kereiakes, Dean; Kersh, Robert; Kershner, Dawn; Meilman, Henry; Kerwin, Peter; Khera, Amit; Kieval, Joshua; Kim, Edward; Kobayashi, John; Nelson, Ronald; Kosinski, Edward; Kovacich, David; Kraft, Philip; Kramer, Jeffrey; Kruse, Kevin; Kuvin, Jeffrey; Labib, Atef; Labroo, Ajay; Langer, Michael; Lau, Theodore; Lee, Kwan; Lee, Tobias; Levite, Howard; Lewis, David; Lieber, Ira; Loh, Irving; Lopez, Mario; Lui, Henry; Malkowski, Michael; Mammen, George; Mascolo, Richard; Matsumura, Martin; Matthews, George; Corbelli, John; Mayer, Thomas; McAlhany, Christopher; McCullum, Kevin; Meholick, Alan; Mehta, Viral; Melhado, Mauricio; Menees, Daniel; Miller, Michael; Minisi, Anthony; Minor, Steven; Moore, Carl; Nygaard, Thomas; Morcos, Nabil; Morris, Pamela; Morrow, David; Mostel, Edward; Murdock, David; Nadar, Venkatesh; Nahhas, Ahed; Navas, Jorge; Nukta, Emad; Oberoi, Mandeep; O'Donnell, Philip; Ostfeld, Robert; Pacheco, Theodore; Panchal, Vipul; Parang, Pirouz; Paraschos, Alexander; Pasquini, John; Williams, Jerome; Patlola, Raghotham; Peart, Brenda; Penny, William; Pepine, Carl; Perlman, Richard; Pavlides, Andreas; Popeil, Larry; Prashad, Rakesh; Price, Daniel; Price, Robert; Puleo, Peter; Puri, Sanjeev; Raikhel, Marina; Ramachandran, Atul; Ramos, Mark; Concha, Mauricio; Randhawa, Preet; Reichek, Nathaniel; Riba, Arthur; Ricciardi, Mark; Rider, James; Fenton, Sarah; Rizvi, Mohammad Ali; Dahiya, Ranjan; Rogers, William; Roth, David; Rowe, William; Saba, Fadi; Sabri, Moustafa; Patel, Parag; Sandoval, Jaime; Sangrigoli, Renee; Schwartzbard, Arthur; Seidner, Michael; Shah, Anil; Shanes, Jeffrey; Sharma, Mukesh; Siegel, Craig; Singal, Dinesh; Singh, Narendra; Smith, Andrew; Panetta, Carmelo; Smith, Steven; Whitaker, Jack; Snell, Jeffrey; Snyder, Harvey; Soffer, Ariel; Sonel, Ali; Spencer, Robert; Staniloae, Cezar; Stephenson, Christopher; Sundaram, Senthil; Sutton, Laddeus; Letts, Dustin; Swint, Robert; Tallet, Julio; Tami, Luis; Taylor, Richard; Hanovich, Gary; Tedder, Barry; Teufel, Edward; Brett, Craig; Thomas, James; Thompson, Paul; Polk, Donna; Tilkian, Ara; Tinkel, Jodi; Pandya, Utpal; Tobiansky, Joel; Trippi, James; Tuohy, Edward; Uretsky, Barry; Uusinarkaus, Kari; Varma, Shalendra; Velasquez, Enrique; Vogel, Craig; Voyce, Stephen; Wainwright, William; Hancock, Holly; Walder, James; Wali, Andreas; Watkins, Stanley; Weiss, Robert; Wickemeyer, William; Wilson, Dennis; Wilson, Vance; Wiseman, Alan; Wright, William; Xenakis, Mark; Zelenka, Jason; Zilz, Nathan; Amidon, Thomas

    2014-01-01

    IMPORTANCE Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE To evaluate the efficacy and safety of darapladib in patients

  16. Senescent intimal foam cells are deleterious at all stages of atherosclerosis

    NARCIS (Netherlands)

    Childs, B.G.; Baker, D.J.; Wijshake, T.; Conover, C.A.; Campisi, J.; Deursen, J.M.A. van

    2016-01-01

    Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these

  17. Senescent intimal foam cells are deleterious at all stages of atherosclerosis

    NARCIS (Netherlands)

    Childs, Bennett G.; Baker, Darren J.; Wijshake, Tobias; Conover, Cheryl A.; Campisi, Judith; van Deursen, Jan M.

    2016-01-01

    Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, we show that

  18. Extravascular inflammation in experimental atherosclerosis : the role of the liver and lungs

    NARCIS (Netherlands)

    Wong, Man Chi

    2013-01-01

    In this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved in atherogenesis. We show that continuous enhanced inflammation in hepatocytes increased the hepatic

  19. Leukocyte activation by triglyceride-rich lipoproteins

    NARCIS (Netherlands)

    A. Alipour (Arash); A.J.H.H.M. van Oostrom; A. Izraeljan (Alisa); C. Verseyden; J.M. Collins (Jennifer); K.N. Frayn (Keith); T.W.M. Plokker (Thijs); J.W.F. Elte (Jan Willem); M. Castro Cabezas (Manuel)

    2008-01-01

    textabstractOBJECTIVE - Postprandial lipemia has been linked to atherosclerosis and inflammation. Because leukocyte activation is obligatory for atherogenesis, leukocyte activation by triglyceride-rich lipoproteins (TRLs) was investigated. METHODS AND RESULTS - The expression of CD11b and CD66b

  20. The effect of haemophilia and von Willebrand disease on arterial thrombosis : A systematic review

    NARCIS (Netherlands)

    Biere-Rafi, S.; Zwiers, M.; Peters, M.; van der Meer, J.; Rosendaal, F. R.; Buller, H. R.; Kamphuisen, P. W.

    Background: Patients with haemophilia and von Willebrand disease (VWD) may have a reduced cardiovascular mortality, due to a hypocoagulable state or decreased atherogenesis. We performed a systematic review to assess the association between haemophilia and VWD, and fatal and nonfatal arterial

  1. Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression

    DEFF Research Database (Denmark)

    Tsimikas, Sotirios; Miyanohara, Atsushi; Hartvigsen, Karsten

    2011-01-01

    We sought to assess the in vivo importance of scavenger receptor (SR)-mediated uptake of oxidized low-density lipoprotein (OxLDL) in atherogenesis and to test the efficacy of human antibody IK17-Fab or IK17 single-chain Fv fragment (IK17-scFv), which lacks immunologic properties of intact antibod...

  2. Soy diet inhibits expression of inflammation-induced vascular cell adhesion molecules in endothelial cells

    Science.gov (United States)

    Recently we reported that dietary soy attenuated atherogenesis in apolipoprotein E knockout (apoE-/-) mice. However, the molecular mechanisms contributing to the atheroprotective effect of soy-based diets is not clear. Since interactions between endothelial cells and monocytes play a pivotal role ...

  3. Effect of human scavenger receptor class A overexpression in bone marrow-derived cells on lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knockout mice

    NARCIS (Netherlands)

    Herijgers, N.; Winther, M.P.J. de; Eck, M. van; Havekes, L.M.; Hofker, M.H.; Hoogerbrugge, P.M.; Berkel, T.J.C. van

    2000-01-01

    Scavenger receptors, which include various classes, play an important role in atherogenesis by mediating the unrestricted uptake of modified lipoproteins, resulting in the massive accumulation of cholesteryl esters. Because macrophage-derived foam cells are considered to be an important feature in

  4. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment

    NARCIS (Netherlands)

    Bernhagen, J.; Krohn, R.; Lue, H.; Gregory, J.L.; Zernecke, A.; Koenen, R.R.; Dewor, M.; Georgiev, I.; Schober, A.; Leng, L.; Kooistra, T.; Fingerle-Rowson, G.; Ghezzi, P.; Kleemann, R.; McColl, S.R.; Bucala, R.; Hickey, M.J.; Weber, C.

    2007-01-01

    The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G αi- and integrin-dependent arrest and chemotaxis of monocytes and T cells,

  5. Lipids, inflammation, and the Renin-Angiotensin System

    NARCIS (Netherlands)

    Harst, Pim van der

    2006-01-01

    Summary and Future Perspectives Impaired endothelial function is recognized as one of the earliest events of atherogenesis.1, 2 In Part I, chapter 1, we discussed the clinical value of the different techniques to evaluate endothelium-dependent vasomotor function. We also reviewed the efficacy of

  6. Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women

    NARCIS (Netherlands)

    Princen, H.M.G.; Duyvenvoorde, W. van; Buytenhek, R.; Laarse, A. van der; Poppel, G. van; Gevers Leuven, J.A.; Hinsbergh, V.W.M. van

    1995-01-01

    There is accumulating evidence that oxidative modification of LDL is an important step in the process of atherogenesis and that antioxidants may protect LDL from oxidation. We and others have previously shown that ingestion of pharmacological doses of the antioxidant D,L-α-tocopherol (vitamin E),

  7. HDL-LDL Ratio: A Significant Predisposition to the Onset of ...

    African Journals Online (AJOL)

    The significance of high-density lipoprotein/low density lipoprotein (HDL-LDL) ratio as a predisposing factor to the onset of atherogenesis has been studied. Standard enzymatic method using Cholesterol kit to extract cholesterol was used. HDL was analysed using standard HDL Kit and LDL concentration was derived by a ...

  8. Mannose-Binding Lectin Deficiency Is Associated with Myocardial Infarction

    DEFF Research Database (Denmark)

    Vengen, Inga Thorsen; Madsen, Hans O; Garred, Peter

    2012-01-01

    Mannose-binding lectin (MBL) and ficolins activate the complement cascade, which is involved in atherogenesis. Based on a pilot study, we hypothesized that functional polymorphisms in the MBL gene (MBL2) leading to dysfunctional protein are related to development of myocardial infarction (MI...

  9. SIRT1 gene is associated with cardiovascular disease in the Iranian ...

    African Journals Online (AJOL)

    N. Mohtavinejad

    2015-01-20

    Jan 20, 2015 ... upregulation of SIRT1 has extensively been shown to prevent atherogenesis, premature cardiac hypertrophy, apoptosis, cardiac fibrosis, cardiac dysfunction ..... expression in skeletal muscle of overweight individuals com- pared to the CC genotype [26]. In our study, the CC genotype. (low SIRT1 producer) ...

  10. [Antiphospholipid syndrome in valvular heart diseases, ischemic heart disease and vascular thrombosis].

    Science.gov (United States)

    Grabowski, M; Brzezińska, A

    2000-01-01

    The antiphospholipid syndrome (APS) leads to venous and arterial thrombosis, cardiac diseases, neurological, gastroenterological and dermatological complications. The role of antiphospholipid antibodies in genesis of thrombi by interaction with plasma clotting factors is well known. There is no evidence of their influence on valvular heart diseases or atherogenesis. This paper presents views and opinions about APS and related cardiovascular complications.

  11. Effects of HMG-COA Reductase Inhibitor Therapy on LDL Cholesterol Blood Levels in Hyperlipidemia: A Longitudinal Retrospective Anlaysis Using a Department of Defense Integrated Database.

    Science.gov (United States)

    1998-05-21

    Kinlay, and Peter Ganz, Atherogenesis and Ischemic Heart Disease. American Journal of Cardiology 1997; 80(8B):3H-7H. 33. A. L. Lehninger , D. L. Nelson...of its Pharmacology and Therapeutic Potential in the Management of Hyperlipidaemias. Drugs 1997; 53(5):828-847. A. L. Lehninger , D. L. Nelson, and M

  12. Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions

    NARCIS (Netherlands)

    de Boer, Onno J.; van der Meer, Jelger J.; Teeling, Peter; van der Loos, Chris M.; van der Wal, Allard C.

    2007-01-01

    BACKGROUND: T cell mediated inflammation contributes to atherogenesis and the onset of acute cardiovascular disease. Effector T cell functions are under a tight control of a specialized T cell subset, regulatory T cells (Treg). At present, nothing is known about the in situ presence of Treg in human

  13. Fatty Acid binding protein 4 is associated with carotid atherosclerosis and outcome in patients with acute ischemic stroke

    DEFF Research Database (Denmark)

    Holm, Sverre; Ueland, Thor; Dahl, Tuva B

    2011-01-01

    Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke....

  14. Trained innate immunity and atherosclerosis

    NARCIS (Netherlands)

    Bekkering, S.; Joosten, L.A.B.; Meer, J.W.M. van der; Netea, M.G.; Riksen, N.P.

    2013-01-01

    PURPOSE OF REVIEW: Monocytes/macrophages play a decisive role in the development and progression of atherosclerosis. It is currently unknown what stimuli initiate and orchestrate the activation of these cells in atherogenesis. In this review, we postulate that the novel concept of 'trained immunity'

  15. Obesity-related inflammation & cardiovascular disease: Efficacy of a yoga-based lifestyle intervention

    OpenAIRE

    Sarvottam, Kumar; Yadav, Raj Kumar

    2014-01-01

    Obesity is a global health burden and its prevalence is increasing substantially due to changing lifestyle. Chronic adiposity is associated with metabolic imbalance leading to dyslipidaemia, diabetes, hypertension and cardiovascular diseases (CVD). Adipose tissue acts as an endocrine organ releasing several adipocytokines, and is associated with increased levels of tissue and circulating inflammatory biomolecules causing vascular inflammation and atherogenesis. Further, inflammation is also a...

  16. Oxidative Stress-Mediated Atherosclerosis: Mechanisms and Therapies

    Science.gov (United States)

    Yang, Xinyu; Li, Yang; Li, Yanda; Ren, Xiaomeng; Zhang, Xiaoyu; Hu, Dan; Gao, Yonghong; Xing, Yanwei; Shang, Hongcai

    2017-01-01

    Atherogenesis, the formation of atherosclerotic plaques, is a complex process that involves several mechanisms, including endothelial dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, inflammation, and thrombosis. The pathogenesis and progression of atherosclerosis are explained differently by different scholars. One of the most common theories is the destruction of well-balanced homeostatic mechanisms, which incurs the oxidative stress. And oxidative stress is widely regarded as the redox status realized when an imbalance exists between antioxidant capability and activity species including reactive oxygen (ROS), nitrogen (RNS) and halogen species, non-radical as well as free radical species. This occurrence results in cell injury due to direct oxidation of cellular protein, lipid, and DNA or via cell death signaling pathways responsible for accelerating atherogenesis. This paper discusses inflammation, mitochondria, autophagy, apoptosis, and epigenetics as they induce oxidative stress in atherosclerosis, as well as various treatments for antioxidative stress that may prevent atherosclerosis. PMID:28878685

  17. An ex-vivo model for evaluating bioenergetics in aortic rings

    Directory of Open Access Journals (Sweden)

    Kyle P. Feeley

    2014-01-01

    Full Text Available Cardiovascular disease (CVD is the leading cause of death worldwide and it exhibits a greatly increasing incidence proportional to aging. Atherosclerosis is a chronic condition of arterial hardening resulting in restriction of oxygen delivery and blood flow to the heart. Relationships between mitochondrial DNA damage, oxidant production, and early atherogenesis have been recently established and it is likely that aspects of atherosclerotic risk are metabolic in nature. Here we present a novel method through which mitochondrial bioenergetics can be assessed from whole aorta tissue. This method does not require mitochondrial isolation or cell culture and it allows for multiple technical replicates and expedient measurement. This procedure facilitates quantitative bioenergetic analysis and can provide great utility in better understanding the link between mitochondria, metabolism, and atherogenesis.

  18. Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs

    DEFF Research Database (Denmark)

    Al-Mashhadi, Rozh H; Bjørklund, Martin M; Mortensen, Martin B

    2015-01-01

    AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease, but whether there is a direct and independent role for impaired glucose control in atherogenesis remains uncertain. We investigated whether diabetes with poor glycaemic control would accelerate...... atherogenesis in a novel pig model of atherosclerosis, the D374Y-PCSK9 (+) transgenic minipig. METHODS: Nineteen minipigs were fed a cholesterol-enriched, high-fat diet; ten of these pigs were injected with streptozotocin to generate a model of diabetes. Restricted feeding was implemented to control the pigs...... that hyperglycaemia per se is not an independent promoter of atherosclerotic disease, but that other diabetes-associated risk factors are important....

  19. Alteration of mean wall shear stress near an oscillating stagnation point.

    Science.gov (United States)

    Hazel, A L; Pedley, T J

    1998-04-01

    The site opposite an end-to-side anastomosis, resulting from femoral bypass surgery, and the carotid sinus are two regions well known to be prone to fibrous intimal hyperplasia or atherogenesis, respectively. The blood flow at these two sites features a stagnation point, which oscillates in strength and position. Mathematical models are used to determine some of the features of such a flow; in particular, the mean wall shear stress is calculated. The positional oscillations cause a significant change in the distribution and magnitude of the mean wall shear stress from that of the well-studied case of a stagnation point that oscillates only in strength. It is therefore proposed that the recorded effect of time dependence in the flow upon atherogenesis could still be a result of the distribution of the mean and not the time-varying components of the wall shear stress.

  20. Cigarette Smoking as a Risk Factor of Coronary Artery Disease and its Effects on Platelet Function

    Directory of Open Access Journals (Sweden)

    Inoue Teruo

    2004-03-01

    Full Text Available Abstract It has been well established that cigarette smoking is a powerful risk factor for coronary artery disease. A number of epidemiologic studies have shown a strong association between cigarette smoking and atherosclerosis, myocardial infarction and death from coronary artery disease. In addition to active smoking, passive smoking can also carry a risk of coronary artery disease. Although the detailed mechanism through which cigarette smoking is associated with cardiovascular disease has not yet been clarified, it is suggested that cigarette smoking is related to thrombogenesis, as well as atherogenesis, and blood platelet behavior is thought to be prominent among the proposed mechanisms involved in atherogenesis and thrombogenesis. The following is a review of evidence that cigarette smoking affects platelet function.

  1. Obesity and cardiovascular disease: from pathophysiology to risk stratification.

    Science.gov (United States)

    Marinou, Kyriakoula; Tousoulis, Dimitris; Antonopoulos, Alexios S; Stefanadi, Elli; Stefanadis, Christodoulos

    2010-01-07

    Obesity is associated with numerous co-morbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension and others. As obesity is considered to be a major risk factor for atherosclerosis, understanding of the underlying mechanisms leading to obesity and linking obesity with atherogenesis is necessary, for the development of therapeutic strategies against atherosclerosis. The pathophysiology of CVD linked to obesity is an area of intensive research. In this review we examine the role of obesity on CVD, and we focus on specific mechanisms of major importance in atherogenesis, such as the role of adipokines, insulin resistance, endothelial function and cardiac structure with emphasis on the effects of obesity on vascular endothelium and atherosclerosis. We then proceed from the pathophysiology of obesity to clinical practice, and we discuss clinical studies linking obesity with subclinical or overt CVD. We highlight that obesity is an easily assessed cardiovascular risk factor in the clinical setting and strategies to promote optimal body weight should be encouraged.

  2. Trained innate immunity and atherosclerosis.

    Science.gov (United States)

    Bekkering, Siroon; Joosten, Leo A B; van der Meer, Jos W M; Netea, Mihai G; Riksen, Niels P

    2013-12-01

    Monocytes/macrophages play a decisive role in the development and progression of atherosclerosis. It is currently unknown what stimuli initiate and orchestrate the activation of these cells in atherogenesis. In this review, we postulate that the novel concept of 'trained immunity' modulates the development and progression of atherosclerosis. Recently, results from our laboratory challenged the current paradigm that innate immunity is static and does not have an immunological memory. Stimulation by various microbial products, including Candida albicans and bacille Calmette-Guérin, appeared to bring monocytes into a long-term enhanced functional state, showing a stronger proinflammatory response to a second stimulus. This 'trained immunity' was mediated by increased and stable histone methylation. We describe the hypothesis that this functional reprogramming of monocytes, either by microbial products or by metabolic products, contributes to atherogenesis and propose epigenetic reprogramming of monocytes as a novel pharmacological target for preventing or treating atherosclerosis in the future.

  3. Hemodynamics Influences Vascular Peroxynitrite Formation: Implication for LDL Apo B-100 Nitration

    OpenAIRE

    Hsiai, Tzung K.; Hwang, Juliana; Barr, Mark L.; Correa, Adria; Hamilton, Ryan; Alavi, Mohammad; Rouhanizadeh, Mahsa; Cadenas, Enrique; Hazen, Stanley L

    2006-01-01

    Hemodynamics, specifically, fluid shear stress, modulates the focal nature of atherogenesis. Superoxide anion (O2−.) reacts with nitric oxide (.NO) at a rapid diffusion-limited rate to form peroxynitrite (O2−. +.NO → ONOO−). Immunohistostaining of human coronary arterial bifurcations or curvatures, where oscillatory shear stress (OSS) develops, revealed presence of nitrotyrosine staining, a fingerprint of peroxynitrite; whereas in straight segments, where pulsatile shear stress (PSS) occurs, ...

  4. Macrophage phenotype modulation by CXCL4 in vascular disease

    Directory of Open Access Journals (Sweden)

    Christian Albert Gleissner

    2012-01-01

    Full Text Available During atherogenesis, blood monocytes transmigrate into the subendothelial space and differentiate towards macrophages and foam cells. The major driver of this differentiation process is macrophage colony-stimulation factor (M-CSF. M-CSF-induced macrophages are important promoters of atherogenesis as demonstrated in M-CSF and M-CSF receptor knock out mice. However, M-CSF is not the only relevant promoter of macrophage differentiation. The platelet chemokine CXCL4 prevents monocyte apoptosis and promotes macrophage differentiation in vitro. It is secreted from activated platelets and has effects on various cell types relevant in atherogenesis. Knocking out the Pf4 gene coding for CXCL4 in Apoe-/- mice leads to reduced atherogenesis. Thus, it seems likely that CXC4-induced macrophages may have specific pro-atherogenic capacities. We have studied CXC4-induced differentiation of human macrophages using gene chips, systems biology and functional in vitro and ex vivo experiments. Our data indicate that CXCL4-induced macrophages are distinct from both their M-CSF-induced counterparts and other known macrophage polarizations like M1 macrophages (induced by LPS and interferon-gamma or M2 macrophages (induced by interleukin-4. CXCL4-induced macrophages have distinct phenotypic and functional characteristics, e.g. the complete loss of the hemoglobin-haptoglobin (Hb-Hp scavenger receptor CD163 which is necessary for effective hemoglobin clearance after plaque hemorrhage. Lack of CD163 is accompanied by the inability to upregulate the atheroprotective enzyme heme oxygenase-1 in response to Hb-Hp complexes.This review covers the current knowledge about CXCL4-induced macrophages, which based on their unique properties we have suggested to call these macrophages M4. CXCL4 may represent an important driver of macrophage heterogeneity within atherosclerotic lesions. Further dissecting its effects on macrophage differentiation may help to identify novel

  5. Effects of Thyme Extract Oils (from Thymus vulgaris, Thymus zygis, and Thymus hyemalis) on Cytokine Production and Gene Expression of oxLDL-Stimulated THP-1-Macrophages

    OpenAIRE

    Ocaña, A.; Reglero, G.

    2012-01-01

    Properties of thyme extracts from three different species (Thymus vulgaris, Thymus zygis, and Thymus hyemalis) were examined. Two oil fractions from each species were obtained by CO2 supercritical fluid extraction. Main compounds presented in the supercritical extracts of the three thyme varieties were 1,8 cineole, thymol, camphor, borneol, and carvacrol. As a cellular model of inflammation/atherogenesis, we use human macrophages derived from THP-1 monocytes and activated by oxidized LDLs. Th...

  6. Cholesteryl ester hydrolase activity is abolished in HSL macrophages but unchanged in macrophages lacking KIAA1363[S

    OpenAIRE

    Buchebner, Marlene; Pfeifer, Thomas; Rathke, Nora; Chandak, Prakash G.; Lass, Achim; Schreiber, Renate; Kratzer, Adelheid; Zimmermann, Robert; Sattler, Wolfgang; Koefeler, Harald; Fröhlich, Eleonore; Kostner, Gerhard M.; Birner-Gruenberger, Ruth; Chiang, Kyle P.; Haemmerle, Guenter

    2010-01-01

    Cholesteryl ester (CE) accumulation in macrophages represents a crucial event during foam cell formation, a hallmark of atherogenesis. Here we investigated the role of two previously described CE hydrolases, hormone-sensitive lipase (HSL) and KIAA1363, in macrophage CE hydrolysis. HSL and KIAA1363 exhibited marked differences in their abilities to hydrolyze CE, triacylglycerol (TG), diacylglycerol (DG), and 2-acetyl monoalkylglycerol ether (AcMAGE), a precursor for biosynthesis of platelet-ac...

  7. HDL as a Causal Factor in Atherosclerosis: Insights from Human Genetics.

    Science.gov (United States)

    Brunham, Liam R

    2016-12-01

    High-density lipoprotein cholesterol (HDL-C) levels are inversely related to risk of atherosclerotic cardiovascular disease (ASCVD). However, the simplistic assumption that HDL-C levels directly and causally impact atherogenesis has been challenged in recent years. The purpose of this article is to review the current state of knowledge regarding genetically determined HDL-C levels and ASCVD risk and determine what insight these studies provide into the causal relationship between HDL and atherosclerosis.

  8. PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study

    OpenAIRE

    Schlitt, Axel; Blankenberg, Stefan; Bickel, Christoph; Lackner, Karl J; Heine, Gunnar H.; Buerke, Michael; Werdan, Karl; Maegdefessel,Lars; Raaz, Uwe; Rupprecht, Hans J.; Munzel, Thomas; Jiang, Xian-Cheng

    2009-01-01

    Phospholipid transferprotein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Although many studies have investigated the role of PLTP in atherogenesis, the role of PLTP in atherosclerotic diseases is unclear. We investigated the association of serum PLTP activity with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and its relation to other markers of atherosclerosis in 1,085 patients with angiographically d...

  9. Microbial Risk Factors of Cardiovascular and Cerebrovascular Diseases: Potential Therapeutical Options

    Science.gov (United States)

    Abdalla Abbas, Mohammed; Guenther, Albrecht; Galantucci, Sebastiano; Fawi, Gharib; Comi, Giancarlo; Kwan, Joseph; Corea, Francesco

    2008-01-01

    Infection and inflammation may have a crucial role in the pathogenesis of atherosclerosis. This hypothesis is supported by an increasing number of reports on the interaction between chronic infection, inflammation, and atherogenesis. Assessment of serological and inflammatory markers of infection may be useful adjuncts in identifying those patients who are at a higher risk of developing vascular events, and in whom more aggressive treatments might be warranted. PMID:19018303

  10. Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice

    DEFF Research Database (Denmark)

    Skarpengland, Tonje; Holm, Sverre; Scheffler, Katja

    2016-01-01

    an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe-/- Neil3-/- mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation...... of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage....

  11. RAGE and Soluble RAGE: Potential Therapeutic Targets for Cardiovascular Diseases

    OpenAIRE

    Koyama, Hidenori; Yamamoto, Hiroshi; Nishizawa, Yoshiki

    2007-01-01

    Receptor for advanced glycation end-products (RAGE) is known to be involved in microvascular complications in diabetes. RAGE is also profoundly associated with macrovascular complications in diabetes through regulation of atherogenesis, angiogenic response, vascular injury, and inflammatory response. The potential significance of RAGE in the pathogenesis of cardiovascular disease appears not to be confined solely to nondiabetic rather than diabetic conditions. Numerous truncated forms of RAGE...

  12. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J

    2009-01-01

    OBJECTIVES: High-salt diet likely elevates blood pressure (BP), thus increasing the risk of cardiovascular events. We hypothesized that a high-salt diet plays a critical role in subjects whose renin-angiotensin systems cannot adjust to variable salt intake, rendering them more susceptible to athe......-salt diet combined with fixed high Ang II levels accelerates atherogenesis synergistically, beyond the effect of BP....

  13. Oxyradical Stress, Endocannabinoids, and Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Anberitha T. Matthews

    2015-12-01

    Full Text Available Atherosclerosis is responsible for most cardiovascular disease (CVD and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG. Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.

  14. Effect of 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin lesions on systemic inflammation and atherosclerosis in hypercholesterolaemic apolipoprotein E deficient mice

    DEFF Research Database (Denmark)

    Madsen, Marie; Hansen, Peter Riis; Nielsen, Lars Bo

    2016-01-01

    skin inflammation with increased epidermal thickness, infiltration of inflammatory-like cells and augmented tissue interleukin-17F levels. Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation...... systemic immune-inflammatory effects, but did not affect atherogenesis. The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients....

  15. Exercise and Dietary-Mediated Reductions in Postprandial Lipemia

    OpenAIRE

    Plaisance, Eric P.; Gordon Fisher

    2014-01-01

    Postprandial hyperlipemia produces long-term derangements in lipid/lipoprotein metabolism, vascular endothelial dysfunction, hypercoagulability, and sympathetic hyperactivity which are strongly linked to atherogenesis. The purpose of this review is to (1) provide a qualitative analysis of the available literature examining the dysregulation of postprandial lipid metabolism in the presence of obesity, (2) inspect the role of adiposity distribution and sex on postprandial lipid metabolism, and ...

  16. Small high-density lipoprotein is associated with monocyte subsets in stable coronary artery disease

    OpenAIRE

    Krychtiuk, Konstantin A.; Kastl, Stefan P.; Pfaffenberger, Stefan; Pongratz, Thomas; Hofbauer, Sebastian L.; Wonnerth, Anna; Katsaros, Katharina M.; Goliasch, Georg; Gaspar, Ludovit; Huber, Kurt; Maurer, Gerald; Dostal, Elisabeth; Oravec, Stanislav; Wojta, Johann; Speidl, Walter S.

    2014-01-01

    Objective: High-density lipoprotein (HDL) particles are heterogeneous in structure and function and the role of HDL subfractions in atherogenesis is not well understood. It has been suggested that small HDL may be dysfunctional in patients with coronary artery disease (CAD). Monocytes are considered to play a key role in atherosclerotic diseases. Circulating monocytes can be divided into three subtypes according to their surface expression of CD14 and CD16. Our aim was to examine whether mono...

  17. Pathophysiological Role of Adiponectin, Leptin and Asymmetric Dimethylarginine in the Process of Atherosclerosis

    OpenAIRE

    Koleva Daniela Iv.; Orbetzova Maria M.; Nikolova Julia G.; Deneva Tanya I.

    2016-01-01

    Adipose tissue is recognized as a rich source of proinflammatory mediators that may directly contribute to vascular injury, insulin resistance, and atherogenesis. Many studies have shown that adiponectin has antiatherogenic and anti-inflammatory properties. Adiponectin acts not only as a factor increasing insulin sensitivity, and the protective effect may result from its ability to suppress production of proinflammatory cytokines. It negatively regulates the expression of TNF-alpha and C-reac...

  18. Understanding Selective Downregulation of c-Myc Expression through Inhibition of General Transcription Regulators in Multiple Myeloma

    Science.gov (United States)

    2015-06-01

    system organ failure and death (Medzhitov et al., 2012). Chronic, low-grade inflammation is a pathogenic feature of autoimmune disorders as well as...bromodomain inhibition has been shown to abrogate global, maladaptive tran- scriptional programs during sepsis and heart failure, implicating BRD4 in stress...inflammatory disorders , including atherogenesis, in which activation of ECs is pathogenic (Gim- brone et al., 1990; Ley et al., 2007). Despite these

  19. Atherosclerosis in rheumatoid arthtritis: the role of high-resolution B mode ultrasound in the measurement of the arterial intima-media thickness

    OpenAIRE

    G.M. Giuseppetti; Cerioni, A.; Mangiacotti, M.; Salaffi, F; Carotti, M; W. Grassi

    2011-01-01

    Background: Patients with rheumatoid arthritis (RA) have a reduced life expectancy and high cardiovascular morbidity and mortality as compared to the general population. A number of possible factors for the atherogenesis in this disease have been described, such as homocysteine, altered serum levels of selected lipopotroteins and treatment. Recent findigs indicate that the systemic inflammation may contribute to the development of atherosclerosis and confer an additional risk for cardiovascul...

  20. Treatment of hyperlipidemia.

    Science.gov (United States)

    Kane, J P; Malloy, M J

    1990-01-01

    The rationale of treatment to prevent or delay the onset of atherosclerotic disease is based upon recognition that a key process in atherogenesis is the uptake of certain lipoproteins by scavenger cells in the artery wall. These lipoproteins enter the artery wall from blood. Thus the risk of atherogenesis is linked to the concentrations of these lipoproteins in plasma. Although a number of processes involved in atherogenesis may ultimately yield to additional means of intervention, the current central strategy is to reduce levels of atherogenic lipoproteins in blood. This strategy draws support from several recent intervention trials, which have shown reduction of progression of coronary disease and, in one instance, reduced total mortality. Recent advances in therapy, including the advent of HMG CoA reductase inhibitors and the development of combined drug regimes of unprecedented effectiveness, now permit the reduction of plasma lipoprotein levels to the optimum in a majority of individuals. Rational selection of single-drug regimens and drug combinations is based on phenotypic characterization of lipoprotein disorders. The physician also needs to be aware of disease that can lead to secondary hyperlipoproteinemia so that the underlying disorders can be treated if possible. The treatment by diet of all individuals with hyperlipidemia or atherosclerotic disease is recommended. The decision to treat with drugs should involve consideration of risk factors such as the patient's sex, blood pressure, smoking habits, levels of HDL, and family history of atherosclerosis.

  1. Influences of a-tocopherol on cholesterol metabolism and fatty streak development in apolipoprotein E-deficient mice fed an atherogenic diet

    Directory of Open Access Journals (Sweden)

    Peluzio M.C.G.

    2001-01-01

    Full Text Available Although the role of oxidized lipoproteins is well known in atherogenesis, the role of vitamin E supplementation is still controversial. There is also little information about cholesterol metabolism (hepatic concentration and fecal excretion in the new models of atherosclerosis. In the present study, we evaluated the effect of moderate vitamin E supplementation on cholesterol metabolism and atherogenesis in apolipoprotein E (apo E-deficient mice. Apo E-deficient mice were fed an atherogenic diet containing 40 or 400 mg/kg of alpha-tocopherol acetate for 6 weeks. Total cholesterol in serum and liver and 3-OH-alpha-sterols in feces, and fecal excretion of bile acids were determined and histological analyses of aortic lesion were performed. A vitamin E-rich diet did not affect body weight, food intake or serum cholesterol. Serum and hepatic concentrations of cholesterol as well as sterol concentration in feces were similar in both groups. However, when compared to controls, the alpha-tocopherol-treated mice showed a reduction of about 60% in the atherosclerotic lesions when both the sum of lesion areas and the average of the largest lesion area were considered. These results demonstrate that supplementation of moderate doses of alpha-tocopherol was able to slow atherogenesis in apo E-deficient mice and to reduce atherogenic lipoproteins without modifying the hepatic pool or fecal excretion of cholesterol and bile acids.

  2. 9-cis -carotene Inhibits Atherosclerosis Development in Female LDLR-/- Mice

    Directory of Open Access Journals (Sweden)

    Noa Zolberg Relevy

    2015-02-01

    Full Text Available Background: Several epidemiological studies have shown that diets rich in carotenoids are associated with a reduced risk of cardiovascular disease. However, administration of synthetic all-trans -carotene was reported to have no effect on cardiovascular disease. We previously showed that the 9-cis -carotene-rich powder of the alga Dunaliella bardawil inhibits atherogenesis and reduces plasma non-HDL cholesterol levels in mice. Context and purpose of this study: We sought to study whether isolated 9-cis -carotene inhibits atherogenesis in a murine model of atherosclerosis. Results: Twelve-week-old female LDL receptor knockout mice (LDLR-/- were pretreated for 2 weeks with regular chow diet fortified with the alga Dunaliella powder, 9-cis β-carotene isomer, all-trans β-carotene isomer, or 9-cis retinoic acid, followed by 10 weeks of a high-fat diet with the same fortifications. In contrast to Dunaliella, 9-cis β-carotene did not inhibit the high fat dietinduced elevation of plasma cholesterol. In addition, diet fortification with Dunaliella powder, β-carotene isomers, or 9-cis retinoic acid did not change the plasma retinol or retinoic acid levels.Nevertheless, 9-cis β-carotene significantly inhibited atherogenesis compared to the control mice (39% reduction. Conclusions: The results suggest that 9-cis β-carotene should be considered as an antiatherogenic agent in the human diet

  3. Elucidation of the effects of a high fat diet on trace elements in rabbit tissues using atomic absorption spectroscopy.

    Science.gov (United States)

    Abdelhalim, Mohamed Anwar K; Alhadlaq, Hisham A; Moussa, Sherif Abdelmottaleb

    2010-01-12

    The mechanism of atherogenesis is not yet fully understood despite intense study in this area. The effects of high fat diet (HFD) on the changes of trace elements [iron (Fe), copper (Cu) and zinc (Zn)] in several tissues of rabbits have not been documented before. Thus, the aim of this study was to elucidate the changes in trace elements in several tissues of rabbits fed on HFD for a period of feeding of 10 weeks. The HFD group was fed a NOR rabbit chow supplemented with 1.0% cholesterol plus 1.0% olive oil. Fe, Cu and Zn concentrations were measured in four types of tissue from control and HFD rabbits using atomic absorption spectroscopy (AAS). Comparing HFD rabbits to control rabbits, we found that the highest percentage change of increase of Fe was 95% in lung tissue, while the lowest percentage change of increase of Fe was 7% in kidney tissue; the highest percentage change of decrease of Cu was 16% in aortic tissue, while the lowest percentage change of decrease of Cu was 6% in kidney tissue; and the highest percentage change of decrease of Zn was 71% in kidney tissue, while the lowest percentage change of decrease of Zn was 8% in lung tissue. These results suggest that Fe plays a major role in atherogenesis; it may accelerate the process of atherosclerosis probably through the production of free radicals, deposition and absorption of intracellular and extracellular lipids in the intima, connective tissue formation, smooth muscle proliferation, lower matrix degradation capacity and increased plaque stability. Furthermore, inducing anemia in HFD rabbits may delay or inhibit the progression of atherosclerosis. Cu plays a minor role in atherogenesis and Cu supplements may inhibit the progression of atherogenesis, perhaps by reducing the migration of smooth muscle cells from the media to the intima. Zn plays a major role in atherogenesis and that it may act as an endogenous protective factor against atherosclerosis perhaps by reducing lesion Fe content

  4. Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M.; Brown, Robert J., E-mail: rbrown@mun.ca

    2014-09-05

    Highlights: • Lipoprotein hydrolysis products were produced by lipoprotein lipase. • Hydrolysis products lowers expression of macrophage cholesterol transporters. • Hydrolysis products reduces expression of select nuclear receptors. • Fatty acid products lowers cholesterol transporters and select nuclear receptors. • Fatty acid products reduces cholesterol efflux from macrophages. - Abstract: Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL.

  5. Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis.

    Science.gov (United States)

    Ichiki, Tomoko; Izumi, Ririko; Cataliotti, Alessandro; Larsen, Amy M; Sandberg, Sharon M; Burnett, John C

    2013-10-01

    Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12 mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors.

    Science.gov (United States)

    Goodman, Krista B; Bury, Michael J; Cheung, Mui; Cichy-Knight, Maria A; Dowdell, Sarah E; Dunn, Allison K; Lee, Dennis; Lieby, Jeffrey A; Moore, Michael L; Scherzer, Daryl A; Sha, Deyou; Suarez, Dominic P; Murphy, Dennis J; Harpel, Mark R; Manas, Eric S; McNulty, Dean E; Annan, Roland S; Matico, Rosalie E; Schwartz, Benjamin K; Trill, John J; Sweitzer, Thomas D; Wang, Da-Yuan; Keller, Paul M; Krawiec, John A; Jaye, Michael C

    2009-01-01

    Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors.

  7. Role of gut microbiota in the modulation of atherosclerosis-associated immune response

    Directory of Open Access Journals (Sweden)

    Dimitry A Chistiakov

    2015-06-01

    Full Text Available Inflammation and metabolic abnormalities are linked to each other. At present, pathogenic inflammatory response was recognized as a major player in metabolic diseases. In humans, intestinal microflora could significantly influence the development of metabolic diseases including atherosclerosis. Commensal bacteria were shown to activate inflammatory pathways through altering lipid metabolism in adipocytes, macrophages, and vascular cells, inducing insulin resistance, and producing trimethylamine-N-oxide. However, gut microbiota could also play the atheroprotective role associated with anthocyanin metabolism and administration of probiotics and their components. Here, we review the mechanisms by which the gut microbiota may influence atherogenesis.

  8. Unveiling LOX-1 receptor interplay with nanotopography: mechanotransduction and atherosclerosis onset

    Science.gov (United States)

    di Rienzo, Carmine; Jacchetti, Emanuela; Cardarelli, Francesco; Bizzarri, Ranieri; Beltram, Fabio; Cecchini, Marco

    2013-01-01

    Lectin-like ox-LDL receptors (LOX-1) play a crucial role in the ox-LDL-induced pathological transformation of vessel-wall components, a crucial early step in atherogenesis. LOX-1 dynamics is quantitatively investigated in human endothelial cells (HUVECs) exposed to environmental nanotopographies. We demonstrate distinct nanotopography-induced cell phenotypes, characterized by different morphology, LOX-1 diffusivity and oligomerization state: HUVECs on flat surfaces exhibit the behavior found in pro-atherogenic conditions, while growth on nanogratings can interfere with LOX-1 dynamics and lead to a behavior characteristic of normal, non-pathological conditions.

  9. Monocyte chemoattractant protein-1: a key mediator in inflammatory processes.

    Science.gov (United States)

    Melgarejo, Esther; Medina, Miguel Angel; Sánchez-Jiménez, Francisca; Urdiales, José Luis

    2009-05-01

    Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for monocytes and macrophages to areas of inflammation. MCP-1 is a prototypical chemokine subject to coordinated regulation by immunomodulatory agents. Since MCP-1 is implicated in multiple inflammatory diseases, it is a potential target for the treatment of these disorders. In this review, we will provide background information and summarize the MCP-1 structure and signaling pathways. Its involvement in multiple diseases, such as tumour development, atherogenesis and rare autoimmune diseases is also revised.

  10. Diabetes and Coronary Heart Disease: A Risk Factor for the Global Epidemic

    Directory of Open Access Journals (Sweden)

    Maguy Chiha

    2012-01-01

    Full Text Available Cardiovascular disease remains a leading cause of death in the United States and the world. In this we will paper focus on type 2 diabetes mellitus as a risk factor for coronary heart disease, review the mechanisms of atherogenesis in diabetics, the impact of hypertension and the treatment goals in diabetics, the guidelines for screening, and review the epidemiologic consequences of diabetes and heart disease on a global scale. The underlying premise to consider diabetes a cardiovascular disease equivalent will be explored as well as the recommendations for screening and cardiac testing for asymptomatic diabetic patients.

  11. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

    DEFF Research Database (Denmark)

    2016-01-01

    Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B...... that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production...... of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis....

  12. Cardiovascular toxicity of nicotine: Implications for electronic cigarette use.

    Science.gov (United States)

    Benowitz, Neal L; Burbank, Andrea D

    2016-08-01

    The cardiovascular safety of nicotine is an important question in the current debate on the benefits vs. risks of electronic cigarettes and related public health policy. Nicotine exerts pharmacologic effects that could contribute to acute cardiovascular events and accelerated atherogenesis experienced by cigarette smokers. Studies of nicotine medications and smokeless tobacco indicate that the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease. Electronic cigarettes deliver nicotine without combustion of tobacco and appear to pose low-cardiovascular risk, at least with short-term use, in healthy users. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Proceedings - II Scientific Conferences CBIOS

    OpenAIRE

    L. Monteiro Rodrigues, et al.

    2016-01-01

    1st Session - CBIOS Group PT (Pharmacology and Therapeutics) Keynote Lecture C.01 - High-density lipoproteins beyond atherogenesis. José Delgado Alves Speakers / Prelectores C.02 - Mind the GAAP: a tale of camels, calcium, channels and cancer. Nuno Saraiva C.03 - Case study: Ochratoxin A, ROS and Antioxidants. João G. Costa, Nuno Saraiva, Patrícia S. Guerreiro, Henriqueta Louro, Maria J. Silva, Joana P. Miranda, Matilde Castro, Ines BatinicHaberle, Ana S. Fernandes and Nuno G. ...

  14. Complement activation by cholesterol crystals triggers a subsequent cytokine response

    DEFF Research Database (Denmark)

    Niyonzima, Nathalie; Halvorsen, Bente; Sporsheim, Bjørnar

    2017-01-01

    may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation. CC is recognized by the lectin...... of inflammation processes before downstream release of cytokines including IL-1β. Another therapeutic candidate can be broad-acting 2-hydroxypropyl-β-cyclodextrin, a compound that targets several mechanisms such as cholesterol efflux, complement gene expression, and the NLRP3 pathway. In summary, emerging...

  15. Effects of a 12-week alpine skiing intervention on endothelial progenitor cells, peripheral arterial tone and endothelial biomarkers in the elderly

    DEFF Research Database (Denmark)

    Niederseer, David; Steidle-Kloc, Eva; Mayr, Matthias

    2016-01-01

    : +0.18±0.76) and CG (-0.39±0.85; p=0.045), as did homocysteine (IG: -1.3±1.3μmol/l; CG: -0.4±1.4μmol/l; p=0.037) while other endothelial biomarkers remained essentially unchanged. CONCLUSIONS: This study shows that skiing induces several beneficial effects on markers of atherogenesis including EPCs......, peripheral arterial tone and homocysteine. Our findings suggest that recreational alpine skiing may serve as a further mode of preventive exercise training, which might result in improved compliance with current recommendations....

  16. Cardioprotection by Phytochemicals via Antiplatelet Effects and Metabolism Modulations.

    Science.gov (United States)

    Zhang, Pei-Ying

    2015-11-01

    The multi-factorial aetiology is the characteristic element of cardiac disorders. Further scientific research had recognized for a long time that platelet function is related to the risk of developing atherosclerosis. Activated blood platelets play a central role in this chronic inflammatory condition as they contribute to plaque formation within blood vessels in the early stages of atherogenesis. The present review article summarizes the cardioprotective role played by Phytochemicals via antiplatelet effects. Also, various metabolic modifications have been included that have protective effect during cardiac pathology.

  17. Peculiarities of Lipid Metabolism in Patients with Prolactinomas during Suppressive Dopamine Agonist Therapy

    Directory of Open Access Journals (Sweden)

    T.H. Hohitidze

    2015-05-01

    Full Text Available The article presents the data of lipid metabolism at the stages of long-term (12 months suppressive therapy with dopamine agonist cabergoline in 61 patients with prolactinoma. It is proved that the normalization of prolactin levels during therapy reduces the risk of development and progression of atherogenesis through reduction of total cholesterol content and increase in high-density lipoprotein cholesterol. Suppressive pharmacotherapy with cabergoline reduces the total cholesterol level in both men and women. Men had most pronounced improvement in the ratio of pro- and antiatherogenic lipid fractions

  18. Effect of darapladib on major coronary events after an acute coronary syndrome

    DEFF Research Database (Denmark)

    O'Donoghue, Michelle L; Braunwald, Eugene; White, Harvey D

    2014-01-01

    IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients...... after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI...

  19. Commensal bacteria at the crossroad between cholesterol homeostasis and chronic inflammation in atherosclerosis.

    Science.gov (United States)

    Kasahara, Kazuyuki; Tanoue, Takeshi; Yamashita, Tomoya; Yodoi, Keiko; Matsumoto, Takuya; Emoto, Takuo; Mizoguchi, Taiji; Hayashi, Tomohiro; Kitano, Naoki; Sasaki, Naoto; Atarashi, Koji; Honda, Kenya; Hirata, Ken-Ichi

    2017-03-01

    The gut microbiota were shown to play critical roles in the development of atherosclerosis, but the detailed mechanism is limited. The purpose of this study is to clarify the influence of gut microbiota on atherogenesis via lipid metabolism and systemic inflammation. Germ-free or conventionally raised (Conv) ApoE-deficient (ApoE-/-) mice were fed chow diet and euthanized at 20 weeks of age. We found that the lack of gut microbiota in ApoE-/- mice caused a significant increase in the plasma and hepatic cholesterol levels compared with Conv ApoE-/- mice. The absence of gut microbiota changed the bile acid composition in the ileum, which was associated with activation of the enterohepatic fibroblast growth factor 15, fibroblast growth factor receptor 4 axis, and reduction of cholesterol 7α-hydroxylase and hepatic bile acid synthesis, resulting in the accumulation of liver cholesterol content. However, we found that the lack of microbiota caused a significant reduction in atherosclerotic lesion formation compared with Conv ApoE-/- mice, which might be associated with the attenuation of lipopolysaccharide-mediated inflammatory responses. Our findings indicated that the gut microbiota affected both hypercholesterolemia and atherogenesis in mice. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  20. New promising potential in fighting atherosclerosis: HDL and reverse cholesterol transport.

    Science.gov (United States)

    Ginter, E; Simko, V

    2013-01-01

    Atherogenesis and cardiovascular disease (CVD) mortality remain an outstanding population health risk. Its importance grows with rising affluence leading to obesity in the developing countries. Inspite of an enormous initial enthusiasm related to the breakthrough success with the statins, there remains a substantial residual risk of CVD. While statins are effective in lowering the low density lipoproteins, LDL (the "bad" cholesterol), the residual risk is also related to unsatisfactorily low levels of high density lipoprotein, HDL (the "good" cholesterol). It has been long known that low levels of HDL are associated with CVD as an independent risk factor. The original concept of a direct transfer of cholesterol from LDL to HDL has been proved to be oversimplified. Recent studies confirm direct participation of HDL in anti-atherogenesis by promoting the efflux of cholesterol contained in the foam cells that constitute atherosclerotic lesions. The challenge is to identify therapeutic interventions aimed at raising HDL, thus assisting statins that have until recently been mostly used as a monotherapy (Fig. 5, Ref. 26).

  1. ATP-binding cassette transporters A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis.

    Science.gov (United States)

    Ye, Dan; Lammers, Bart; Zhao, Ying; Meurs, Illiana; Van Berkel, T J; Van Eck, Miranda

    2011-05-01

    Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in arteries. Plasma high density lipoprotein (HDL) levels bear a strong independent inverse relationship with atherosclerotic cardiovascular disease. One central antiatherogenic role of HDL is believed to be its ability to remove excessive peripheral cholesterol back to the liver for subsequent catabolism and excretion, a physiologic process termed reverse cholesterol transport (RCT). Cholesterol efflux from macrophage foam cells, the initial step of RCT is the most relevant step with respect to atherosclerosis. The ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 play crucial roles in the efflux of cellular cholesterol to HDL and its apolipoproteins. Moreover, ABCA1 and ABCG1 affect cellular inflammatory cytokine secretion by modulating cholesterol content in the plasma membrane and within intracellular compartments. In humans, ABCA1 mutations can cause a severe HDL-deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. Disrupting Abca1 or Abcg1 in mice promotes accumulation of excessive cholesterol in macrophages, and physiological manipulation of ABCA1 expression affects atherogenesis. Here we review recent advances in the role of ABCA1 and ABCG1 in HDL metabolism, macrophage cholesterol efflux, inflammation, and atherogenesis. Next, we summarize the structure, expression, and regulation of ABCA1 and ABCG1. Finally, we give an update on the progress and pitfalls of therapeutic approaches that target ABCA1 and ABCG1 to stimulate the flux of lipids through the RCT pathway.

  2. Effects of a 12-week alpine skiing intervention on endothelial progenitor cells, peripheral arterial tone and endothelial biomarkers in the elderly.

    Science.gov (United States)

    Niederseer, David; Steidle-Kloc, Eva; Mayr, Matthias; Müller, Edith E; Cadamuro, Janne; Patsch, Wolfgang; Dela, Flemming; Müller, Erich; Niebauer, Josef

    2016-07-01

    Endothelial dysfunction occurs early during atherogenesis and it can be normalized by exercise training. Unfortunately, patients' compliance with exercise prescription remains low, often because the given choices do not appeal to them. In Alpine regions, skiing is a popular mode of exercise, and therefore we set out to assess whether it can induce antiatherogenic effects. We randomized 42 subjects into a group of 12weeks of guided skiing (intervention group, IG, n=22; 12 males/10 females; age: 66.6±2.1years) or a control group (CG, n=20; 10 males/10 females; age: 67.3±4.4years). Early (CD3-CD34+CD45+) and late endothelial progenitor cells (EPCs; CD45dimCD34+KDR+ peripheral blood mononuclear cells, PBMCs), peripheral arterial tonometry and endothelial biomarkers were assessed at the beginning and end of the study. In the IG, participants completed 28.5±2.6 skiing days at an average heart rate of 72.7±8.5% of their maximum heart rate. Changes in early (IG: +0.001±0.001% PBMC; CG: -0.001±0.001% PBMC; IG vs. CG: pskiing induces several beneficial effects on markers of atherogenesis including EPCs, peripheral arterial tone and homocysteine. Our findings suggest that recreational alpine skiing may serve as a further mode of preventive exercise training, which might result in improved compliance with current recommendations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Esculeogenin A, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT.

    Science.gov (United States)

    Fujiwara, Yukio; Kiyota, Naoko; Hori, Masaharu; Matsushita, Sayaka; Iijima, Yoko; Aoki, Koh; Shibata, Daisuke; Takeya, Motohiro; Ikeda, Tsuyoshi; Nohara, Toshihiro; Nagai, Ryoji

    2007-11-01

    We recently identified esculeoside A, a new spirosolane-type glycoside, with a content in tomatoes that is 4-fold higher than that of lycopene. In the present study, we examined the effects of esculeoside A and esculeogenin A, a new aglycon of esculeoside A, on foam cell formation in vitro and atherogenesis in apoE-deficient mice. Esculeogenin A significantly inhibited the accumulation of cholesterol ester (CE) induced by acetylated low density lipoprotein (acetyl-LDL) in human monocyte-derived macrophages (HMDM) in a dose-dependent manner without inhibiting triglyceride accumulation, however, it did not inhibit the association of acetyl-LDL to the cells. Esculeogenin A also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-coenzymeA (CoA): cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that esculeogenin A suppresses the activity of both ACAT-1 and ACAT-2. Furthermore, esculeogenin A prevented the expression of ACAT-1 protein, whereas that of SR-A and SR-BI was not suppressed. Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol, triglycerides, LDL-cholesterol, and the areas of atherosclerotic lesions without any detectable side effects. Our study provides the first evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis.

  4. Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting acyl-CoA:cholesterol acyl-transferase (ACAT).

    Science.gov (United States)

    Fujiwara, Yukio; Kiyota, Naoko; Tsurushima, Keiichiro; Yoshitomi, Makiko; Horlad, Hasita; Ikeda, Tsuyoshi; Nohara, Toshihiro; Takeya, Motohiro; Nagai, Ryoji

    2012-03-14

    It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice. This study examined whether tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions. The study provides the first evidence that tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis.

  5. Antiatherogenic activity of extracts of Argania spinosa L. pericarp: beneficial effects on lipid peroxidation and cholesterol homeostasis.

    Science.gov (United States)

    Berrougui, Hicham; Cherki, Mounia; Koumbadinga, Geremy Abdull; Isabelle, Maxim; Douville, Jasmin; Spino, Claude; Khalil, Abdelouahed

    2007-09-01

    Prevention of lipoprotein oxidation by natural compounds may prevent atherosclerosis via reducing early atherogenesis. In this study, we investigated for the first time the beneficial properties of methanolic extract of argania pericarp (MEAP) towards atherogenesis by protecting human low-density lipoprotein (LDL) against oxidation while promoting high-density lipoprotein (HDL)-mediated cholesterol efflux. By measuring the formation of malondialdehyde (MDA) and conjugated diene as well as the lag phase and the progression rate of lipid peroxidation, the MEAP was found to possess an inhibitory effect. In addition, MEAP reduced the rate of disappearance of alpha-tocopherol as well as the apoB electrophoretic mobility in a dose-dependent manner. These effects are related to the free radical scavenging and copper-chelating effects of MEAP. In terms of cell viability, MEAP has shown a cytotoxic effect (0-40 microg/mL). Incubation of 3H-cholesterol-loaded J774 macrophages with HDL in the presence of increasing concentrations of MEAP enhanced HDL-mediated cholesterol efflux independently of ABCA1 receptor pathways. Our findings suggest that argania seed pericarp provides a source of natural antioxidants that inhibit LDL oxidation and enhance cholesterol efflux and thus can prevent development of cardiovascular diseases.

  6. Monocyte-Derived Dendritic Cells Upregulate Extracellular Catabolism of Aggregated Low-Density Lipoprotein on Maturation, Leading to Foam Cell Formation.

    Science.gov (United States)

    Haka, Abigail S; Singh, Rajesh K; Grosheva, Inna; Hoffner, Haley; Capetillo-Zarate, Estibaliz; Chin, Harvey F; Anandasabapathy, Niroshana; Maxfield, Frederick R

    2015-10-01

    Although dendritic cells are known to play a role in atherosclerosis, few studies have examined the contribution of the wide variety of dendritic cell subsets. Accordingly, their roles in atherogenesis remain largely unknown. We investigated the ability of different dendritic cell subsets to become foam cells after contact with aggregated low-density lipoprotein (LDL; the predominant form of LDL found in atherosclerotic plaques). We demonstrate that both murine and human monocyte-derived dendritic cells use exophagy to degrade aggregated LDL, leading to foam cell formation, whereas monocyte-independent dendritic cells are unable to clear LDL aggregates by this mechanism. Exophagy is a catabolic process in which objects that cannot be internalized by phagocytosis (because of their size or association with extracellular structures) are initially digested in an extracellular acidic lytic compartment. Surprisingly, we found that monocyte-derived dendritic cells upregulate exophagy on maturation. This contrasts various forms of endocytic internalization in dendritic cells, which decrease on maturation. Finally, we show that our in vitro results are consistent with dendritic cell lipid accumulation in plaques of an ApoE(-/-) mouse model of atherosclerosis. Our results show that monocyte-derived dendritic cells use exophagy to degrade aggregated LDL and become foam cells, whereas monocyte-independent dendritic cells are unable to clear LDL deposits. Furthermore, we find that exophagy is upregulated on dendritic cell maturation. Thus, exophagy-mediated foam cell formation in monocyte-derived dendritic cells could play a significant role in atherogenesis. © 2015 American Heart Association, Inc.

  7. Monocyte-derived dendritic cells upregulate extracellular catabolism of aggregated LDL upon maturation, leading to foam cell formation

    Science.gov (United States)

    Haka, Abigail S.; Singh, Rajesh K.; Grosheva, Inna; Hoffner, Haley; Capetillo-Zarate, Estibaliz; Chin, Harvey F.; Anandasabapathy, Niroshana; Maxfield, Frederick R.

    2015-01-01

    Objective Although dendritic cells are known to play a role in atherosclerosis, few studies have examined the contribution of the wide variety of dendritic cell subsets. Accordingly, their roles in atherogenesis remain largely unknown. We investigated the ability of different dendritic cell subsets to become foam cells following contact with aggregated LDL (the predominant form of LDL found in atherosclerotic plaques). Approach and Results We demonstrate that both murine and human monocyte-derived dendritic cells use exophagy to degrade aggregated LDL, leading to foam cell formation, while monocyte-independent dendritic cells are unable to clear LDL aggregates by this mechanism. Exophagy is a catabolic process in which objects that cannot be internalized by phagocytosis (due to their size or association with extracellular structures) are initially digested in an extracellular acidic lytic compartment. Surprisingly, we found that monocyte-derived dendritic cells upregulate exophagy upon maturation. This contrasts various forms of endocytic internalization in dendritic cells, which decrease upon maturation. Finally, we show that our in vitro results are consistent with dendritic cell lipid accumulation in plaques of an ApoE−/− mouse model of atherosclerosis. Conclusions Our results show that monocyte-derived dendritic cells use exophagy to degrade aggregated LDL and become foam cells, while monocyte-independent dendritic cells are unable to clear LDL deposits. Further, we find that exophagy is upregulated upon dendritic cell maturation. Thus, exophagy-mediated foam cell formation in monocyte-derived dendritic cells could play a significant role in atherogenesis. PMID:26293468

  8. Antiatherogenic effect of bisvanillyl-hydralazone, a new hydralazine derivative with antioxidant, carbonyl scavenger, and antiapoptotic properties.

    Science.gov (United States)

    Bouguerne, Benaissa; Belkheiri, Nadji; Bedos-Belval, Florence; Vindis, Cécile; Uchida, Koji; Duran, Hubert; Grazide, Marie-Hélène; Baltas, Michel; Salvayre, Robert; Nègre-Salvayre, Anne

    2011-06-01

    Reactive oxygen species (ROS) generated within the vascular wall trigger low-density lipoprotein (LDL) oxidation, lipid peroxidation, and carbonyl stress that are involved in atherogenesis. We recently reported that the antihypertensive drug, hydralazine, exhibits carbonyl scavenger and antiatherogenic properties, but only moderate antioxidant activity, so that high concentrations are required for inhibiting LDL oxidation. We aimed to develop agents sharing both antioxidant and carbonyl scavenger properties. We have synthesized a new hydralazine derivative, the bisvanillyl-hydralazone (BVH). BVH strongly inhibited LDL oxidation induced by copper and by human endothelial cells (HMEC-1), and prevented the formation of macrophagic foam cells. BVH reduced both the extracellular generation of ROS (superoxide anion and hydrogen peroxide) induced by oxidized LDL (oxLDL), as well as intracellular oxidative stress and proteasome activation, NFkappaB activation, and oxLDL-mediated proinflammatory signaling. In parallel, BVH prevented the carbonyl stress induced by oxLDL on cellular proteins, and blocked the apoptotic cascade as assessed by the inhibition of Bid cleavage, cytochrome C release, and DEVDase activation. Lastly, BVH prevented atherogenesis and carbonyl stress in apoE(-/-) mice. In conclusion, BVH is the prototype of a new class of antioxidant and carbonyl scavenger agents designed for new therapeutical approaches in atherosclerosis.

  9. Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice.

    Science.gov (United States)

    Barski, Oleg A; Xie, Zhengzhi; Baba, Shahid P; Sithu, Srinivas D; Agarwal, Abhinav; Cai, Jian; Bhatnagar, Aruni; Srivastava, Sanjay

    2013-06-01

    Atherosclerotic lesions are associated with the accumulation of reactive aldehydes derived from oxidized lipids. Although inhibition of aldehyde metabolism has been shown to exacerbate atherosclerosis and enhance the accumulation of aldehyde-modified proteins in atherosclerotic plaques, no therapeutic interventions have been devised to prevent aldehyde accumulation in atherosclerotic lesions. We examined the efficacy of carnosine, a naturally occurring β-alanyl-histidine dipeptide, in preventing aldehyde toxicity and atherogenesis in apolipoprotein E-null mice. In vitro, carnosine reacted rapidly with lipid peroxidation-derived unsaturated aldehydes. Gas chromatography mass-spectrometry analysis showed that carnosine inhibits the formation of free aldehydes 4-hydroxynonenal and malonaldialdehyde in Cu(2+)-oxidized low-density lipoprotein. Preloading bone marrow-derived macrophages with cell-permeable carnosine analogs reduced 4-hydroxynonenal-induced apoptosis. Oral supplementation with octyl-D-carnosine decreased atherosclerotic lesion formation in aortic valves of apolipoprotein E-null mice and attenuated the accumulation of protein-acrolein, protein-4-hydroxyhexenal, and protein-4-hydroxynonenal adducts in atherosclerotic lesions, whereas urinary excretion of aldehydes as carnosine conjugates was increased. The results of this study suggest that carnosine inhibits atherogenesis by facilitating aldehyde removal from atherosclerotic lesions. Endogenous levels of carnosine may be important determinants of atherosclerotic lesion formation, and treatment with carnosine or related peptides could be a useful therapy for the prevention or the treatment of atherosclerosis.

  10. “Gum Bug, Leave My Heart Alone!”—Epidemiologic and Mechanistic Evidence Linking Periodontal Infections and Atherosclerosis

    Science.gov (United States)

    Kebschull, M.; Demmer, R.T.; Papapanou, P.N.

    2010-01-01

    Evidence from epidemiologic studies suggests that periodontal infections are independently associated with subclinical and clinical atherosclerotic vascular disease. Although the strength of the reported associations is modest, the consistency of the data across diverse populations and a variety of exposure and outcome variables suggests that the findings are not spurious or attributable only to the effects of confounders. Analysis of limited data from interventional studies suggests that periodontal treatment generally results in favorable effects on subclinical markers of atherosclerosis, although such analysis also indicates considerable heterogeneity in responses. Experimental mechanistic in vitro and in vivo studies have established the plausibility of a link between periodontal infections and atherogenesis, and have identified biological pathways by which these effects may be mediated. However, the utilized models are mostly mono-infections of host cells by a limited number of ‘model’ periodontal pathogens, and therefore may not adequately portray human periodontitis as a polymicrobial, biofilm-mediated disease. Future research must identify in vivo pathways in humans that may (i) lead to periodontitis-induced atherogenesis, or (ii) result in treatment-induced reduction of atherosclerosis risk. Data from these studies will be essential for determining whether periodontal interventions have a role in the primary or secondary prevention of atherosclerosis. PMID:20639510

  11. Activated human mast cells induce LOX-1-specific scavenger receptor expression in human monocyte-derived macrophages.

    Directory of Open Access Journals (Sweden)

    Mervi Alanne-Kinnunen

    Full Text Available Activated mast cells in atherosclerotic lesions degranulate and release bioactive compounds capable of regulating atherogenesis. Here we examined the ability of activated human primary mast cells to regulate the expression of the major scavenger receptors in cultured human primary monocyte-derived macrophages (HMDMs.Components released by immunologically activated human primary mast cells induced a transient expression of lectin-like oxidized LDL receptor (LOX-1 mRNA in HMDMs, while the expression of two other scavenger receptors, MSR1 and CD36, remained unaffected. The LOX-1-inducing secretory components were identified as histamine, tumor necrosis factor alpha (TNF-α, and transforming growth factor beta (TGF-β1, which exhibited a synergistic effect on LOX-1 mRNA expression. Histamine induced a transient expression of LOX-1 protein. Mast cell -induced increase in LOX-1 expression was not associated with increased uptake of oxidized LDL by the macrophages.Mast cell-derived histamine, TNF-α, and TGF-β1 act in concert to induce a transient increase in LOX-1 expression in human primary monocyte-derived macrophages. The LOX-1-inducing activity potentially endows mast cells a hitherto unrecognized role in the regulation of innate immune reactions in atherogenesis.

  12. "Gum bug, leave my heart alone!"--epidemiologic and mechanistic evidence linking periodontal infections and atherosclerosis.

    Science.gov (United States)

    Kebschull, M; Demmer, R T; Papapanou, P N

    2010-09-01

    Evidence from epidemiologic studies suggests that periodontal infections are independently associated with subclinical and clinical atherosclerotic vascular disease. Although the strength of the reported associations is modest, the consistency of the data across diverse populations and a variety of exposure and outcome variables suggests that the findings are not spurious or attributable only to the effects of confounders. Analysis of limited data from interventional studies suggests that periodontal treatment generally results in favorable effects on subclinical markers of atherosclerosis, although such analysis also indicates considerable heterogeneity in responses. Experimental mechanistic in vitro and in vivo studies have established the plausibility of a link between periodontal infections and atherogenesis, and have identified biological pathways by which these effects may be mediated. However, the utilized models are mostly mono-infections of host cells by a limited number of 'model' periodontal pathogens, and therefore may not adequately portray human periodontitis as a polymicrobial, biofilm-mediated disease. Future research must identify in vivo pathways in humans that may (i) lead to periodontitis-induced atherogenesis, or (ii) result in treatment-induced reduction of atherosclerosis risk. Data from these studies will be essential for determining whether periodontal interventions have a role in the primary or secondary prevention of atherosclerosis.

  13. Inflammation and coagulation in atherosclerosis.

    Science.gov (United States)

    Krychtiuk, K A; Kastl, S P; Speidl, W S; Wojta, J

    2013-01-01

    Cardiovascular diseases remain to be the leading cause of death in Western societies. Despite major findings in vascular biology that lead to a better understanding of the pathomechanisms involved in atherosclerosis, treatment of the disease has only changed slightly within the last years. A big body of evidence suggests that atherosclerosis is a chronic inflammatory disease of the vessel wall. Accumulation and peroxidation of LDL-particles within the vessel wall trigger a strong inflammatory response, causing macrophage and T-cell accumulation within the vessel wall. Additionally, B-cells and specific antibodies against LDL-particles, as well as the complement system are implicated in atherogenesis. Besides data from clinical trials and autopsy studies it was the implementation of mouse models of atherosclerosis and the emerging field of direct gen-modification that lead to a thorough description of the pathophysiological mechanisms involved in the disease and created overwhelming evidence for a participation of the immune system. Recently, the cross-talk between coagulation and inflammation in atherogenesis has gained attention. Serious limitations and disparities in the pathophysiology of atherosclerosis in mice and men complicated the translation of experimental data into clinical practice. Despite these limitations, new anti-inflammatory medical therapies in cardiovascular disease are currently being tested in clinical trials.

  14. Low-Density Lipoprotein Modified by Myeloperoxidase in Inflammatory Pathways and Clinical Studies

    Directory of Open Access Journals (Sweden)

    Cédric Delporte

    2013-01-01

    Full Text Available Oxidation of low-density lipoprotein (LDL has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNFα and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

  15. The genesis of atherosclerosis and risk factors: a review.

    Science.gov (United States)

    Tegos, T J; Kalodiki, E; Sabetai, M M; Nicolaides, A N

    2001-02-01

    Atherosclerosis constitutes the most common medical and surgical problem. This can be manifested clinically as stroke, coronary artery disease, or peripheral vascular disease. In the present review the microscopic appearance of the normal arterial wall, the definition of atherosclerosis and the five theories of atherogenesis are described. These are: the lipid theory, the hemodynamic theory, the fibrin incrustation theory, the nonspecific mesenchymal hypothesis and the response to injury hypothesis. Based on the above theories the sequence of events in atherogenesis is analyzed. The classification of the atherosclerotic lesions according to Stary (types I-VI) and their characteristics appear in a table. The epidemiology and the role of the following risk factors are presented in detail: age, sex, lipid abnormalities, cigarette smoking, hypertension, diabetes mellitus, physical inactivity, alcohol consumption, obesity, and hemostatic factors. In addition, less common genetically determined associations like homocystinuria, Tangier disease, Hutchinson-Gilford syndrome (progeria), Werner's syndrome, radiation induced atherosclerosis and the implications of Chlamydia pneumoniae on the arterial wall are discussed.

  16. C-peptide promotes lesion development in a mouse model of arteriosclerosis.

    Science.gov (United States)

    Vasic, Dusica; Marx, Nikolaus; Sukhova, Galina; Bach, Helga; Durst, Renate; Grüb, Miriam; Hausauer, Angelina; Hombach, Vinzenz; Rottbauer, Wolfgang; Walcher, Daniel

    2012-04-01

    Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C-peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C-peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C-peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide-treated mice contained significantly more macrophages (1.6 ± 0.3% versus 0.7 ± 0.2% positive area; P arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  17. Enzymatically Modified Low-Density Lipoprotein Is Recognized by C1q and Activates the Classical Complement Pathway

    Directory of Open Access Journals (Sweden)

    Gérard J. Arlaud

    2011-01-01

    Full Text Available Several studies suggest that the complement system is involved in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of LDL to bind and activate C1, the complex protease that triggers the classical pathway of complement. Unlike native LDL, oxidized (oxLDL and enzymatically modified (E-LDL derivatives were both recognized by the C1q subunit of C1, but only E-LDL particles, obtained by sequential treatment with a protease and then with cholesterol esterase, had the ability to trigger C1 activation. Further investigations revealed that C1q recognizes a lipid component of E-LDL. Several approaches, including reconstitution of model lipid vesicles, cosedimentation, and electron microscopy analyses, provided evidence that C1 binding to E-LDL particles is mediated by the C1q globular domain, which senses unesterified fatty acids generated by cholesterol esterase. The potential implications of these findings in atherogenesis are discussed.

  18. The role of inflammatory and immunological mediators in periodontitis and cardiovascular disease.

    Science.gov (United States)

    De Nardin, E

    2001-12-01

    Epidemiological studies have implicated periodontitis (PD) as a risk factor for development of cardiovascular disease (CVD). Persistent infections such as periodontitis induce inflammatory and immune responses which may contribute to coronary atherogenesis, and, in conjunction with other risk factors, may lead to coronary heart disease (CHD). In this review, mechanisms are described that may help explain the association between periodontal infections and CHD. Periodontal diseases are bacterial infections associated with bacteremia, inflammation, and a strong immune response, all of which may represent significant risk factors for the development of atherogenesis, CHD, and myocardial infarction (MI). Several mechanisms may participate in this association, including those induced by oral organisms, and those associated with host response factors. This review will focus on host factors. Oral pathogens and inflammatory mediators (such as interleukin [IL]-1 and tumor necrosis factor [TNF]-alpha) from periodontal lesions intermittently reach the bloodstream inducing systemic inflammatory reactants such as acute-phase proteins, and immune effectors including systemic antibodies to periodontal bacteria. This review will describe the potential role of various inflammatory as well as immunologic factors that may play a role in periodontitis as a possible risk factor for CHD.

  19. Folic acid attenuates homocysteine and enhances antioxidative capacity in atherosclerotic rats.

    Science.gov (United States)

    Cui, Shanshan; Li, Wen; Lv, Xin; Wang, Pengyan; Huang, Guowei; Gao, Yuxia

    2017-10-01

    Atherosclerosis is a chronic disease that can seriously endanger human life. Folic acid supplementation modulates several disorders, including atherosclerosis, via its antiapoptotic and antioxidative properties. This study investigated whether folic acid alleviates atherogenesis by restoring homocysteine levels and antioxidative capacity in atherosclerosis Wistar rats. To this end, 28 Wistar rats were randomly divided into 4 groups (7 rats/group) as follows: (i) wild-type group, fed only the AIN-93 semi-purified rodent diet (folic acid: 2.1 mg/kg); (ii) high-fat + folic acid-deficient group (HF+DEF) (folic acid: 0.2 mg/kg); (iii) high-fat + normal folic acid group (folic acid: 2.1 mg/kg); and (iv) high-fat + folic acid-supplemented group (folic acid: 4.2 mg/kg). After 12 weeks, histopathological changes in the atherosclerotic lesions of the aortic arch were determined. In addition, serum folate levels, plasma homocysteine levels, plasma S-adenosyl-homocysteine levels, antioxidant status, oxidant status, and lipid profiles were evaluated. The results show aggravated atherosclerotic lesions in the HF+DEF group. Folic acid supplementation increased concentrations of serum folate. Further, folic acid supplementation increased high-density lipoprotein-cholesterol, decreased plasma homocysteine levels, and improved antioxidant capacity in atherogenic rats. These findings are consistent with the hypothesis that folic acid alleviates atherogenesis by reducing plasma homocysteine levels and improving antioxidant capacity in rats fed a high-fat diet.

  20. 7-Dehydrocholesterol (7-DHC), But Not Cholesterol, Causes Suppression of Canonical TGF-β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD).

    Science.gov (United States)

    Huang, Shuan Shian; Liu, I-Hua; Chen, Chun-Lin; Chang, Jia-Ming; Johnson, Frank E; Huang, Jung San

    2017-06-01

    For several decades, cholesterol has been thought to cause ASCVD. Limiting dietary cholesterol intake has been recommended to reduce the risk of the disease. However, several recent epidemiological studies do not support a relationship between dietary cholesterol and/or blood cholesterol and ASCVD. Consequently, the role of cholesterol in atherogenesis is now uncertain. Much evidence indicates that TGF-β, an anti-inflammatory cytokine, protects against ASCVD and that suppression of canonical TGF-β signaling (Smad2-dependent) is involved in atherogenesis. We had hypothesized that cholesterol causes ASCVD by suppressing canonical TGF-β signaling in vascular endothelium. To test this hypothesis, we determine the effects of cholesterol, 7-dehydrocholesterol (7-DHC; the biosynthetic precursor of cholesterol), and other sterols on canonical TGF-β signaling. We use Mv1Lu cells (a model cell system for studying TGF-β activity) stably expressing the Smad2-dependent luciferase reporter gene. We demonstrate that 7-DHC (but not cholesterol or other sterols) effectively suppresses the TGF-β-stimulated luciferase activity. We also demonstrate that 7-DHC suppresses TGF-β-stimulated luciferase activity by promoting lipid raft/caveolae formation and subsequently recruiting cell-surface TGF-β receptors from non-lipid raft microdomains to lipid rafts/caveolae where TGF-β receptors become inactive in transducing canonical signaling and undergo rapid degradation upon TGF-β binding. We determine this by cell-surface 125 I-TGF-β-cross-linking and sucrose density gradient ultracentrifugation. We further demonstrate that methyl-β-cyclodextrin (MβCD), a sterol-chelating agent, reverses 7-DHC-induced suppression of TGF-β-stimulated luciferase activity by extrusion of 7-DHC from resident lipid rafts/caveolae. These results suggest that 7-DHC, but not cholesterol, promotes lipid raft/caveolae formation, leading to suppression of canonical TGF-β signaling and atherogenesis. J

  1. Apolipoprotein B levels, APOB alleles, and risk of ischemic cardiovascular disease in the general population, a review

    DEFF Research Database (Denmark)

    Benn, Marianne

    2009-01-01

    . The present review examines, with focus on general population studies, apolipoprotein B levels as a predictor of ischemic cardiovascular disease, as well as the association of mutations and polymorphisms in APOB with plasma apolipoprotein B levels, and risk of ischemic cardiovascular disease. The studies can...... be summarized as follows: (1) apolipoprotein B predicts ischemic cardiovascular events in both genders, and is better than LDL cholesterol in this respect; (2) linkage disequilibrium structure in APOB is more complex than expected from HapMap data, because a minimal set of tag single nucleotide polymorphisms......Apolipoprotein B is a key component in lipid metabolism. Subendothelial retention of apolipoprotein B containing lipoproteins is a necessary initiating event in atherogenesis, and high plasma levels of apolipoprotein B is a risk factor for atherosclerosis, whereas low levels may provide protection...

  2. Surfactant protein D is proatherogenic in mice

    DEFF Research Database (Denmark)

    Sorensen, Grith L; Madsen, Jens; Kejling, Karin

    2006-01-01

    Surfactant protein D (SP-D) is an important innate immune defense molecule that mediates clearance of pathogens and modulates the inflammatory response. Moreover, SP-D is involved in lipid homeostasis, and pulmonary accumulation of phospholipids has previously been observed in SP-D-deficient (Spd......-/-) mice. Atherogenesis involves both inflammation and lipid deposition, and we investigated the role of SP-D in the development of atherosclerosis. SP-D synthesis was localized to vascular endothelial cells. Atherosclerotic lesion areas were 5.6-fold smaller in the aortic roots in Spd-/- mice compared...... with wild-type C57BL/6N mice on an atherogenic diet. HDL cholesterol (HDL-C) was significantly elevated in Spd-/- mice. Treatment of Spd-/- mice with a recombinant fragment of human SP-D resulted in decreases of HDL-C (21%) as well as total cholesterol (26%), and LDL cholesterol (28%). Plasma TNF...

  3. The Gut Microbiota and Atherosclerosis: The State of the Art and Novel Perspectives

    Directory of Open Access Journals (Sweden)

    Giulio La Rosa

    2016-09-01

    Full Text Available The human gut microbiota is composed of more than 100 trillion microbes. Most communities are dominated by species belonging to the phyla Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia. Microflora-derived short-chain fatty acids play a pivotal role in the framework of insulin resistance, obesity, and metabolic syndrome. They are an important energy source and are involved in several pathways, with proatherogenic and antiatherogenic effects. The increased gut microbiota lipopolysaccharide levels (defined as “metabolic endotoxemia” induce a state of low-grade inflammation and are involved in atherosclerotic disease through Toll-like receptor 4. Another important inflammatory trigger in gut microbiota–mediated atherosclerotic promotion is trimethylamine N-oxide. On the other hand, protocatechuic acid was found to promote cholesterol efflux from macrophages, showing an antiatherogenic effect. Further studies to clarify specific gut composition involved in cardiometabolic syndrome and atherogenesis are needed for greater use of targeted approaches.

  4. Role of gut microbiota in atherosclerosis

    DEFF Research Database (Denmark)

    Jonsson, Annika Lindskog; Bäckhed, Gert Fredrik

    2017-01-01

    describe three pathways by which microbiota might affect atherogenesis. First, local or distant infections might cause a harmful inflammatory response that aggravates plaque development or triggers plaque rupture. Second, metabolism of cholesterol and lipids by gut microbiota can affect the development...... of atherosclerotic plaques. Third, diet and specific components that are metabolized by gut microbiota can have various effects on atherosclerosis; for example, dietary fibre is beneficial, whereas the bacterial metabolite trimethylamine-N-oxide is considered harmful. Although specific bacterial taxa have been......Infections have been linked to the development of cardiovascular disease and atherosclerosis. Findings from the past decade have identified microbial ecosystems residing in different habitats of the human body that contribute to metabolic and cardiovascular-related disorders. In this Review, we...

  5. Distinct Functions of Specialized Dendritic Cell Subsets in Atherosclerosis and the Road Ahead

    Directory of Open Access Journals (Sweden)

    Alma Zernecke

    2014-01-01

    Full Text Available Atherosclerotic vascular disease is modulated by immune mechanisms. Dendritic cells (DCs and T cells are present within atherosclerotic lesions and function as central players in the initiation and modulation of adaptive immune responses. In previous years, we have studied the functional contribution of distinct DC subsets in disease development, namely, that of CCL17-expressing DCs as well as that of plasmacytoid DCs that play specialized roles in disease development. This review focuses on important findings gathered in these studies and dissects the multifaceted contribution of CCL17-expressing DCs and pDCs to the pathogenesis of atherosclerosis. Furthermore, an outlook on future challenges faced when studying DCs in this detrimental disease are provided, and hurdles that will need to be overcome in order to enable a better understanding of the contribution of DCs to atherogenesis are discussed, a prerequisite for their therapeutic targeting in atherosclerosis.

  6. The influence of angiotensin-(1-7) Mas receptor agonist (AVE 0991) on mitochondrial proteome in kidneys of apoE knockout mice.

    Science.gov (United States)

    Suski, Maciej; Olszanecki, Rafał; Stachowicz, Aneta; Madej, Józef; Bujak-Giżycka, Beata; Okoń, Krzysztof; Korbut, Ryszard

    2013-12-01

    Excessive action of angiotensin II on mitochondria has been shown to play an important role in mitochondrial dysfunction, a common feature of atherogenesis and kidney injury. Angiotensin-(1-7)/Mas receptor axis constitutes a countermeasure to the detrimental effects of angiotensin II on AT1 receptors. The aim of the study was to assess the effects of angiotensin-(1-7) peptidomimetic AVE0991 on the kidney mitochondrial proteome in widely used animal model of atherosclerosis (apoE(-/-) mice). Proteins changed in apoE(-/-) mice belonged to the groups of antioxidant enzymes, apoptosis regulators, inflammatory factors and metabolic enzymes. Importantly, AVE0991 partially reversed atherosclerosis-related changes in apoE(-/-) mice. © 2013.

  7. Mannose 6-phosphate receptor and sortilin mediated endocytosis of α-galactosidase A in kidney endothelial cells

    DEFF Research Database (Denmark)

    Prabakaran, Thaneas; Nielsen, Rikke Skovgaard; Satchell, Simon C

    2012-01-01

    Prominent vasculopathy in Fabry disease patients is caused by excessive intracellular accumulation of globotriaosylceramide (GL-3) throughout the vascular endothelial cells causing progressive cerebrovascular, cardiac and renal impairments. The vascular lesions lead to myocardial ischemia......, atherogenesis, stroke, aneurysm, thrombosis, and nephropathy. Hence, injury to the endothelial cells in the kidney is a key mechanism in human glomerular disease and endothelial cell repair is an important therapeutic target. We investigated the mechanism of uptake of α-galactosidase A (α-Gal A) in renal...... endothelial cells, in order to clarify if the recombinant enzyme is targeted to the lysosomes via the universal mannose 6-phosphate receptor (M6PR) and possibly other receptors. Immunohistochemical localization of infused recombinant α-Gal A in a renal biopsy from a classic Fabry disease patient showed...

  8. Inhibition of cytokine-induced vascular cell adhesion molecule-1 expression; possible mechanism for anti-atherogenic effect of Agastache rugosa.

    Science.gov (United States)

    Hong, J J; Choi, J H; Oh, S R; Lee, H K; Park, J H; Lee, K Y; Kim, J J; Jeong, T S; Oh, G T

    2001-04-27

    Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) play an important role during the early stages of atherogenesis. Agastache rugosa has an anti-atherogenic effect in low density lipoprotein receptor -/- mice. Moreover, A. rugosa reduced macrophage infiltration and VCAM-1 expression has been localized in aortic endothelium that overlies early foam cell lesions. This study ascertained that tilianin (100 microM), a major component of A. rugosa, inhibits the tumor necrotic factor-alpha (TNF-alpha)-induced expression of VCAM-1 by 74% in cultured human umbilical vein endothelial cells (HUVECs). Also, tilianin (100 microM) reduced TNF-alpha-induced activation of nuclear factor-kappaB in HUVECs.

  9. Influence of virtual intervention and blood rheology on mass transfer through thoracic aortic aneurysm.

    Science.gov (United States)

    Lei, Yu; Chen, Ming; Xiong, Guanglei; Chen, Jie

    2015-09-18

    Computational fluid dynamics tools have been used to investigate blood flow through the human thoracic aortic models with aneurysm before and after virtual stent graft operation. The impact of blood rheology and aortic geometry on the wall shear stress (WSS), luminal surface low-density lipoproteins (LDL) concentration, and oxygen flux along the arterial wall is investigated. The stent graft at the aneurysm has significant effects on WSS and mass transport in blood flow. Due to the low flow rate, Newtonian blood assumption generally under-estimates the WSS. The non-Newtonian blood rheology play an important role in the LDL transport as well as oxygen transport. It is found that WSS alone is insufficient to correctly predict the location with high risk of atherogenesis. The results suggest that WSS, luminal surface LDL concentration, and the oxygen flux on the wall have to be considered together to evaluate the performance of virtual operation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. [Osteoporosis and aterosclerosis--is there any pathogenetic association?].

    Science.gov (United States)

    Zofková, I

    2007-01-01

    Fundamental cytokine regulating remodelation of the skeleton is receptor activator of nuclear factor kappa B ligand (RANKL). RANKL is counter regulated by soluble receptor osteoprotegerin (OPG). While RANKL activates osteoclastic bone resorption, the OPG stimulates bone formation. RANKL/OPG system (TRANCE axis) is activated in favour of RANKL in estrogen deficiency, inflammation, bone malignancies and during the treatment with glucocorticoids. TRANCE axis is functional also in other tissues including vessel wall, where dysbalance with superiority of RANKL leads to atherogenesis. Molecules blocking RANKL (specific antibodies and OPG) are potential drugs for treatment of osteoporosis, atherosclerosis, inflammation diseases, myeloma or osteolytic bone metastases. This review is focused on pathogenetic role of TRANCE axis in the development of osteoporosis and atherosclerosis and on its use in diagnosis and treatment of both degenerative diseases.

  11. Surfactant protein D is proatherogenic in mice

    DEFF Research Database (Denmark)

    Sorensen, Grith L; Madsen, Jens; Kejling, Karin

    2006-01-01

    -/-) mice. Atherogenesis involves both inflammation and lipid deposition, and we investigated the role of SP-D in the development of atherosclerosis. SP-D synthesis was localized to vascular endothelial cells. Atherosclerotic lesion areas were 5.6-fold smaller in the aortic roots in Spd-/- mice compared...... with wild-type C57BL/6N mice on an atherogenic diet. HDL cholesterol (HDL-C) was significantly elevated in Spd-/- mice. Treatment of Spd-/- mice with a recombinant fragment of human SP-D resulted in decreases of HDL-C (21%) as well as total cholesterol (26%), and LDL cholesterol (28%). Plasma TNF......-alpha was reduced in Spd-/- mice (45% difference). SP-D was proatherogenic in the mouse model used. The effect is likely to be due to the observed disturbances of plasma lipid metabolism and alteration of the inflammatory process, which underlie the reduced susceptibility to atherosclerosis in Spd-/- mice....

  12. [Obstructive sleep apnea syndrome in patients with chronic obstructive pulmonary disorder].

    Science.gov (United States)

    Markin, A V; Martynenko, T I; Tseĭmakh, I Ia; Shoĭkhet, Ia N

    2012-01-01

    Sleep obstructive apnea syndrome (SOAS) is a life-threatening respiratory disorder. Its combination with COPD further deteriorates respiratory distress and accelerates the development of pulmonary hypertension (crossover syndrome). Systemic inflammation with concomitant oxidative stress in patients with SOAS and COPD suggests their influence on the development of circulatory disorders. Night-time cyclic hypoxia in patients with SOAS triggers systemic inflammation, oxidative stress, and atherogenesis which accounts for the frequent complications more severe in combination of SOAS and COPD than in either of these diseases. Intermittent hypoxia in patients with SOAS is associated with hypoventilation resulting from COPD, deteriorates clinical conditions of the patients, and requires the choice of specific methods of respiratory support.

  13. Are suppressors of cytokine signaling proteins recently identified in atherosclerosis possible therapeutic targets?

    Science.gov (United States)

    Tang, Jingjing; Raines, Elaine W

    2005-10-01

    Atherosclerosis is a slowly progressing chronic inflammatory disease characterized by focal arterial lesions that can ultimately occlude the entire blood vessel and lead to sudden death. Lesions associated with cardiovascular events are those enriched in macrophages and other inflammatory cells. Activation of inflammatory cells within lesions induces the release of cytokines which promotes more inflammation and associated tissue damage if cytokine signaling pathways remain unregulated. Thus, pathways capable of suppressing proinflammatory cytokine signaling hold the potential to limit life-threatening cardiovascular events caused by atherogenesis. This review focuses on suppressors of cytokine signaling proteins recently identified in the atherosclerosis-prone ApoE(-/-) mouse and provides perspectives of their potential for intervention in atherosclerotic lesion progression.

  14. PGE2, Kidney Disease, and Cardiovascular Risk: Beyond Hypertension and Diabetes

    Science.gov (United States)

    Nasrallah, Rania; Hassouneh, Ramzi

    2016-01-01

    An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE2 in these events. This review summarizes the role of PGE2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE2 signaling in hypertension and diabetes, and outlines the contribution of PGE2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE2 could lead to new avenues to improve therapeutic options and disease management strategies. PMID:26319242

  15. Uremia modulates the phenotype of aortic smooth muscle cells

    DEFF Research Database (Denmark)

    Madsen, Marie; Pedersen, Annemarie Aarup; Albinsson, Sebastian

    2017-01-01

    BACKGROUND AND AIMS: Chronic kidney disease leads to uremia and markedly accelerates atherosclerosis. Phenotypic modulation of smooth muscle cells (SMCs) in the arterial media plays a key role in accelerating atherogenesis. The aim of this study was to investigate whether uremia per se modulates...... the phenotype of aortic SMCs in vivo. METHODS: Moderate uremia was induced by 5/6 nephrectomy in apolipoprotein E knockout (ApoE(-/-)) and wildtype C57Bl/6 mice. Plasma analysis, gene expression, histology, and myography were used to determine uremia-mediated changes in the arterial wall. RESULTS: Induction...... in the aortic media. In the aortic arch, mRNA and miRNA expression patterns were consistent with a uremia-mediated phenotypic modulation of SMCs; e.g. downregulation of myocardin, α-smooth muscle actin, and transgelin; and upregulation of miR146a. Notably, these expression patterns were observed after acute (2...

  16. Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins.

    Science.gov (United States)

    Haka, Abigail S; Grosheva, Inna; Chiang, Ethan; Buxbaum, Adina R; Baird, Barbara A; Pierini, Lynda M; Maxfield, Frederick R

    2009-12-01

    A critical event in atherogenesis is the interaction of macrophages with subendothelial lipoproteins. Although most studies model this interaction by incubating macrophages with monomeric lipoproteins, macrophages in vivo encounter lipoproteins that are aggregated. The physical features of the lipoproteins require distinctive mechanisms for their uptake. We show that macrophages create an extracellular, acidic, hydrolytic compartment to carry out digestion of aggregated low-density lipoproteins. We demonstrate delivery of lysosomal contents to these specialized compartments and their acidification by vacuolar ATPase, enabling aggregate catabolism by lysosomal acid hydrolases. We observe transient sealing of portions of the compartments, allowing formation of an "extracellular" proton gradient. An increase in free cholesterol is observed in aggregates contained in these compartments. Thus, cholesteryl ester hydrolysis can occur extracellularly in a specialized compartment, a lysosomal synapse, during the interaction of macrophages with aggregated low-density lipoprotein. A detailed understanding of these processes is essential for developing strategies to prevent atherosclerosis.

  17. A Case of Severe Carotid Stenosis in a Patient with Familial Hypercholesterolemia without Significant Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Marcos Aurélio Lima Barros

    2014-01-01

    Full Text Available Familial hypercholesterolemia (FH is an inherited metabolic disorder characterized by elevated low-density lipoprotein cholesterol levels in the blood. In its heterozygous form, it occurs in 1 in 500 individuals in the general population. It is an important contributor to the early onset of coronary artery disease (CAD, accounting for 5–10% of cases of cardiovascular events in people younger than 50 years. Atherogenesis triggered by hypercholesterolemia generally progresses faster in the coronary arteries, followed by the subsequent involvement of other arteries such as the carotids. Thus, symptoms of CAD commonly appear before the onset of significant carotid stenosis. Herein, we report the case of a patient with untreated FH who had severe carotid atherosclerosis at the age of 46 years but had no evidence of significant CAD.

  18. Mechanisms of Lethal Cerebrovascular Accidents in Turner Syndrome.

    Science.gov (United States)

    Byard, Roger W

    2016-05-01

    A case of intracerebral hemorrhage in Turner syndrome is reported with an analysis of possible causes of cerebrovascular accidents in this condition. A 42-year-old woman with known Turner syndrome died soon after hospital admission having been found unconscious at her home address. At autopsy, she showed typical features of Turner syndrome with short stature, webbing of the neck, underdeveloped breasts, and an increased carrying angle of the arm. Death was due to a large left-sided intracerebral hemorrhage extending from the left basal ganglia into the white matter of the frontal lobe and lateral ventricle. Cases of unexpected death in Turner syndrome may arise from occult cerebrovascular accidents which may be hemorrhagic or nonhemorrhagic. Associated features include hypertension, vascular malformations, accelerated atherogenesis, cystic medial necrosis, and moyamoya syndrome. The possibility of Turner syndrome should be considered in cases where there has been a lethal cerebrovascular event in a younger woman. © 2016 American Academy of Forensic Sciences.

  19. Nonfasting hyperlipidemia and cardiovascular disease

    DEFF Research Database (Denmark)

    Nordestgaard, B G; Langsted, A; Freiberg, J J

    2009-01-01

    Most humans are in the nonfasting or postprandial state in the majority of a 24 hour cycle; however, lipids, lipoproteins, and apolipoproteins are usually measured in the fasting state. Recent studies demonstrate that these values at most change minimally in response to normal food intake, changes...... that are clinically unimportant. Also, elevated levels of nonfasting triglycerides as a marker of elevated remnant lipoprotein cholesterol associate strongly with increased risk of myocardial infarction, ischemic stroke, and early death. The mechanism behind these findings likely involves entrance of remnant...... lipoproteins into the arterial intima with subsequent retention leading to atherogenesis, while low HDL cholesterol levels may be an innocent bystander. Finally, nonfasting levels of total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, HDL cholesterol, apolipoprotein A1...

  20. Protective properties of artichoke (Cynara scolymus) against oxidative stress induced in cultured endothelial cells and monocytes.

    Science.gov (United States)

    Zapolska-Downar, Danuta; Zapolski-Downar, Andrzej; Naruszewicz, Marek; Siennicka, Aldona; Krasnodebska, Barbara; Kołdziej, Blanka

    2002-11-01

    It is currently believed that oxidative stress and inflammation play a significant role in atherogenesis. Artichoke extract exhibits hypolipemic properties and contains numerous active substances with antioxidant properties in vitro. We have studied the influence of aqueous and ethanolic extracts from artichoke on intracellular oxidative stress stimulated by inflammatory mediators (TNFalpha and LPS) and ox-LDL in endothelial cells and monocytes. Oxidative stress which reflects the intracellular production of reactive oxygen species (ROS) was followed by measuring the oxidation of 2', 7'-dichlorofluorescin (DCFH) to 2', 7'-dichlorofluorescein (DCF). Agueous and ethanolic extracts from artichoke were found to inhibit basal and stimulated ROS production in endothelial cells and monocytes in dose dependent manner. In endothelial cells, the ethanolic extract (50 microg/ml) reduced ox-LDL-induced intracellular ROS production by 60% (partichoke extracts have marked protective properties against oxidative stress induced by inflammatory mediators and ox-LDL in cultured endothelial cells and monocytes.

  1. Roles of xenobiotic receptors in vascular pathophysiology.

    Science.gov (United States)

    Xiao, Lei; Zhang, Zihui; Luo, Xiaoqin

    2014-01-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR), 2 closely related and liver-enriched members of the nuclear receptor superfamily, and aryl hydrocarbon receptor (AhR), a nonnuclear receptor transcription factor (TF), are major receptors/TFs regulating the expression of genes for the clearance and detoxification of xenobiotics. They are hence defined as "xenobiotic receptors". Recent studies have demonstrated that PXR, CAR and AhR also regulate the expression of key proteins involved in endobiotic responses such as the metabolic homeostasis of lipids, glucose, and bile acid, and inflammatory processes. It is suggested that the functions of PXR, CAR and AhR may be closely implicated in the pathogeneses of metabolic vascular diseases, such as hyperlipidemia, atherogenesis, and hypertension. Therefore, manipulation of the activities of these receptors may provide novel strategies for the treatment of vascular diseases. Here, we review the pathophysiological roles of PXR, CAR and AhR in the vascular system.

  2. The HDL paradox: what does it mean and how to manage low serum HDL cholesterol level?

    Science.gov (United States)

    Cybulska, Barbara; Kłosiewicz-Latoszek, Longina

    2014-01-01

    The topic of this article is an important practical lipidologic issue, along with familial hypercholesterolaemia and severe hypertriglyceridaemia which have also been recently reviewed in the Polish literature. In this paper, we attempted to summarise current scientific evidence and views on the complex role of HDL in atherogenesis, as well as therapeutic recommendations in patients with low HDL-C level. In summary, it should be noted that the available evidence does not indicate that HDL are not antiatherogenic lipoproteins but rather directs our attention towards their functionality and dysfunctionality accompanying numerous pathologic conditions associated with inflammation. It may be hoped that effective methods to increase the number of functional HDL in the plasma will be developed in future studies, translating to a reduction in CV events and thus deserving a place in clinical practice guidelines.

  3. Macrophages, Dendritic Cells, and Regression of Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Jonathan E. Feig

    2012-07-01

    Full Text Available Atherosclerosis is the number one cause of death in the Western world. It results from the interaction between modified lipoproteins and monocyte-derived cells such as macrophages, dendritic cells, T cells, and other cellular elements of the arterial wall. This inflammatory process can ultimately lead to the development of complex lesions, or plaques, that protrude into the arterial lumen. Ultimately, plaque rupture and thrombosis can occur leading to the clinical complications of myocardial infarction or stroke. Although each of the cell types plays roles in the pathogenesis of atherosclerosis, in this review, the focus will be primarily on the monocyte derived cells- macrophages and dendritic cells. The roles of these cell types in atherogenesis will be highlighted. Finally, the mechanisms of atherosclerosis regression as it relates to these cells will be discussed.

  4. Senescent intimal foam cells are deleterious at all stages of atherosclerosis.

    Science.gov (United States)

    Childs, Bennett G; Baker, Darren J; Wijshake, Tobias; Conover, Cheryl A; Campisi, Judith; van Deursen, Jan M

    2016-10-28

    Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis. Copyright © 2016, American Association for the Advancement of Science.

  5. Redox regulation of a novel L1Md-A2 retrotransposon in vascular smooth muscle cells.

    Science.gov (United States)

    Lu, Kim P; Ramos, Kenneth S

    2003-07-25

    Activation and reintegration of retrotransposons into the genome is linked to several diseases in human and rodents, but mechanisms of gene activation remain largely unknown. Here we identify a novel gene of L1Md-A2 lineage in vascular smooth muscle cells and show that environmental hydrocarbons enhance gene expression and activate monomer-driven transcription via a redox-sensitive mechanism. Site-directed mutagenesis and progressive deletion analyses identified two antioxidant/electrophile response-like elements (5'-GTGACTCGAGC-3') within the A2/3 and A3 region. These elements mediated activation, with the A3 monomer playing an essential role in transactivation. This signaling pathway may contribute to gene instability during the course of atherogenesis.

  6. Multilevel systems biology modeling characterized the atheroprotective efficiencies of modified dairy fats in a hamster model.

    Science.gov (United States)

    Martin, Jean-Charles; Berton, Amélie; Ginies, Christian; Bott, Romain; Scheercousse, Pierre; Saddi, Alessandra; Gripois, Daniel; Landrier, Jean-François; Dalemans, Daniel; Alessi, Marie-Christine; Delplanque, Bernadette

    2015-09-01

    We assessed the atheroprotective efficiency of modified dairy fats in hyperlipidemic hamsters. A systems biology approach was implemented to reveal and quantify the dietary fat-related components of the disease. Three modified dairy fats (40% energy) were prepared from regular butter by mixing with a plant oil mixture, by removing cholesterol alone, or by removing cholesterol in combination with reducing saturated fatty acids. A plant oil mixture and a regular butter were used as control diets. The atherosclerosis severity (aortic cholesteryl-ester level) was higher in the regular butter-fed hamsters than in the other four groups (P fat. Under conditions that promote atherosclerosis, the impact of dairy fats on atherogenesis could be greatly ameliorated by technological modifications. Our modeling approach allowed for identifying and quantifying the contribution of complex factors to atherogenic development in each dietary setup. Copyright © 2015 the American Physiological Society.

  7. Alcohol and atherosclerosis

    Directory of Open Access Journals (Sweden)

    Foppa Murilo

    2001-01-01

    Full Text Available Observational studies have attributed a protective effect to alcohol consumption on the development of atherosclerosis and cardiovascular morbidity and mortality. Alcohol intake in the amount of one to two drinks per day results in an estimated 20-40% reduction in cardiovascular events. An additional protective effect, according to major cohort studies, has been attributed to wine, probably due to antioxidant effects and platelet antiaggregation agents. On the other hand, the influence of different patterns of alcohol consumption and environmental factors may explain a great part of the additional effect of wine. Protection may be mediated by modulation of other risk factors, because alcohol increases HDL-C, produces a biphasic response on blood pressure, and modulates the endothelial function, while it neither increases body weight nor impairs glucose-insulin homeostasis. Alcohol may also have a direct effect on atherogenesis. Despite these favorable effects, the current evidence is not enough to justify prescribing alcohol to prevent cardiovascular disease.

  8. The dynamic lives of macrophage and dendritic cell subsets in atherosclerosis

    Science.gov (United States)

    Taghavie-Moghadam, Paresa L.; Butcher, Matthew J.; Galkina, Elena V.

    2014-01-01

    Atherosclerosis, the major pathological process through which arterial plaques are formed, is a dynamic chronic inflammatory disease of large and medium sized arteries in which the vasculature, lipid metabolism, and the immune system all play integral roles. Both the innate and adaptive immune systems are involved in the development and progression of atherosclerosis but myeloid cells represent the major component of the burgeoning atherosclerotic plaque. Various myeloid cells, including monocytes, macrophages, and dendritic cells can be found within the healthy and atherosclerotic arterial wall, where they can contribute to or regulate inflammation. However, the precise behaviors and functions of these cells in situ are still active areas of investigation that continue to yield exciting and surprising new data. Here, we review recent progress in understanding of the complex biology of macrophages and dendritic cells, focusing particularly on the dynamic regulation of these subsets in the arterial wall and novel, emerging functions of these cells during atherogenesis. PMID:24628328

  9. A review about biomarkers for the investigation of vascular function and impairment in diabetes mellitus.

    Science.gov (United States)

    Derosa, Giuseppe; Maffioli, Pamela

    2016-01-01

    The aim of this review was to analyze the main biomarkers of vascular function and impairment in patients with type 2 diabetes. Medline, SCOPUS, Web of Science, and Google Scholar databases were searched. We concluded that proatherogenic adhesion molecules (soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and soluble E selectin) and inflammatory cytokines (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α) were elevated in type 2 diabetes mellitus. Their increased expression and release contribute to the accelerated atherogenesis typical of these patients. For these reasons, the early identification of high levels of these biomarkers will help to establish new strategies to reduce cardiovascular complications.

  10. Role of RANKL-RANK/Osteoprotegerin Pathway in Cardiovascular and Bone Disease Associated with HIV Infection

    Science.gov (United States)

    Kelesidis, Theodoros; Currier, Judith S.; Yang, Otto O.; Brown, Todd T

    2016-01-01

    Patients with HIV-1 infection often develop multiple complications and comorbidities, including osteoporosis and atherosclerosis. The receptor activator of nuclear factor kappa-B/receptor activator of nuclear factor kappa-B ligand/osteoprotegerin axis has been identified as a possible common link between osteoporosis and vascular diseases. Since the discovery of this axis, much has been learned about its role in controlling skeletal biology and less about its role in the context of vascular biology. However, the exact role of the receptor activator of nuclear factor kappa-B ligand/osteoprotegerin axis in HIV infection is not completely understood. In this review we examine the mechanisms by which inflammation and immune dysregulation in HIV-1 infection may impact bone turnover and atherogenesis through perturbations in the receptor activator of nuclear factor kappa-B/receptor activator of nuclear factor kappa-B ligand/osteoprotegerin axis. PMID:25102334

  11. Mechanisms of endothelial dysfunction in obstructive sleep apnea

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    Amy Atkeson

    2008-12-01

    Full Text Available Amy Atkeson, Sanja JelicDivision of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NYAbstract: Endothelial activation and inflammation are important mediators of accelerated atherogenesis and consequent increased cardiovascular morbidity in obstructive sleep apnea (OSA. Repetitive episodes of hypoxia/reoxygenation associated with transient cessation of breathing during sleep in OSA resemble ischemia/reperfusion injury and may be the main culprit underlying endothelial dysfunction in OSA. Additional factors such as repetitive arousals resulting in sleep fragmentation and deprivation and individual genetic suseptibility to vascular manifestations of OSA contribute to impaired endothelial function in OSA. The present review focuses on possible mechanisms that underlie endothelial activation and inflammation in OSA.Keywords: endothelial, obstructive sleep apnea, inflammation, dysfunction

  12. Insulin Resistance: A Proinflammatory State Mediated by Lipid-Induced Signaling Dysfunction and Involved in Atherosclerotic Plaque Instability

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    François Mach

    2008-06-01

    Full Text Available The dysregulation of the insulin-glucose axis represents the crucial event in insulin resistance syndrome. Insulin resistance increases atherogenesis and atherosclerotic plaque instability by inducing proinflammatory activities on vascular and immune cells. This condition characterizes several diseases, such as type 2 diabetes, impaired glucose tolerance (IGT, impaired fasting glucose (IFG, obesity, hypertension, dyslipidemia, and other endocrinopathies, but also cancer. Recent studies suggest that the pathophysiology of insulin resistance is closely related to interferences with insulin-mediated intracellular signaling on skeletal muscle cells, hepatocytes, and adipocytes. Strong evidence supports the role of free fatty acids (FFAs in promoting insulin resistance. The FFA-induced activation of protein kinase C (PKC delta, inhibitor kappaB kinase (IKK, or c-Jun N-terminal kinase (JNK modulates insulin-triggered intracellular pathway (classically known as PI3-K-dependent. Therefore, reduction of FFA levels represents a selective target for modulating insulin resistance.

  13. Redox balance and blood elemental levels in atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Napoleao, P. [Centro de Biologia Ambiental and Departamento de Biologia Animal, Faculdade de Ciencias de Lisboa, C2, Campo Grande, 1749-016 Lisbon (Portugal) and Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. no 10, 2685-953 Sacavem (Portugal)]. E-mail: pnapoleao@itn.pt; Lopes, P.A. [Centro de Biologia Ambiental and Departamento de Biologia Animal, Faculdade de Ciencias de Lisboa, C2, Campo Grande, 1749-016 Lisbon (Portugal); Santos, M. [Centro de Quimica e Bioquimica and Departamento de Quimica e Bioquimica, Faculdade de Ciencias de Lisboa, 1749-016 Lisbon (Portugal); Steghens, J.-P. [Federation de Biochimie, Hopital Edouard Herriot, 3 Place d' Arsonval, 69437 03 Lyon (France); Viegas-Crespo, A.M. [Centro de Biologia Ambiental and Departamento de Biologia Animal, Faculdade de Ciencias de Lisboa, C2, Campo Grande, 1749-016 Lisbon (Portugal); Pinheiro, T. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. no 10, 2685-953 Sacavem (Portugal); Centro de Fisica Nuclear, Universidade de Lisboa, Av. Prof. Egas Moniz, 1700 Lisbon (Portugal)

    2006-08-15

    Oxidation of lipids and proteins represents a causative event for atherogenesis, which can be opposed by antioxidant activity. Elements, such as, Fe, Cu, Zn and Se can be involved in both mechanisms. Thus, evaluation of blood elemental levels, easily detected by PIXE, and of redox parameters may be useful in assessing the risk of atherosclerosis. A group of stable patients suffering from atherosclerosis, was matched with a cohort of normo-tensive and -lipidemic volunteers. Although no major discrepancies were observed for trace elemental levels in blood, increased concentrations of K and Ca were found in atherosclerotic group. Patients presented enhance levels of antioxidant ({alpha}-tocopherol) and decreased of protein oxidation (protein carbonyls), while for the lipid oxidation marker (malondialdehyde) no variation was observed. This study contributes to a better understanding of atherosclerosis development and its relationship with blood elemental levels, and set basis for further clinical trials with pathological groups in acute phase.

  14. A New Approach to Determining the Rates of Recruitment of Circulating Leukocytes into Tissues: Application to the Measurement of Leukocyte Recruitment into Atherosclerotic Lesions

    Science.gov (United States)

    Steinberg, Daniel; Khoo, John C.; Glass, Christopher K.; Palinski, Wulf; Almazan, Felicidad

    1997-04-01

    Recruitment of circulating monocytes into the artery wall is an important feature of early atherogenesis. In vitro studies have identified a number of adhesion molecules and chemokines that may control this process but very little work has been done to evaluate their relative importance in vivo, in part because there have been no methods available of sufficient sensitivity and reliability. This paper proposes a new approach in which advantage is taken of naturally occurring or transgenically induced mutations to ``mark'' donor cells and to follow their fate in recipient animals using highly sensitive PCR methods. The feasibility of the approach is demonstrated by preliminary studies of monocyte recruitment into atherosclerotic lesions. However, the method should in principle be applicable to the study of any of the circulating leukocytes and their rate of entry into any tissue or tissues of interest.

  15. Hyper-coagulable profile with elevated pro-thrombotic biomarkers and increased cerebro- and cardio-vascular disease risk exist among healthy dyslipidemic women.

    Science.gov (United States)

    Ferreira, Cláudia N; Carvalho, Maria G; Reis, Helton J; Gomes, Karina B; Sousa, Marinez O; Palotás, András

    2014-05-01

    Dyslipidemia is one of the pathognomonic elements of athero-genesis, as well as cerebro- and cardio-vascular disease (CCVD). Hemostatic factors are also involved in athero-sclerosis and ischemic changes, however their relationship with disrupted lipid homeostasis is not well characterized. The aim of this study was to determine the coagulation state of dyslipidemic patients and to evaluate their association with CCVD risk factors. Biochemical and hematological parameters, as well as neuro-psychiatric profile of 109 dyslipidemic subjects and 107 normo-lipidic healthy volunteers were assessed. Serum bio-marker levels and cognitive performance generally did not differ in the groups, but prothrombin fragment 1+2 (F1+2) and D-dimer concentrations were markedly higher among women. Hyper-coagulability was not associated with dyslipidemia, but was correlated with the female gender, which might pose an increased thromboembolic risk in asymptomatic women.

  16. Microvascular inflammation in atherosclerosis

    Directory of Open Access Journals (Sweden)

    Laura Vitiello

    2014-06-01

    Full Text Available Atherogenesis is the pathogenetic process leading to formation of the atheroma lesion. It is associated to a chronic inflammatory state initially stimulated by an aberrant accumulation of lipid molecules beyond the endothelial barrier. This event triggers a cascade of deleterious events mainly through immune cell stimulation with the consequent liberation of potent pro-inflammatory and tissue damaging mediators. The atherogenetic process implies marked modifications of endothelial cell functions and a radical change in the endothelial–leukocyte interaction pattern. Moreover, accumulating evidence shows an important link between microvascular and inflammatory responses and major cardiovascular risk factors. This review illustrates the current knowledge on the effects of obesity, hypercholesterolemia and diabetes on microcirculation; their pathophysiological implications will be discussed.

  17. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.

    Science.gov (United States)

    Kojima, Yoko; Volkmer, Jens-Peter; McKenna, Kelly; Civelek, Mete; Lusis, Aldons Jake; Miller, Clint L; Direnzo, Daniel; Nanda, Vivek; Ye, Jianqin; Connolly, Andrew J; Schadt, Eric E; Quertermous, Thomas; Betancur, Paola; Maegdefessel, Lars; Matic, Ljubica Perisic; Hedin, Ulf; Weissman, Irving L; Leeper, Nicholas J

    2016-08-04

    Atherosclerosis is the disease process that underlies heart attack and stroke. Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Why these cells are not cleared remains unknown. Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or 'efferocytosis'. We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.

  18. Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets

    Science.gov (United States)

    Moss, Joe W. E.; Ramji, Dipak P.

    2017-01-01

    Atherosclerosis, the primary cause of cardiovascular disease (CVD), is a chronic inflammatory disorder in the walls of medium and large arteries. CVD is currently responsible for about one in three global deaths and this is expected to rise in the future due to an increase in the prevalence of obesity and diabetes. Current therapies for atherosclerosis mainly modulate lipid homeostasis and whilst successful at reducing the risk of a CVD-related death, they are associated with considerable residual risk and various side effects. There is therefore a need for alternative therapies aimed at regulating inflammation in order to reduce atherogenesis. This review will highlight the key role cytokines play during disease progression as well as potential therapeutic strategies to target them. PMID:27357616

  19. Atherogenic Factors and Their Epigenetic Relationships

    Directory of Open Access Journals (Sweden)

    Ana Z. Fernandez

    2010-01-01

    Full Text Available Hypercholesterolemia, homocysteine, oxidative stress, and hyperglycemia have been recognized as the major risk factors for atherogenesis. Their impact on the physiology and biochemistry of vascular cells has been widely demonstrated for the last century. However, the recent discovery of the role of epigenetics in human disease has opened up a new field in the study of atherogenic factors. Thus, epigenetic tags in endothelial, smooth muscle, and immune cells seem to be differentially affected by similar atherogenic stimuli. This paper summarizes some recent works on expression of histone-modifying enzymes and DNA methylation directly linked to the presence of risk factors that could lead to the development or prevention of the atherosclerotic process.

  20. Role of quercetin in cardiovascular diseases

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    Dr. Deepak Kumar Rai

    2008-01-01

    Full Text Available Cardiovascular disease constitutes a major public health concern in industrialized nations. Over recent decades, a large body of evidence has accumulated indicating that oxidative stress induced free radicals play a critical role in cellular processes implicated in atherosclerosis and many other heart diseases. However a diet high in antioxidants is associated with a reduced risk of cardiovascular disease. The compound quercetin is a dietary antioxidant with a polyphenolic structure that is present in many foods, such as onion, apples, wine and tea. An increased intake of quercetin has been correlated with a decrease in the risk of cardiovascular diseases. Quercetin has been reported to exhibit a wide range of biological and pharmacological effects in animals and man besides its antioxidative and free radical scavenging actions. This paper reviews various steps of oxidative stress mediated atherogenesis and their signaling pathways and also emphasizes the role of quercetin in controlling oxidative stress and reducing the incidence of cardiovascular diseases.

  1. The relationships between exogenous and endogenous antioxidants with the lipid profile and oxidative damage in hemodialysis patients

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    Brucker Natália

    2011-10-01

    Full Text Available Abstract Background We sought to investigate the relationships among the plasma levels of carotenoids, tocopherols, endogenous antioxidants, oxidative damage and lipid profiles and their possible effects on the cardiovascular risk associated with hemodialysis (HD patients. Methods The study groups were divided into HD and healthy subjects. Plasma carotenoid, tocopherol and malondialdehyde (MDA levels, as well as erythrocyte reduced glutathione (GSH, were measured by HPLC. Blood antioxidant enzymes, kidney function biomarkers and the lipid profiles were analyzed by spectrophotometric methods. Results Plasma lycopene levels and blood glutathione peroxidase (GPx activity were significantly decreased in HD patients compared with healthy subjects. Total cholesterol, low-density lipoprotein cholesterol (LDL-c, creatinine, urea, MDA, GSH, superoxide dismutase (SOD and catalase (CAT were significantly increased in HD (p Conclusions Lycopene may represent an additional factor that contributes to reduced lipid peroxidation and atherogenesis in hemodialysis patients.

  2. Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction

    DEFF Research Database (Denmark)

    O'Donoghue, Michelle L; Glaser, Ruchira; Cavender, Matthew A

    2016-01-01

    attenuates inflammation and may improve outcomes. OBJECTIVE: To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. DESIGN, SETTING, AND PATIENTS: LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel......IMPORTANCE: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod...... potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS: Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline...

  3. Race, infection, and arteriosclerosis in the past

    Science.gov (United States)

    Costa, Dora L.; Helmchen, Lorens A.; Wilson, Sven

    2007-01-01

    We document racial trends in chronic conditions among older men between 1910 and 2004. The 1910 black arteriosclerosis rate was six times higher than the white 2004 rate and more than two times higher than the 2004 black rate. We argue that blacks' greater lifelong burden of infection led to high arteriosclerosis rates in 1910. Infectious disease, especially respiratory infections at older ages and rheumatic fever and syphilis at younger ages, predicted arteriosclerosis in 1910, suggesting that arteriosclerosis has an infectious cause. Additional risk factors for arteriosclerosis were being born in the second relative to the fourth quarter, consistent with studies implying that atherogenesis begins in utero, and a low body mass index, consistent with an infectious disease origin of arteriosclerosis. PMID:17686992

  4. Regional gene expression of LOX-1, VCAM-1, and ICAM-1 in aorta of HIV-1 transgenic rats

    DEFF Research Database (Denmark)

    Hag, Anne Mette Fisker; Kristoffersen, Ulrik Sloth; Pedersen, Sune Folke

    2009-01-01

    endpoints, studies in animal models could be attractive alternatives. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated gene expression of lectin-like oxidized-low-density-lipoprotein receptor-1 (LOX-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in HIV-1...... transgenic (HIV-1Tg) rats; these genes are all thought to play important roles in early atherogenesis. Furthermore, the plasma level of sICAM-1 was measured. We found that gene expressions of LOX-1 and VCAM-1 were higher in the aortic arch of HIV-1Tg rats compared to controls. Also, the level of sICAM-1...... was elevated in the HIV-1Tg rats compared to controls, but the ICAM-1 gene expression profile did not show any differences between the groups. CONCLUSIONS/SIGNIFICANCE: HIV-1Tg rats have gene expression patterns indicating endothelial dysfunction and accelerated atherosclerosis in aorta, suggesting that HIV...

  5. Increased atherosclerosis in mice with increased vascular biglycan content.

    Science.gov (United States)

    Thompson, Joel C; Tang, Tao; Wilson, Patricia G; Yoder, Meghan H; Tannock, Lisa R

    2014-07-01

    The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development. Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4-12 weeks. LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content. Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development. Published by Elsevier Ireland Ltd.

  6. The role of the vascular dendritic cell network in atherosclerosis

    Science.gov (United States)

    Alberts-Grill, Noah; Denning, Timothy L.; Rezvan, Amir

    2013-01-01

    A complex role has been described for dendritic cells (DCs) in the potentiation and control of vascular inflammation and atherosclerosis. Resident vascular DCs are found in the intima of atherosclerosis-prone vascular regions exposed to disturbed blood flow patterns. Several phenotypically and functionally distinct vascular DC subsets have been described. The functional heterogeneity of these cells and their contributions to vascular homeostasis, inflammation, and atherosclerosis are only recently beginning to emerge. Here, we review the available literature, characterizing the origin and function of known vascular DC subsets and their important role contributing to the balance of immune activation and immune tolerance governing vascular homeostasis under healthy conditions. We then discuss how homeostatic DC functions are disrupted during atherogenesis, leading to atherosclerosis. The effectiveness of DC-based “atherosclerosis vaccine” therapies in the treatment of atherosclerosis is also reviewed. We further provide suggestions for distinguishing DCs from macrophages and discuss important future directions for the field. PMID:23552284

  7. Role and Function of MicroRNAs in Extracellular Vesicles in Cardiovascular Biology

    Directory of Open Access Journals (Sweden)

    Philipp Pfeifer

    2015-01-01

    Full Text Available Intercellular communication mediated by extracellular vesicles is crucial for preserving vascular integrity and in the development of cardiovascular disease. Extracellular vesicles consist of apoptotic bodies, microvesicles, and exosomes that can be found in almost every fluid compartment of the body like blood, saliva, and urine. In the recent years, a lot of reports came up suggesting that major cardiovascular and metabolic pathologies like atherogenesis, heart failure, or diabetes are highly influenced by transfer of microRNAs via extracellular vesicles leading to altered protein expression and phenotypes of recipient cells. The following review will summarize the fast developing field of intercellular signaling in cardiovascular biology by microRNA-containing extracellular vesicles.

  8. Fatty Acid binding protein 4 is associated with carotid atherosclerosis and outcome in patients with acute ischemic stroke.

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    Sverre Holm

    Full Text Available BACKGROUND AND PURPOSE: Fatty acid binding protein 4 (FABP4 has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke. METHODS: We examined plasma FABP4 levels in asymptomatic (n = 28 and symptomatic (n = 31 patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages. RESULTS: FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics. CONCLUSIONS: FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke.

  9. Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

    Science.gov (United States)

    Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

    2016-06-15

    Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Cardiovascular Protective Effects of Adjunctive Alternative Medicine (Salvia miltiorrhiza and Pueraria lobata in High-Risk Hypertension

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    K. S. Woo

    2013-01-01

    Full Text Available Introduction. Hypertension in association with diabetes (DM, renal impairment (RI, and left ventricular hypertrophy (LVH increases the risk of future cardiovascular events. We hypothesize, traditional herbal medicines Danshen and Gegen (D&G have beneficial effects on atherogenesis in these high-risk hypertensive subjects. Subjects and Methods. 90 asymptomatic hypertensive subjects associated with LVH (63.3%, DM (62.2%, or RI (30% were randomized to receive D&G herbal capsules 1 gm/day, 2 gm/day, or identical placebo capsules in double-blind and parallel fashion for 12 months. Brachial flow-mediated dilation (endothelium-dependent dilation, FMD and carotid intima-media thickness (IMT were measured by ultrasound. All data were analyzed using the Statistical Package for Social Sciences in Windows 16.0. Results. Their mean age was 55±8 years, and 74.4% were male. After 12 months of adjunctive therapies and compared with baseline, there were no significant changes in blood pressure, heart rate, hematological, glucose, and creatinine profiles in both placebo and D&G groups. FMD improved significantly during D&G (P=0.0001 and less so after placebo treatment (P=0.001. There was a mild but significant decrease in carotid IMT after D&G (P<0.001 but no significant changes after placebo. A trend of better improvement in FMD after higher versus lower D&G dosages was seen. D&G were well tolerated, with no significant adverse events or blood biochemistry changes. Conclusion. D&G adjunctive treatment was well tolerated and significantly improved atherogenesis in high-risk hypertensive patients, with potential in primary atherosclerosis prevention.

  11. Stimulatory interactions between human coronary smooth muscle cells and dendritic cells.

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    Sara Paccosi

    Full Text Available Despite inflammatory and immune mechanisms participating to atherogenesis and dendritic cells (DCs driving immune and non-immune tissue injury response, the interactions between DCs and vascular smooth muscle cells (VSMCs possibly relevant to vascular pathology including atherogenesis are still unclear. To address this issue, immature DCs (iDCs generated from CD14+ cells isolated from healthy donors were matured either with cytokines (mDCs, or co-cultured (ccDCs with human coronary artery VSMCs (CASMCs using transwell chambers. Co-culture induced DC immunophenotypical and functional maturation similar to cytokines, as demonstrated by flow cytometry and mixed lymphocyte reaction. In turn, factors from mDCs and ccDCs induced CASMC migration. MCP-1 and TNFα, secreted from DCs, and IL-6 and MCP-1, secreted from CASMCs, were primarily involved. mDCs adhesion to CASMCs was enhanced by CASMC pre-treatment with IFNγ and TNFα ICAM-1 and VCAM-1 were involved, since the expression of specific mRNAs for these molecules increased and adhesion was inhibited by neutralizing antibodies to the counter-receptors CD11c and CD18. Adhesion was also inhibited by CASMC pre-treatment with the HMG-CoA-reductase inhibitor atorvastatin and the PPARγ agonist rosiglitazone, which suggests a further mechanism for the anti-inflammatory action of these drugs. Adhesion of DCs to VSMCs was shown also in vivo in rat carotid 7 to 21 days after crush and incision injury. The findings indicate that DCs and VSMCs can interact with reciprocal stimulation, possibly leading to perpetuate inflammation and vascular wall remodelling, and that the interaction is enhanced by a cytokine-rich inflammatory environment and down-regulated by HMGCoA-reductase inhibitors and PPARγ agonists.

  12. Molecular mechanisms of irbesartan suppressing atherosclerosis in high cholesterol-diet apolipoprotein E knock-out mice.

    Science.gov (United States)

    Yao, Rui; Cheng, Xiang; Chen, Yong; Xie, Jiang-Jiao; Yu, Xian; Liao, Meng-Yang; Ding, Ying-Jun; Tang, Ting-Ting; Liao, Yu-Hua

    2010-03-04

    Atherosclerosis is a chronic inflammatory disease in which the renin-angiotensin-aldosterone system plays an important role. Evidence indicate that the angiotensin type 1 receptor blockers can suppress atherogenesis, but the exact mechanisms have not been fully elucidated. The study was undertaken to investigate the potential effects and molecular mechanisms of an angiotensin type 1 receptor blocker irbesartan on atherogenesis in high cholesterol-diet apolipoprotein E knock-out mice. Adult male apolipoprotein E knock-out mice were given normal diet or high cholesterol-diet and randomized to receive no treatment or irbesartan 10 mg kg(-1) d(-1) for 12 weeks. The apolipoprotein E knock-out mice with high cholesterol-diet were associated with a marked increase in atherosclerotic lesion area, plasma lipid and angiotensin II levels, as well as the expressions of angiotensin type 1 receptor in the aorta. High cholesterol-diet feeding increases the activity of NADPH oxidase subunits (p47(phox) and Rac), extracellular signal-regulated kinase 1/2, janus kinase 2, signal transducer and activator of transcription 3, nuclear factor-kappaB and the expression of tumor necrosis factor-alpha, interleukin 6, monocyte chemoattactant protein-1 and vascular cell adhesion molecule-1 in the aortas. These changes were suppressed in mice that were treated with irbesartan 10 mg kg(-1) d(-1), with no significant change in systolic blood pressure and plasma lipid levels. The results suggest that irbesartan can attenuate atherosclerosis, and this effect is partly related to the inhibition of oxidative stress and inflammatory signal transduction pathways which eventually leads to the decrease in the expression of inflammatory cytokines. Copyright 2008 Elsevier Ireland Ltd. All rights reserved.

  13. P2Y6 receptor potentiates pro-inflammatory responses in macrophages and exhibits differential roles in atherosclerotic lesion development.

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    Ricardo A Garcia

    Full Text Available BACKGROUND: P2Y(6, a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in pro-inflammatory responses of key vascular cell types and macrophages. Evidence for its involvement in atherogenesis, however, has been lacking. Here we use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y(6 deficiency on atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y(6 receptors, showed that exogenous expression of P2Y(6 induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y(6-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y(6 and in acute peritonitis models of inflammation. To evaluate the role of P2Y(6 in atherosclerotic lesion development, we used P2Y(6-deficient mice in three mouse models of atherosclerosis. A 43% reduction in aortic arch plaque was observed in high fat-fed LDLR knockout mice lacking P2Y(6 receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y(6xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y(6 deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice. CONCLUSIONS: P2Y(6 receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y(6 deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y(6 in vascular disease pathophysiologies, such as aneurysm formation.

  14. Cardiovascular Protective Effects of Adjunctive Alternative Medicine (Salvia miltiorrhiza and Pueraria lobata) in High-Risk Hypertension.

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    Woo, K S; Yip, Thomas W C; Chook, Ping; Kwong, S K; Szeto, C C; Li, June K Y; Yu, Alex W Y; Cheng, William K F; Chan, Thomas Y K; Fung, K P; Leung, P C

    2013-01-01

    Introduction. Hypertension in association with diabetes (DM), renal impairment (RI), and left ventricular hypertrophy (LVH) increases the risk of future cardiovascular events. We hypothesize, traditional herbal medicines Danshen and Gegen (D&G) have beneficial effects on atherogenesis in these high-risk hypertensive subjects. Subjects and Methods. 90 asymptomatic hypertensive subjects associated with LVH (63.3%), DM (62.2%), or RI (30%) were randomized to receive D&G herbal capsules 1 gm/day, 2 gm/day, or identical placebo capsules in double-blind and parallel fashion for 12 months. Brachial flow-mediated dilation (endothelium-dependent dilation, FMD) and carotid intima-media thickness (IMT) were measured by ultrasound. All data were analyzed using the Statistical Package for Social Sciences in Windows 16.0. Results. Their mean age was 55 ± 8 years, and 74.4% were male. After 12 months of adjunctive therapies and compared with baseline, there were no significant changes in blood pressure, heart rate, hematological, glucose, and creatinine profiles in both placebo and D&G groups. FMD improved significantly during D&G (P = 0.0001) and less so after placebo treatment (P = 0.001). There was a mild but significant decrease in carotid IMT after D&G (P < 0.001) but no significant changes after placebo. A trend of better improvement in FMD after higher versus lower D&G dosages was seen. D&G were well tolerated, with no significant adverse events or blood biochemistry changes. Conclusion. D&G adjunctive treatment was well tolerated and significantly improved atherogenesis in high-risk hypertensive patients, with potential in primary atherosclerosis prevention.

  15. The Upregulation of Integrin αDβ2 (CD11d/CD18) on Inflammatory Macrophages Promotes Macrophage Retention in Vascular Lesions and Development of Atherosclerosis.

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    Aziz, Moammir H; Cui, Kui; Das, Mitali; Brown, Kathleen E; Ardell, Christopher L; Febbraio, Maria; Pluskota, Elzbieta; Han, Juying; Wu, Huaizhu; Ballantyne, Christie M; Smith, Jonathan D; Cathcart, Martha K; Yakubenko, Valentin P

    2017-06-15

    Macrophage accumulation is a critical step during development of chronic inflammation, initiating progression of many devastating diseases. Leukocyte-specific integrin αDβ2 (CD11d/CD18) is dramatically upregulated on macrophages at inflammatory sites. Previously we found that CD11d overexpression on cell surfaces inhibits in vitro cell migration due to excessive adhesion. In this study, we have investigated how inflammation-mediated CD11d upregulation contributes to macrophage retention at inflammatory sites during atherogenesis. Atherosclerosis was evaluated in CD11d(-/-)/ApoE(-/-) mice after 16 wk on a Western diet. CD11d deficiency led to a marked reduction in lipid deposition in aortas and isolated macrophages. Macrophage numbers in aortic sinuses of CD11d(-/-) mice were reduced without affecting their apoptosis and proliferation. Adoptive transfer of fluorescently labeled wild-type and CD11d(-/-) monocytes into ApoE(-/-) mice demonstrated similar recruitment from circulation, but reduced accumulation of CD11d(-/-) macrophages within the aortas. Furthermore, CD11d expression was significantly upregulated on macrophages in atherosclerotic lesions and M1 macrophages in vitro. Interestingly, expression of the related ligand-sharing integrin CD11b was not altered. This difference defines their distinct roles in the regulation of macrophage migration. CD11d-deficient M1 macrophages demonstrated improved migration in a three-dimensional fibrin matrix and during resolution of peritoneal inflammation, whereas migration of CD11b(-/-) M1 macrophages was not affected. These results prove the contribution of high densities of CD11d to macrophage arrest during atherogenesis. Because high expression of CD11d was detected in several inflammation-dependent diseases, we suggest that CD11d/CD18 upregulation on proinflammatory macrophages may represent a common mechanism for macrophage retention at inflammatory sites, thereby promoting chronic inflammation and disease

  16. Platelets and their chemokines in atherosclerosis – clinical applications

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    Philipp evon Hundelshausen

    2014-08-01

    Full Text Available The concept of platelets as important players in the process of atherogenesis has become increasingly accepted due to accumulating experimental and clinical evidence. Despite the progress in understanding the molecular details of atherosclerosis, particularly by using animal models, the inflammatory and thrombotic roles of activated platelet s especially in the human system remain difficult to dissect, as often only the complications of atherosclerosis i.e. stroke and myocardial infarction are definable but not the plaque burden.Platelet indices including platelet count and mean platelet volume and soluble mediators released by activated platelets are associated with atherosclerosis. The chemokine CXCL4 has multiple atherogenic activities e.g. altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5. CCL5 is released and deposited on endothelium by activated platelets thereby triggering atherogenic monocyte recruitment, which can be attenuated by blocking the corresponding chemokine receptor CCR5. Atheroprotective and plaque stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells. Its release from luminal attached platelets accelerates endothelial healing after injury. Platelet surface molecules GPIIb/IIIa, GP1bα, P-selectin, JAM-A and the CD40/CD40L dyade are crucially involved in the interaction with endothelial cells, leukocytes and matrix molecules affecting atherogenesis. Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages. Current medical therapies for the prevention of atherosclerotic therapies enable the elucidation of mechanisms linking platelets to inflammation

  17. Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner.

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    Julian I Borissoff

    Full Text Available BACKGROUND: Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. Published experimental studies have yielded contradictory findings on the role of hypercoagulability in atherogenesis. We therefore sought to address this matter by extensively investigating the in vivo significance of genetic alterations and pharmacologic inhibition of thrombin formation for the onset and progression of atherosclerosis, and plaque phenotype determination. METHODOLOGY/PRINCIPAL FINDINGS: We generated transgenic atherosclerosis-prone mice with diminished coagulant or hypercoagulable phenotype and employed two distinct models of atherosclerosis. Gene-targeted 50% reduction in prothrombin (FII(-/WT:ApoE(-/- was remarkably effective in limiting disease compared to control ApoE(-/- mice, associated with significant qualitative benefits, including diminished leukocyte infiltration, altered collagen and vascular smooth muscle cell content. Genetically-imposed hypercoagulability in TM(Pro/Pro:ApoE(-/- mice resulted in severe atherosclerosis, plaque vulnerability and spontaneous atherothrombosis. Hypercoagulability was associated with a pronounced neutrophilia, neutrophil hyper-reactivity, markedly increased oxidative stress, neutrophil intraplaque infiltration and apoptosis. Administration of either the synthetic specific thrombin inhibitor Dabigatran etexilate, or recombinant activated protein C (APC, counteracted the pro-inflammatory and pro-atherogenic phenotype of pro-thrombotic TM(Pro/Pro:ApoE(-/- mice. CONCLUSIONS/SIGNIFICANCE: We provide new evidence highlighting the importance of neutrophils in the coagulation-inflammation interplay during atherogenesis. Our findings reveal that thrombin-mediated proteolysis is an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that

  18. TRPV4 calcium-permeable channel is a novel regulator of oxidized LDL-induced macrophage foam cell formation.

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    Goswami, Rishov; Merth, Michael; Sharma, Shweta; Alharbi, Mazen O; Aranda-Espinoza, Helim; Zhu, Xiaoping; Rahaman, Shaik O

    2017-09-01

    Cardiovascular disease is the number one cause of death in United States, and atherosclerosis, a chronic inflammatory arterial disease, is the most dominant underlying pathology. Macrophages are thought to orchestrate atherosclerosis by generating lipid-laden foam cells and by secreting inflammatory mediators. Emerging data support a role for a mechanical factor, e.g., matrix stiffness, in regulation of macrophage function, vascular elasticity, and atherogenesis. However, the identity of the plasma membrane mechanosensor and the mechanisms by which pro-atherogenic signals are transduced/maintained are unknown. We have obtained evidence that TRPV4, an ion channel in the transient receptor potential vanilloid family and a known mechanosensor, is the likely mediator of oxidized low-density lipoprotein (oxLDL)-dependent macrophage foam cell formation, a critical process in atherogenesis. Specifically, we found that: i) genetic ablation of TRPV4 or pharmacologic inhibition of TRPV4 activity by a specific antagonist blocked oxLDL-induced macrophage foam cell formation, and ii) TRPV4 deficiency prevented pathophysiological range matrix stiffness or scratch-induced exacerbation of oxLDL-induced foam cell formation. Mechanistically, we found that: i) plasma membrane localization of TRPV4 was sensitized to the increasing level of matrix stiffness, ii) lack of foam cell formation in TRPV4 null cells was not due to lack of expression of CD36, a major receptor for oxLDL, and iii) TRPV4 channel activity regulated oxLDL uptake but not its binding on macrophages. Altogether, these findings identify a novel role for TRPV4 in regulating macrophage foam cell formation by modulating uptake of oxLDL. These findings suggest that therapeutic targeting of TRPV4 may provide a selective approach to the treatment of atherosclerosis. Copyright © 2017. Published by Elsevier Inc.

  19. In silico design of anti-atherogenic biomaterials.

    Science.gov (United States)

    Lewis, Daniel R; Kholodovych, Vladyslav; Tomasini, Michael D; Abdelhamid, Dalia; Petersen, Latrisha K; Welsh, William J; Uhrich, Kathryn E; Moghe, Prabhas V

    2013-10-01

    Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Protein kinase C beta mediates CD40 ligand-induced adhesion of monocytes to endothelial cells.

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    Zeyu Wu

    Full Text Available Accumulating evidence supports the early involvement of monocyte/macrophage recruitment to activated endothelial cells by leukocyte adhesion molecules during atherogenesis. CD40 and its ligand CD40L are highly expressed in vascular endothelial cells, but its impact on monocyte adhesion and the related molecular mechanisms are not fully understood. The present study was designed to evaluate the direct effect of CD40L on monocytic cell adhesion and gain mechanistic insight into the signaling coupling CD40L function to the proinflammatory response. Exposure of cultured human aortic endothelial cells (HAECs to clinically relevant concentrations of CD40L (20 to 80 ng/mL dose-dependently increased human monocytic THP-1 cells to adhere to them under static condition. CD40L treatment induced the expression of vascular cell adhesion molecule-1 (VCAM-1 mRNA and protein expression in HAECs. Furthermore, exposure of HAECs to CD40L robustly increased the activation of protein kinase C beta (PKCβ in ECs. A selective inhibitor of PKCβ prevented the rise in VCAM-1 and THP-1 cell adhesion to ECs. Moreover, stimulation of ECs to CD40L induced nuclear factor-κB (NF-κB activation. PKCβ inhibition abolished CD40L-induced NF-κB activation, and NF-κB inhibition reduced expression of VCAM-1, each resulting in reduced THP-1 cell adhesion. Our findings provide the evidence that CD40L increases VCAM-1 expression in ECs by activating PKCβ and NF-κB, suggesting a novel mechanism for EC activation. Finally, administration of CD40L resulted in PKCβ activation, increased VCAM-1 expression and activated monocytes adhesiveness to HAECs, processes attenuated by PKCβ inhibitor. Therefore, CD40L may contribute directly to atherogenesis by activating ECs and recruiting monocytes to them.

  1. Benefits of napping and an extended duration of recovery sleep on alertness and immune cells after acute sleep restriction.

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    Faraut, Brice; Boudjeltia, Karim Zouaoui; Dyzma, Michal; Rousseau, Alexandre; David, Elodie; Stenuit, Patricia; Franck, Thierry; Van Antwerpen, Pierre; Vanhaeverbeek, Michel; Kerkhofs, Myriam

    2011-01-01

    Understanding the interactions between sleep and the immune system may offer insight into why short sleep duration has been linked to negative health outcomes. We, therefore, investigated the effects of napping and extended recovery sleep after sleep restriction on the immune and inflammatory systems and sleepiness. After a baseline night, healthy young men slept for a 2-h night followed by either a standard 8-h recovery night (n=12), a 30-min nap (at 1 p.m.) in addition to an 8-h recovery night (n=10), or a 10-h extended recovery night (n=9). A control group slept 3 consecutive 8-h nights (n=9). Subjects underwent continuous electroencephalogram polysomnography and blood was sampled every day at 7 a.m. Leukocytes, inflammatory and atherogenesis biomarkers (high-sensitivity C-reactive protein, interleukin-8, myeloperoxidase, fibrinogen and apolipoproteins ApoB/ApoA), sleep patterns and sleepiness were investigated. All parameters remained unchanged in the control group. After sleep restriction, leukocyte and - among leukocyte subsets - neutrophil counts were increased, an effect that persisted after the 8-h recovery sleep, but, in subjects who had a nap or a 10-h recovery sleep, these values returned nearly to baseline. Inflammatory and atherogenesis biomarkers were unchanged except for higher myeloperoxidase levels after sleep restriction. The increased sleepiness after sleep restriction was reversed better in the nap and extended sleep recovery conditions. Saliva cortisol decreased immediately after the nap. Our results indicate that additional recovery sleep after sleep restriction provided by a midday nap prior to recovery sleep or a sleep extended night can improve alertness and return leukocyte counts to baseline values. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. NLRP3 inflammasome: Its regulation and involvement in atherosclerosis.

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    Hoseini, Zahra; Sepahvand, Fatemeh; Rashidi, Bahman; Sahebkar, Amirhossein; Masoudifar, Aria; Mirzaei, Hamed

    2018-03-01

    Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1β and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1β, IL-18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome. In addition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and lysosome rupture, which are implicated in inflammasome activation, have been discussed as important events in atherosclerosis. In spite of these clues, some studies have reported that NLRP3 inflammasome has no significant effect in atherogenesis. Our review reveals that some molecules such as JNK-1 and ASK-1 (upstream regulators of inflammasome activation) can reduce atherosclerosis through inducing apoptosis in macrophages. Notably, NLRP3 inflammasome can also cause apoptosis in macrophages, suggesting that NLRP3 inflammasome may mediate JNK-induced apoptosis, and the apoptotic function of NLRP3 inflammasome may be a reason for the conflicting results reported. The present review shows that the role of NLRP3 in atherogenesis can be significant. Here, the molecular pathways of NLRP3 inflammasome activation and the implications of this activation in atherosclerosis are explained. © 2017 Wiley Periodicals, Inc.

  3. Addition of omega-3 fatty acid and coenzyme Q10 to statin therapy in patients with combined dyslipidemia.

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    Tóth, Štefan; Šajty, Matej; Pekárová, Tímea; Mughees, Adil; Štefanič, Peter; Katz, Matan; Spišáková, Katarína; Pella, Jozef; Pella, Daniel

    2017-07-26

    Statins represent a group of drugs that are currently indicated in the primary and secondary prevention of cardiovascular events. Their administration can be associated with side effects and the insufficient reduction of triacylglyceride (TAG) levels. This study aimed to assess the effect of the triple combination of statins with omega-3 fatty acids and coenzyme Q10 (CoQ10) on parameters associated with atherogenesis and statin side effects. In this pilot randomized double-blind trial, 105 subjects who met the criteria of combined dislipidemia and elevated TAG levels were randomly divided into three groups. In the control group, unaltered statin therapy was indicated. In the second and third groups, omega-3 PUFA 2.52 g/day (Zennix fa Pleuran) and omega-3 PUFA 2.52 g+CoQ10 200 mg/day (Pharma Nord ApS) were added, res//. At the end of the 3-month period (±1 week), all patients were evaluated. Significant reduction of hepatic enzymes activity, systolic blood preasure, inflammatory markers and TAG levels were detected in both groups in comparison to the control group. Activity of SOD and GPx increased significantly after additive therapy. Coenzyme Q10 addition significantly reduced most of the abovementioned parameters (systolic blood preasure, total cholesterol, LDL, hsCRP, IL-6, SOD) in comparison with the statin+omega-3 PUFA group. The intensity of statin adverse effects were significantly reduced in the group with the addition of CoQ10. The results of this pilot study suggest the possible beneficial effects of triple combination on the lipid and non-lipid parameters related to atherogenesis and side effects of statin treatment.

  4. Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.

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    Yu, Emma P K; Reinhold, Johannes; Yu, Haixiang; Starks, Lakshi; Uryga, Anna K; Foote, Kirsty; Finigan, Alison; Figg, Nichola; Pung, Yuh-Fen; Logan, Angela; Murphy, Michael P; Bennett, Martin

    2017-12-01

    Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis. Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis. Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen

  5. Toll-like receptor 2 activation and serum amyloid A regulate smooth muscle cell extracellular matrix.

    Science.gov (United States)

    Seidl, Stephanie E; Pessolano, Lawrence G; Bishop, Christopher A; Best, Michael; Rich, Celeste B; Stone, Phillip J; Schreiber, Barbara M

    2017-01-01

    Smooth muscle cells contribute to extracellular matrix remodeling during atherogenesis. De-differentiated, synthetic smooth muscle cells are involved in processes of migration, proliferation and changes in expression of extracellular matrix components, all of which contribute to loss of homeostasis accompanying atherogenesis. Elevated levels of acute phase proteins, including serum amyloid A (SAA), are associated with an increased risk for atherosclerosis. Although infection with periodontal and respiratory pathogens via activation of inflammatory cell Toll-like receptor (TLR)2 has been linked to vascular disease, little is known about smooth muscle cell TLR2 in atherosclerosis. This study addresses the role of SAA and TLR2 activation on smooth muscle cell matrix gene expression and insoluble elastin accumulation. Cultured rat aortic smooth muscle cells were treated with SAA or TLR2 agonists and the effect on expression of matrix metallopeptidase 9 (MMP9) and tropoelastin studied. SAA up-regulated MMP9 expression. Tropoelastin is an MMP9 substrate and decreased tropoelastin levels in SAA-treated cells supported the concept of extracellular matrix remodeling. Interestingly, SAA-induced down-regulation of tropoelastin was not only evident at the protein level but at the level of gene transcription as well. Contributions of proteasomes, nuclear factor κ B and CCAAT/enhancer binding protein β on regulation of MMP9 vs. tropoleastin expression were revealed. Effects on Mmp9 and Eln mRNA expression persisted with long-term SAA treatment, resulting in decreased insoluble elastin accumulation. Interestingly, the SAA effects were TLR2-dependent and TLR2 activation by bacterial ligands also induced MMP9 expression and decreased tropoelastin expression. These data reveal a novel mechanism whereby SAA and/or infection induce changes in vascular elastin consistent with atherosclerosis.

  6. Mas receptor deficiency is associated with worsening of lipid profile and severe hepatic steatosis in ApoE-knockout mice.

    Science.gov (United States)

    Silva, Analina R; Aguilar, Edenil C; Alvarez-Leite, Jacqueline I; da Silva, Rafaela F; Arantes, Rosa M E; Bader, Michael; Alenina, Natalia; Pelli, Graziano; Lenglet, Sébastien; Galan, Katia; Montecucco, Fabrizio; Mach, François; Santos, Sérgio H S; Santos, Robson A S

    2013-12-01

    The classical renin-angiotensin system pathway has been recently updated with the identification of additional molecules [such as angiotensin converting enzyme 2, ANG-(1-7), and Mas receptor] that might improve some pathophysiological processes in chronic inflammatory diseases. In the present study, we focused on the potential protective role of Mas receptor activation on mouse lipid profile, liver steatosis, and atherogenesis. Mas/apolipoprotein E (ApoE)-double-knockout (DKO) mice (based on C57BL/6 strain of 20 wk of age) were fed under normal diet and compared with aged-matched Mas and ApoE-single-knockout (KO), as well as wild-type mice. Mas/ApoE double deficiency was associated with increased serum levels of atherogenic fractions of cholesterol, triglycerides, and fasting glucose compared with wild-type or single KO. Serum levels of HDL or leptin in DKO were lower than in other groups. Hepatic lipid content as well as alanine aminotransferase serum levels were increased in DKO compared with wild-type or single-KO animals. Accordingly, the hepatic protein content of mediators related to atherosclerotic inflammation, such as peroxisome proliferator-activated receptor-α and liver X receptor, was altered in an adverse way in DKO compared with ApoE-KO. On the other hand, DKO mice did not display increased atherogenesis and intraplaque inflammation compared with ApoE-KO group. In conclusion, Mas deletion in ApoE-KO mice was associated with development of severe liver steatosis and dyslipidemia without affecting concomitant atherosclerosis. Mas receptor activation might represent promising strategies for future treatments targeting both hepatic and metabolic alterations in chronic conditions clustering these disorders.

  7. Serum Amyloid A Facilitates Early Lesion Development in Ldlr-/- Mice.

    Science.gov (United States)

    Krishack, Paulette A; Bhanvadia, Clarissa V; Lukens, John; Sontag, Timothy J; De Beer, Maria C; Getz, Godfrey S; Reardon, Catherine A

    2015-07-17

    Atherosclerosis is a chronic inflammatory disorder, and several studies have demonstrated a positive association between plasma serum amyloid A (SAA) levels and cardiovascular disease risk. The aim of the study was to examine whether SAA has a role in atherogenesis, the underlying basis of most cardiovascular disease. Mice globally deficient in acute-phase isoforms Saa1 and Saa2 (Saa(-/-)) were crossed to Ldlr(-/-) mice (Saa(-/-)Ldlr(-/-)). Saa(-/-)Ldlr(-/-) mice demonstrated a 31% reduction in lesional area in the ascending aorta but not in the aortic root or innominate artery after consuming a high-fat, high-cholesterol Western-type diet for 6 weeks. The lesions were predominantly macrophage foam cells. The phenotype was lost in more mature lesions in mice fed a Western-type diet for 12 weeks, suggesting that SAA is involved in early lesion development. The decreased atherosclerosis in the Saa(-/-)Ldlr(-/-) mice occurred despite increased levels of blood monocytes and was independent of plasma lipid levels. SAA is produced predominantly by hepatocytes and macrophages. To determine which source of SAA may have a dominant role in lesion development, bone marrow transplantation was performed. Ldlr(-/-) mice that received bone marrow from Saa(-/-)Ldlr(-/-) mice had slightly reduced ascending aorta atherosclerosis compared with Saa(-/-)Ldlr(-/-) mice receiving bone marrow from Ldlr(-/-) mice, indicating that the expression of SAA by macrophages may have an important influence on atherogenesis. The results indicate that SAA produced by macrophages promotes early lesion formation in the ascending aorta. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  8. Low high-density lipoprotein cholesterol and particle concentrations are associated with greater levels of endothelial activation markers in Multi-Ethnic Study of Atherosclerosis participants.

    Science.gov (United States)

    Steffen, Brian T; Bielinski, Suzette J; Decker, Paul A; Berardi, Cecilia; Larson, Nicholas B; Pankow, James S; Michos, Erin D; Hanson, Naomi Q; Herrington, David M; Tsai, Michael Y

    High-density lipoproteins (HDL) are well characterized for their role in reverse cholesterol transport but may confer other cardiovascular benefits-specifically, HDL may suppress the endothelial activation cascade in the initiating stages of atherogenesis. It was the primary aim of this study to examine the relations of HDL cholesterol (HDL-C), total HDL particle (HDL-P) concentrations, and HDL-P subclasses with circulating levels of endothelial activation markers in a subcohort of Multi-Ethnic Study of Atherosclerosis participants. HDL-C was measured by enzymatic assay, and total HDL-P and subclass concentrations were assessed by nuclear magnetic resonance spectroscopy. Concentrations of circulating endothelial activation markers were determined through immunoassay. Multivariable linear regression was used to determine the cross-sectional associations between HDL variables and endothelial markers with statistical adjustment for age, race/ethnicity, sex, education, systolic blood pressure, hypertension medication use, body mass index, smoking status, lipid-lowering medication use, serum creatinine, diabetes, low-density lipoprotein cholesterol, and coronary artery calcium. HDL-C and HDL-P were found to be inversely associated with soluble vascular cell adhesion molecule-1, soluble vascular intracellular adhesion molecule-1, sL-selectin, and sP-selectin; HDL-P was additionally inversely associated with sE-selectin. Participants with low levels of HDL-C (<40 mg/dL) or HDL-P (<25th percentile) showed 3%-12% higher mean levels of soluble vascular cell adhesion molecule and compared with those above these levels (all P < .01). Coupled with previous evidence, our findings suggest a modest to moderate relation of HDL and circulating levels of endothelial activation markers in humans. Whether this relationship may have clinical implications in suppressing atherogenesis or coronary heart disease development requires additional research. Copyright © 2017 National Lipid

  9. Metabolic profile of six oral contraceptives containing norgestimate, gestodene, and desogestrel.

    Science.gov (United States)

    Teichmann, A

    1995-01-01

    The alterations in lipid metabolism that occur with the use of oral contraceptives (OCs) have aroused considerable concern that OCs might increase the risk of premature atherosclerosis. However, most studies examining the role of OCs in atherogenesis were performed using earlier-generation preparations employing larger doses of sex hormones than present formulation. Therefore, we undertook a comparative and standardized determination of the effects on lipid metabolism of six modern, low-dose OCs. This open, randomized, comparative study included patients recruited at 21 study centers throughout Europe. Four hundred sixty-six women, aged 18-38 years, participated. They were randomly assigned to the following OC formulations:(1) norgestimate 250 micrograms + ethinyl estradiol (EE) 35 micrograms (Cilest); (2) norgestimate 180/215/250 micrograms + EE 35 micrograms (Tricilest); (3) desogestrel 150 micrograms + EE 20 micrograms = (Marvelon); (4) desogestrel 150 micrograms + EE 30 micrograms (Mercilon); (5) gestodene 75 micrograms + EE 30 micrograms (Femovan); and (6) gestodene 50/70/100 micrograms + EE 30/40/30 micrograms (Trifemovan). There were three parallel studies with six parallel patient groups. Fasting blood samples were drawn at baseline (between days 24 and 28) and on days 18-22 of cycle 6, and cycle 12. Sample were analyzed for total cholesterol,high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein (apo)A1, and apoB at one central laboratory. Two hundred eighty-two women completed all 12 cycles and were included in the final evaluation. As expected, triglyceride and total cholesterol concentrations increased in all study groups but to lesser levels with the formulations containing gestodene. All OCs, except the monophasic gestodene preparation, slightly but significantly increased HDL. The HDL2 subfraction did ot change significantly except in the group using the monophasic

  10. Bone marrow-specific knock-in of a non-activatable Ikkα kinase mutant influences haematopoiesis but not atherosclerosis in Apoe-deficient mice.

    Directory of Open Access Journals (Sweden)

    Pathricia V Tilstam

    Full Text Available BACKGROUND: The Ikkα kinase, a subunit of the NF-κB-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM-specific activation-resistant Ikkα mutant knock-in on haematopoiesis and atherosclerosis in mice. METHODS AND RESULTS: Apolipoprotein E (Apoe-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AAApoe(-/- or with Ikkα(+/+Apoe(-/- BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AAApoe(-/- BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AAApoe(-/- vs Ikkα(+/+Apoe(-/- BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AAApoe(-/- vs Ikkα(+/+Apoe(-/- mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL, and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. CONCLUSION: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα(AA mutant BM did not affect atherosclerosis in Apoe(-/- mice. This

  11. Endothelial ATP-binding cassette G1 in mouse endothelium protects against hemodynamic-induced atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Shanshan [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Department of Pediatrics, Baodi District People’s Hospital of Tianjin City, Tianjin, 301800 (China); Wang, Jiaxing [Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191 (China); Zhang, Xu; Shi, Ying; Li, Bochuan; Bao, Qiankun [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Pang, Wei [Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191 (China); Ai, Ding [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Zhu, Yi [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China); Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191 (China); He, Jinlong, E-mail: hejinlong@tmu.edu.cn [Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070 (China)

    2016-08-19

    Activated vascular endothelium inflammation under persistent hyperlipidemia is the initial step of atherogenesis. ATP-binding cassette G1 (ABCG1) is a crucial factor maintaining sterol and lipid homeostasis by transporting cholesterol efflux to high-density lipoprotein. In this study, we investigated the protective effects of ABCG1 in endothelial inflammation activation during early-stage atherogenesis in mice and the underlying mechanisms. Endothelial cell (EC)-specific ABCG1 transgenic (EC-ABCG1-Tg) mice were generated and cross-bred with low-density lipoprotein receptor–deficient (Ldlr{sup −/−}) mice. After a 4-week Western-type diet, the mice were sacrificed for assessing atherosclerosis. Human umbilical vein ECs were treated with different flows, and ABCG1 was adenovirally overexpressed to investigate the mechanism in vitro. Compared with Ldlr{sup −/−} mouse aortas, EC-ABCG1-Tg/Ldlr{sup −/−} aortas showed decreased early-stage lesions. Furthermore, the lesion area in the EC-ABCG1-Tg/Ldlr{sup −/−} mouse aortic arch but not thoracic aorta was significantly reduced, which suggests a protective role of ABCG1 under atheroprone flow. In vitro, overexpression of ABCG1 attenuated EC activation caused by oscillatory shear stress. Overexpression of ABCG1 blunted cholesterol-activated ECs in vitro. In exploring the mechanisms of ABCG1 attenuating endothelial inflammation, we found that ABCG1 inhibited oscillatory flow-activated nuclear factor kappa B and NLRP3 inflammasome in ECs. ABCG1 may play a protective role in early-stage atherosclerosis by reducing endothelial activation induced by oscillatory shear stress via suppressing the inflammatory response. - Highlights: • EC-ABCG1-Tg mice in a Ldlr{sup −/−} background showed decreased atherosclerosis. • Overexpression of ABCG1 in ECs decreased OSS-induced EC activation. • NLRP3 and NF-κB might be an underlying mechanism of ABCG1 protective role.

  12. Anti-TNF-α therapy improves insulin sensitivity in non-diabetic patients with psoriasis: a 6-month prospective study.

    Science.gov (United States)

    Pina, T; Armesto, S; Lopez-Mejias, R; Genre, F; Ubilla, B; Gonzalez-Lopez, M A; Gonzalez-Vela, M C; Corrales, A; Blanco, R; Garcia-Unzueta, M T; Hernandez, J L; Llorca, J; Gonzalez-Gay, M A

    2015-07-01

    Psoriasis is a chronic inflammatory disease associated with increased risk of cardiovascular death. Several studies have shown a beneficial effect of anti-TNF-α therapy on the mechanisms associated with accelerated atherogenesis in patients with inflammatory arthritis, including an improvement of insulin sensitivity. In this study, we aimed to determine for the first time whether the anti-TNF-α monoclonal antibody adalimumab may improve insulin sensitivity in non-diabetic patients with psoriasis. Prospective study on a series of consecutive non-diabetic patients with moderate to severe psoriasis seen at the Dermatology Division of Hospital Universitario Marques de Valdecilla (Northern Spain) who completed 6 months of therapy with adalimumab (80 mg at week 0 followed by 40 mg every other week, starting 1 week after the initial dose). Patients with chronic kidney disease, hypertension or body mass index ≥ 35 kg/m(2) were excluded. Metabolic and clinical evaluation including assessment of insulin sensitivity using the Quantitative Insulin Sensitivity Check Index (QUICKI) was performed at the onset of the treatment (time 0) and at month 6. Twenty-nine patients (52% women; 38.6 ± 10.7 years) with moderate to severe psoriasis [body surface area (BSA) 37.9 ± 16.3%], Psoriasis Area and Severity Index [(PASI) 18.9 ± 7.8] were assessed. Statistically significant improvement (P=0.008) of insulin sensitivity was observed after 6 months of adalimumab therapy (QUICKI at time 0: 0.35 ± 0.04 vs. 0.37 ± 0.04 at month 6). Significant improvement of erythrocyte sedimentation rate, ultrasensitive C-reactive protein, BSA, PASI, Nail Psoriasis Severity Index, physician global assessment and psoriatic arthritis screening and evaluation questionnaire was also observed at month 6 (P effect of the anti-TNF-α blockade on the mechanisms associated with accelerated atherogenesis in patients with psoriasis. © 2014 European Academy of Dermatology and Venereology.

  13. Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Hseu, You-Cheng [Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan (China); Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030 (United States); Senthil Kumar, K.J. [Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan (China); Chen, Chih-Sheng; Cho, Hsin-Ju; Lin, Shu-Wei; Shen, Pei-Chun [Institute of Nutrition, China Medical University, Taichung 40402, Taiwan (China); Lin, Cheng-Wen [Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan (China); Lu, Fung-Jou [Institute of Medicine, Chun Shan Medical University, Taichung 40201, Taiwan (China); Yang, Hsin-Ling, E-mail: hlyang@mail.cmu.edu.tw [Institute of Nutrition, China Medical University, Taichung 40402, Taiwan (China); Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030 (United States)

    2014-01-15

    Humic acid (HA) has been implicated as one of the etiological factors in the peripheral vasculopathy of blackfoot disease (BFD) in Taiwan. However, the underlying pathophysiological mechanisms of BFD are not well defined. In this study, we used an in vitro and in vivo model, in which HA (25–200 μg/mL) activated macrophages to produce pro-inflammatory molecules by activating their transcriptional factors. HA exposure induced NO and PGE{sub 2} production followed by induction of iNOS and COX-2 through NF-κB/AP-1 transactivation in macrophages. In addition, the production of TNF-α and IL-1β was significantly increased by HA. Moreover, HA-induced iNOS and COX-2 expression were down-regulated by the NF-κB and AP-1 inhibitors pyrrolidine dithiocarbamate (PDTC) and Tanshinone, respectively. Furthermore, generations of ROS and nitrotyrosine, as well as activation of the AKT and MAPKs signaling cascades were observed after HA exposure. Specifically, HA-induced NF-κB activation was mediated by ROS and AKT, and that HA-induced AP-1 activation was mediated by JNK and ERK. Notably, HA-mediated AKT, JNK, and ERK activation was ROS-independent. The inflammatory potential of HA was correlated with increased expression of HO-1 and Nrf2. Furthermore, an in vivo study confirms that mice exposed to HA, the serum levels of TNF-α and IL-1β was significantly increased in a dose-dependent manner. This report marks the first confirmation that environmental exposure of HA induces inflammation in macrophages, which may be one of the main causes of early atherogenesis in blackfoot disease. - Highlights: • Humic acid (HA) induce pro-inflammatory cytokines and mediators in macrophages. • HA-induced inflammation is mediated by ROS and NF-κB/AP-1 signaling pathways. • The inflammatory potential of HA correlated with activation of Nrf2/HO-1 genes. • HA exposure to mice increased pro-inflammatory cytokines production in vivo. • HA may be one of the main causes of early

  14. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil

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    Mason

    2011-06-01

    Full Text Available R Preston MasonCardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and Elucida Research, Beverly, MA, USAAbstract: Cardiovascular (CV disease is a major factor in mortality rates around the world and contributes to more than one-third of deaths in the US. The underlying cause of CV disease is atherosclerosis, a chronic inflammatory process that is clinically manifested as coronary artery disease, carotid artery disease, or peripheral artery disease. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Consequently, developing a treatment regimen that can slow or even reverse the atherosclerotic process is imperative. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with CV risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. Since the renin–angiotensin–aldosterone system (RAAS plays a key role in vascular inflammatory responses, hypertension treatment with RAAS-blocking agents (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers [ARBs] may slow inflammatory processes and disease progression. Reduced nitric oxide (NO bioavailability has an important role in the process of endothelial dysfunction and hypertension. Therefore, agents that increase NO and decrease oxidative stress, such as ARBs and ACEIs, may interfere with atherosclerosis. Studies show that angiotensin II type 1 receptor antagonism with an ARB improves endothelial function and reduces atherogenesis. In patients with hypertension, the ARB olmesartan medoxomil provides effective blood pressure lowering, with inflammatory marker studies demonstrating significant RAAS suppression. Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris

  15. Multiphase hemodynamic simulation of pulsatile flow in a coronary artery.

    Science.gov (United States)

    Jung, Jonghwun; Lyczkowski, Robert W; Panchal, Chandrakant B; Hassanein, Ahmed

    2006-01-01

    A multiphase transient non-Newtonian three-dimensional (3-D) computational fluid dynamics (CFD) simulation has been performed for pulsatile hemodynamics in an idealized curved section of a human coronary artery. We present the first prediction, to the authors' knowledge, of particulate buildup on the inside curvature using the multiphase theory of dense suspension hemodynamics. In this study, the particulates are red blood cells (RBCs). The location of RBC buildup on the inside curvature correlates with lower wall shear stress (WSS) relative to the outside curvature. These predictions provide insight into how blood-borne particulates interact with artery walls and hence, have relevance for understanding atherogenesis since clinical observations show that atherosclerotic plaques generally form on the inside curvatures of arteries. The buildup of RBCs on the inside curvature is driven by the secondary flow and higher residence times. The higher viscosity in the central portion of the curved vessel tends to block their flow, causing them to migrate preferentially through the boundary layer. The reason for this is the nearly neutrally buoyant nature of the dense two-phase hemodynamic flow. The two-phase non-Newtonian viscosity model predicts greater shear thinning than the single-phase non-Newtonian model. Consequently, the secondary flow induced in the curvature is weaker. The waveforms for computed hemodynamic parameters, such as hematocrit, WSS, and viscosity, follow the prescribed inlet velocity waveforms. The lower oscillatory WSS produced on the inside curvature has implications for understanding thickening of the intimal layer.

  16. Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo

    Science.gov (United States)

    Ballinger, Mandy L; Osman, Narin; Hashimura, Kazuhiko; de Haan, Judy B; Jandeleit-Dahm, Karin; Allen, Terri; Tannock, Lisa R; Rutledge, John C; Little, Peter J

    2010-01-01

    Abstract The ‘response to retention’ hypothesis of atherogenesis proposes that proteoglycans bind and retain low-density lipoproteins (LDL) in the vessel wall. Platelet-derived growth factor (PDGF) is strongly implicated in atherosclerosis and stimulates proteoglycan synthesis. Here we investigated the action of the PDGF receptor inhibitor imatinib on PDGF-mediated proteoglycan biosynthesis in vitro, lipid deposition in the aortic wall in vivo and the carotid artery ex vivo. In human vSMCs, imatinib inhibited PDGF mediated 35S-SO4 incorporation into proteoglycans by 31% (P proteoglycans from PDGF stimulated cells in the presence of imatinib was approximately 2.5-fold higher than for PDGF treatment alone. In high fat fed ApoE−/– mice, imatinib reduced total lipid staining area by ∼31% (P proteoglycans and reduces LDL binding in vitro and in vivo and this effect is mediated via the PDGF receptor. These findings validate a novel mechanism to prevent cardiac disease. PMID:19754668

  17. Actions of Calcium Channel Blockers on Vascular Proteoglycan Synthesis: Relationship to Atherosclerosis

    Science.gov (United States)

    Survase, Soniya; Ivey, Melanie E; Nigro, Julie; Osman, Narin; Little, Peter J

    2005-01-01

    Calcium channel blockers (CCBs) are a widely used group of antihypertensive agents. CCBs are efficacious in the reduction of blood pressure but the extent to which they manifest beneficial effects on cardiovascular disease is variable. Clinical studies indicate that pleiotropic actions make significant contributions to the efficacy of agents aimed at preventing atherosclerosis. The “response to retention” hypothesis implicates the binding and retention of lipoproteins by glycosaminoglycan chains on proteoglycans as an initiating step in atherogenesis. Atherogenic factors act as agonists and several classes of drugs including peroxisome proliferating-activated receptor (PPAR)-α and -γ ligands act as antagonists in this model. Initial data have demonstrated that high concentrations of CCBs inhibit proteoglycan synthesis. Newer preliminary data show that the action is very modest at reasonable concentrations and appears to be independent of calcium channel blocking activity. We have reviewed the role of cardiovascular drugs acting on vascular smooth muscle proteoglycan synthesis and considered the potential action of CCBs in this model. We conclude that the inhibition of proteoglycan synthesis by CCBs does not play a role in the attenuation of atherosclerosis; however, the antihypertensive efficacy and alternative beneficial actions provide support for the use of CCBs in the therapy of cardiovascular disease. PMID:17319105

  18. Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis.

    Science.gov (United States)

    Mulvihill, Erin E; Burke, Amy C; Huff, Murray W

    2016-07-17

    Citrus flavonoids are polyphenolic compounds with significant biological properties. This review summarizes recent advances in understanding the ability of citrus flavonoids to modulate lipid metabolism, other metabolic parameters related to the metabolic syndrome, and atherosclerosis. Citrus flavonoids, including naringenin, hesperitin, nobiletin, and tangeretin, have emerged as potential therapeutics for the treatment of metabolic dysregulation. Epidemiological studies reveal an association between the intake of citrus flavonoid-containing foods and a decreased incidence of cardiovascular disease. Studies in cell culture and animal models, as well as a limited number of clinical studies, reveal the lipid-lowering, insulin-sensitizing, antihypertensive, and anti-inflammatory properties of citrus flavonoids. In animal models, supplementation of rodent diets with citrus flavonoids prevents hepatic steatosis, dyslipidemia, and insulin resistance primarily through inhibition of hepatic fatty acid synthesis and increased fatty acid oxidation. Citrus flavonoids blunt the inflammatory response in metabolically important tissues including liver, adipose, kidney, and the aorta. The mechanisms underlying flavonoid-induced metabolic regulation have not been completely established, although several potential targets have been identified. In mouse models, citrus flavonoids show marked suppression of atherogenesis through improved metabolic parameters as well as through direct impact on the vessel wall. Recent studies support a role for citrus flavonoids in the treatment of dyslipidemia, insulin resistance, hepatic steatosis, obesity, and atherosclerosis. Larger human studies examining dose, bioavailability, efficacy, and safety are required to promote the development of these promising therapeutic agents.

  19. Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Jauhiainen, Matti; Moser, Markus

    2008-01-01

    To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM(-/-)) mice. Plasma apoM was predominantly associated with 10-12-nm alpha-migrating HDL particles. Human apoM overexpression (11-fold...... of alpha- to pre-alpha-migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre-beta-migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 +/- 1.1%, p = 0.06) and decreased in apoM(-/-) mice (0.5 +/- 0.3%, p = 0.......03) versus controls (1.8 +/- 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with approximately 2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic...

  20. Association of periodontitis with rheumatoid arthritis and atherosclerosis: Novel paradigms in etiopathogeneses and management?

    Directory of Open Access Journals (Sweden)

    Mena Soory

    2010-05-01

    Full Text Available Mena SooryKing’s College London Dental Institute, Denmark Hill, London UKAbstract: There is increasing documentation of a link between inflammatory periodontal disease affecting the supporting structure of teeth, rheumatoid arthritis, and coronary artery disease. Periodontitis is initiated predominantly by Gram-negative bacteria and progresses as a consequence of the host inflammatory response to periodontal pathogens. Lipopolysaccharide, a cell wall constituent stimulates the production of inflammatory cytokines via the activation of signaling pathways perpetuating inflammatory pathogenesis in a cyclical manner in susceptible individuals; with an element of autoimmune stimulation, not dissimilar to the sequential events seen in RA. Periodontitis, also implicated as a risk factor for cardiovascular disease, promotes mechanisms for atherosclerosis by enhancing an imbalance in systemic inflammatory mediators; more direct mechanisms attributed to microbial products are also implicated in both RA and atherogenesis. Severe periodontal disease characterized by clinical and radiographic parameters has been associated with ischemic stroke risk, significant levels of C-reactive protein and serum amyloid A, amongst others common to both periodontitis and atherosclerosis. Existing data supports the hypothesis that persistent localized infection in periodontitis may influence systemic levels of inflammatory markers and pose a risk for RA and atherosclerosis. A common nucleus of activity in their pathogeneses provides novel paradigms of therapeutic targeting for reciprocal benefit.Keywords: periodontitis, RA, atherosclerosis, periodontal pathogens, cytokines, therapeutic targets

  1. Oxidative Stress in the Local and Systemic Events of Apical Periodontitis

    Directory of Open Access Journals (Sweden)

    Patricia Hernández-Ríos

    2017-11-01

    Full Text Available Oxidative stress is involved in the pathogenesis of a variety of inflammatory disorders. Apical periodontitis (AP usually results in the formation of an osteolytic apical lesion (AL caused by the immune response to endodontic infection. Reactive oxygen species (ROS produced by phagocytic cells in response to bacterial challenge represent an important host defense mechanism, but disturbed redox balance results in tissue injury. This mini review focuses on the role of oxidative stress in the local and associated systemic events in chronic apical periodontitis. During endodontic infection, ligation of Toll-like receptors (TLRs on phagocytes' surface triggers activation, phagocytosis, synthesis of ROS, activation of humoral and cellular responses, and production of inflammatory mediators, such as, cytokines and matrix metalloproteinases (MMPs. The increment in ROS perturbs the normal redox balance and shifts cells into a state of oxidative stress. ROS induce molecular damage and disturbed redox signaling, that result in the loss of bone homeostasis, increased pro-inflammatory mediators, and MMP overexpression and activation, leading to apical tissue breakdown. On the other hand, oxidative stress has been strongly involved in the pathogenesis of atherosclerosis, where a chronic inflammatory process develops in the arterial wall. Chronic AP is associated with an increased risk of cardiovascular diseases (CVD and especially atherogenesis. The potential mechanisms linking these diseases are also discussed.

  2. Review of clinical practice guidelines for the management of LDL-related risk.

    Science.gov (United States)

    Morris, Pamela B; Ballantyne, Christie M; Birtcher, Kim K; Dunn, Steven P; Urbina, Elaine M

    2014-07-15

    Managing risk related to low-density lipoprotein (LDL) is vital in therapy for patients at risk for atherosclerotic cardiovascular disease (ASCVD) events given its important etiologic role in atherogenesis. Despite decades of research showing reduction of ASCVD risk with multiple approaches to lowering of LDL cholesterol, there continue to be significant gaps in care with inadequate numbers of patients receiving standard of care lipid-lowering therapy. Confusion regarding implementation of the multiple published clinical practice guidelines has been identified as one contributor to suboptimal management of LDL-related risk. This review summarizes the current guidelines for reduction of LDL-related cardiovascular risk provided by a number of major professional societies, which have broad applicability to diverse populations worldwide. Statements have varied in the process and methodology of development of recommendations, the grading system for level and strength of evidence, the inclusion or exclusion of expert opinion, the suggested ASCVD risk assessment tool, the lipoproteins recommended for risk assessment, and the lipoprotein targets of therapy. The similarities and differences among important guidelines in the United States and internationally are discussed, with recommendations for future strategies to improve consistency in approaches to LDL-related ASCVD risk and to reduce gaps in implementation of evidence-based therapies. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  3. Human genetic insights into lipoproteins and risk of cardiometabolic disease.

    Science.gov (United States)

    Stitziel, Nathan O

    2017-04-01

    Human genetic studies have been successfully used to identify genes and pathways relevant to human biology. Using genetic instruments composed of loci associated with human lipid traits, recent studies have begun to clarify the causal role of major lipid fractions in risk of cardiometabolic disease. The causal relationship between LDL cholesterol and coronary disease has been firmly established. Of the remaining two major fractions, recent studies have found that HDL cholesterol is not likely to be a causal particle in atherogenesis, and have instead shifted the causal focus to triglyceride-rich lipoproteins. Subsequent results are refining this view to suggest that triglycerides themselves might not be causal, but instead may be a surrogate for the causal cholesterol content within this fraction. Other studies have used a similar approach to address the association between lipid fractions and risk of type 2 diabetes. Beyond genetic variation in the target of statin medications, reduced LDL cholesterol associated with multiple genes encoding current or prospective drug targets associated with increased diabetic risk. In addition, genetically lower HDL cholesterol and genetically lower triglycerides both appear to increase risk of type 2 diabetes. Results of these and future human genetic studies are positioned to provide substantive insights into the causal relationship between lipids and human disease, and should highlight mechanisms with important implications for our understanding of human biology and future lipid-altering therapeutic development.

  4. Aggregation and fusion of low-density lipoproteins in vivo and in vitro

    Science.gov (United States)

    Gursky, Olga

    2014-01-01

    Low-density lipoproteins (LDLs, also known as ‘bad cholesterol’) are the major carriers of circulating cholesterol and the main causative risk factor of atherosclerosis. Plasma LDLs are 20- to 25-nm nanoparticles containing a core of cholesterol esters surrounded by a phospholipid monolayer and a single copy of apolipoprotein B (550 kDa). An early sign of atherosclerosis is the accumulation of LDL-derived lipid droplets in the arterial wall. According to the widely accepted ‘response-to-retention hypothesis’, LDL binding to the extracellular matrix proteoglycans in the arterial intima induces hydrolytic and oxidative modifications that promote LDL aggregation and fusion. This enhances LDL uptake by the arterial macrophages and triggers a cascade of pathogenic responses that culminate in the development of atherosclerotic lesions. Hence, LDL aggregation, fusion, and lipid droplet formation are important early steps in atherogenesis. In vitro, a variety of enzymatic and nonenzymatic modifications of LDL can induce these reactions and thereby provide useful models for their detailed analysis. Here, we summarize current knowledge of the in vivo and in vitro modifications of LDLs leading to their aggregation, fusion, and lipid droplet formation; outline the techniques used to study these reactions; and propose a molecular mechanism that underlies these pro-atherogenic processes. Such knowledge is essential in identifying endogenous and exogenous factors that can promote or prevent LDL aggregation and fusion in vivo and to help establish new potential therapeutic targets to decelerate or even block these pathogenic reactions. PMID:25197325

  5. Overexpression of TGF-ß1 in macrophages reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice.

    Directory of Open Access Journals (Sweden)

    Kurt Reifenberg

    Full Text Available Although macrophages represent the hallmark of both human and murine atherosclerotic lesions and have been shown to express TGF-ß1 (transforming growth factor β1 and its receptors, it has so far not been experimentally addressed whether the pleiotropic cytokine TGF-ß1 may influence atherogenesis by a macrophage specific mechanism. We developed transgenic mice with macrophage specific TGF-ß1 overexpression, crossed the transgenics to the atherosclerotic ApoE (apolipoprotein E knock-out strain and quantitatively analyzed both atherosclerotic lesion development and composition of the resulting double mutants. Compared with control ApoE(-/- mice, animals with macrophage specific TGF-ß1 overexpression developed significantly less atherosclerosis after 24 weeks on the WTD (Western type diet as indicated by aortic plaque area en face (p<0.05. Reduced atherosclerotic lesion development was associated with significantly less macrophages (p<0.05 after both 8 and 24 weeks on the WTD, significantly more smooth muscle cells (SMCs; p<0.01 after 24 weeks on the WTD, significantly more collagen (p<0.01 and p<0.05 after 16 and 24 weeks on the WTD, respectively without significant differences of inner aortic arch intima thickness or the number of total macrophages in the mice pointing to a plaque stabilizing effect of macrophage-specific TGF-ß1 overexpression. Our data shows that macrophage specific TGF-ß1 overexpression reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice.

  6. Antiobesogenic and Antiatherosclerotic Properties of Caralluma fimbriata Extract

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    Soundararajan Kamalakkannan

    2010-01-01

    Full Text Available There is evidence that the principles present in the widely consumed Indian food plant C. fimbriata extract (CFE suppress appetite, and provide antiobesogenic and metabolic benefits. The Diet-Induced Obesity (DIO rat model was used to investigate CFE's anorexigenic effects. Rats were randomly divided into three groups: (i untreated control (C, (ii control for cafeteria diet (CA, and (iii cafeteria diet fed + CFE treated. Rats in the test group received cafeteria diet and CFE from day one onwards. CFE was administered by gavage at three doses (25, 50, 100 mg/Kg BW per day for 90 days. The antiobesogenic effects of CFE were evaluated by monitoring changes in feed intake, body weight, serum lipid and hormonal (leptin profiles, fat pads, and liver weight. Antiatherosclerotic effects were measured by histology. CFE induced significant and dose-dependent inhibition of food intake, with dose-related prevention of gains in body weight, liver weight, and fat pad mass. Alterations in serum lipid profiles associated with weight gain were similarly inhibited, as were the typical increases in serum leptin levels. These data substantiate CFE's reported anorexigenic effects. CFE treatment also conferred protection against atherogenesis. We conclude that CFE possesses antiobesogenic and antiatherosclerotic properties.

  7. C-reactive protein, inflammation and coronary heart disease

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    Amit Kumar Shrivastava

    2015-06-01

    Full Text Available Inflammation is widely considered to be an important contributing factor of the pathophysiology of coronary heart disease (CHD, and the inflammatory cascade is particularly important in the atherosclerotic process. In consideration of the important role that inflammatory processes play in CHD, recent work has been focused on whether biomarkers of inflammation may help to improve risk stratification and identify patient groups who might benefit from particular treatment strategies. Of these biomarkers, C-reactive protein (CRP has emerged as one of the most important novel inflammatory markers. CRP an acute phase protein is synthesized by hepatocytes in response to proinflammatory cytokines, in particular interleukin-6. Many large-scale prospective studies demonstrate that CRP strongly and independently predicts adverse cardiovascular events, including myocardial infarction, ischemic stroke, and sudden cardiac death in individuals both with and without overt CHD. CRP is believed to be both a marker and a mediator of atherosclerosis and CHD. CRP plays a pivotal role in many aspects of atherogenesis including, activation of complement pathway, lipids uptake by macrophage, release of proinflammatory cytokines, induces the expression of tissue factor in monocytes, promotes the endothelial dysfunction and inhibits nitric oxide production. The commercial availability of CRP high sensitive assays has made screening for this marker simple, reliable, and reproducible and can be used as a clinical guide to diagnosis, management, and prognosis of CHD.

  8. Global Metabolomics Reveals the Metabolic Dysfunction in Ox-LDL Induced Macrophage-Derived Foam Cells

    Directory of Open Access Journals (Sweden)

    Wenjuan Xu

    2017-08-01

    Full Text Available Atherosclerosis (AS is a chronic disorder of large arteries that is a major risk factors of high morbidity and mortality. Oxidative modification LDL is one of the important contributors to atherogenesis. Macrophages take up ox-LDL and convert into foam cells, which is the hallmark of AS. To advance the understanding of the metabolic perturbation involved in ox-LDL induced macrophage-derived foam cells and discover the potential biomarkers of early AS, a global metabolomics approach was applied based on UHPLC-QTOF/MS. Multivariate statistical analyses identified five metabolites (25-azacholesterol, anandamide, glycocholate, oleoyl ethanolamide, and 3-oxo-4, 6-choladienoate for distinguishing foamy macrophages from controls. Among the six main metabolic pathways, the unsaturated fatty acid, especially arachidonic acid metabolism, contributed importantly to early AS. A new biomarker, anandamide (AEA, whose synthesis and metabolism in macrophages are disturbed by overloaded ox-LDL, results in metabolic obstruction. This study is the first to investigate the metabolic disturbance in macrophage-derived foam cells induced by ox-LDL and screen potential biomarkers and metabolic pathways associated with early AS. Our findings provide a new insight in the underlying pathophysiological mechanisms and also help to identify novel targets for the intervention of AS.

  9. Serum amyloid A stimulates macrophage foam cell formation via lectin-like oxidized low-density lipoprotein receptor 1 upregulation

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    Lee, Ha Young, E-mail: hayoung@skku.edu [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Kim, Sang Doo [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Baek, Suk-Hwan [Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Joon Hyuk [Department of Pathology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Cho, Kyung-Hyun [School of Biotechnology, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Zabel, Brian A. [Palo Alto Institute for Research and Education, Veterans Affairs Hospital, Palo Alto, CA 94304 (United States); Bae, Yoe-Sik, E-mail: yoesik@skku.edu [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710 (Korea, Republic of)

    2013-03-29

    Highlights: ► SAA induced macrophage foam cell formation. ► SAA stimulated upregulation of lectin-like oxidized low-density lipoprotein receptor 1 (LOX1). ► SAA-induced LOX1 expression and foam cell formation is mediated by JNK/NF-κB signaling. ► HDL-conjugated SAA also stimulates foam cell formation via LOX1 upregulation. ► The finding reveals a novel mechanism of action of SAA in the pathogenesis of atherosclerosis. -- Abstract: Elevated levels of serum amyloid A (SAA) is a risk factor for cardiovascular diseases, however, the role of SAA in the pathophysiology of atherosclerosis remains unclear. Here we show that SAA induced macrophage foam cell formation. SAA-stimulated foam cell formation was mediated by c-jun N-terminal kinase (JNK) signaling. Moreover, both SAA and SAA-conjugated high density lipoprotein stimulated the expression of the important scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) via nuclear factor-κB (NF-κB). A LOX1 antagonist carrageenan significantly blocked SAA-induced foam cell formation, indicating that SAA promotes foam cell formation via LOX1 expression. Our findings therefore suggest that SAA stimulates foam cell formation via LOX1 induction, and thus likely contributes to atherogenesis.

  10. Systemic Redox Imbalance in Chronic Kidney Disease: A Systematic Review

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    Konstantina P. Poulianiti

    2016-01-01

    Full Text Available Patients with chronic kidney disease (CKD experience imbalance between oxygen reactive species (ROS production and antioxidant defenses leading to cell and tissue damage. However, it remains unclear at which stage of renal insufficiency the redox imbalance becomes more profound. The aim of this systematic review was to provide an update on recent advances in our understanding of how the redox status changes in the progression of renal disease from predialysis stages 1 to 4 to end stage 5 and whether the various treatments and dialysis modalities influence the redox balance. A systematic review was conducted searching PubMed and Scopus by using the Cochrane and PRISMA guidelines. In total, thirty-nine studies met the inclusion criteria and were reviewed. Even from an early stage, imbalance in redox status is evident and as the kidney function worsens it becomes more profound. Hemodialysis therapy per se seems to negatively influence the redox status by the elevation of lipid peroxidation markers, protein carbonylation, and impairing erythrocyte antioxidant defense. However, other dialysis modalities do not so far appear to confer advantages. Supplementation with antioxidants might assist and should be considered as an early intervention to halt premature atherogenesis development at an early stage of CKD.

  11. Computational modelling of flow and tip variations of aortic cannulae in cardiopulmonary bypass procedure

    Science.gov (United States)

    Thomas, Siti A.; Empaling, Shirly; Darlis, Nofrizalidris; Osman, Kahar; Dillon, Jeswant; Taib, Ishkrizat; Khudzari, Ahmad Zahran Md

    2017-09-01

    Aortic cannulation has been the gold standard for maintaining cardiovascular function during open heart surgery while being connected onto the heart lung machine. These cannulation produces high velocity outflow which may lead to adverse effect on patient condition, especially sandblasting effect on aorta wall and blood cells damage. This paper reports a novel design that was able to decrease high velocity outflow. There were three design factors of that was investigated. The design factors consist of the cannula type, the flow rate, and the cannula tip design which result in 12 variations. The cannulae type used were the spiral flow inducing cannula and the standard cannula. The flow rates are varied from three to five litres per minute (lpm). Parameters for each cannula variation included maximum velocity within the aorta, pressure drop, wall shear stress (WSS) area exceeding 15 Pa, and impinging velocity on the aorta wall were evaluated. Based on the result, spiral flow inducing cannulae is proposed as a better alternatives due to its ability to reduce outflow velocity. Meanwhile, the pressure drop of all variations are less than the limit of 100 mmHg, although standard cannulae yielded better result. All cannulae show low reading of wall shear stress which decrease the possibilities for atherogenesis formation. In conclusion, as far as velocity is concerned, spiral flow is better compared to standard flow across all cannulae variations.

  12. Endothelial C-type natriuretic peptide maintains vascular homeostasis.

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    Moyes, Amie J; Khambata, Rayomand S; Villar, Inmaculada; Bubb, Kristen J; Baliga, Reshma S; Lumsden, Natalie G; Xiao, Fang; Gane, Paul J; Rebstock, Anne-Sophie; Worthington, Roberta J; Simone, Michela I; Mota, Filipa; Rivilla, Fernando; Vallejo, Susana; Peiró, Concepción; Sánchez Ferrer, Carlos F; Djordjevic, Snezana; Caulfield, Mark J; MacAllister, Raymond J; Selwood, David L; Ahluwalia, Amrita; Hobbs, Adrian J

    2014-09-01

    The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor-C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.

  13. s-ICAM-1 and s-VCAM-1 in healthy men are strongly associated with traits of the metabolic syndrome, becoming evident in the postprandial response to a lipid-rich meal

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    Nothnagel Michael

    2008-09-01

    Full Text Available Abstract Background The importance of the postprandial state for the early stages of atherogenesis is increasingly acknowledged. We conducted assessment of association between postprandial triglycerides, insulin and glucose after ingestion of a standardized lipid-rich test meal, and soluble cellular adhesion molecules (sCAM in young healthy subjects. Methods Metabolic parameters and sICAM-1, sVCAM-1 and E-selectin were measured before and hourly until 6 hours after ingestion of a lipid-rich meal in 30 healthy young men with fasting triglycerides 260 mg/dl. Levels of CAM were compared in HR and NR, and correlation with postprandial triglyceride, insulin and glucose response was assessed. Results Fasting sICAM-1 and sVCAM-1 levels were significantly higher in HR as compared to NR (p = 0.046, p = 0.03. For sE-selectin there was such a trend (p = 0.05. There was a strong positive and independent correlation between sICAM-1 and postprandial insulin maxima (r = 0.70, p Conclusion This independent association of postprandial triglycerides with sICAM-1 may indicate a particular impact of postprandial lipid metabolism on endothelial reaction.

  14. Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.

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    Philip L S M Gordts

    Full Text Available OBJECTIVE: Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1 dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE. METHODS AND RESULTS: LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoE-deficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2-fold reduction in LDL-cholesterol levels. CONCLUSION: These findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation.

  15. Drugs Involved in Dyslipidemia and Obesity Treatment: Focus on Adipose Tissue

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    Sofia Dias

    2018-01-01

    Full Text Available Metabolic syndrome can be defined as a state of disturbed metabolic homeostasis characterized by visceral obesity, atherogenic dyslipidemia, arterial hypertension, and insulin resistance. The growing prevalence of metabolic syndrome will certainly contribute to the burden of cardiovascular disease. Obesity and dyslipidemia are main features of metabolic syndrome, and both can present with adipose tissue dysfunction, involved in the pathogenic mechanisms underlying this syndrome. We revised the effects, and underlying mechanisms, of the current approved drugs for dyslipidemia and obesity (fibrates, statins, niacin, resins, ezetimibe, and orlistat; sibutramine; and diethylpropion, phentermine/topiramate, bupropion and naltrexone, and liraglutide on adipose tissue. Specifically, we explored how these drugs can modulate the complex pathways involved in metabolism, inflammation, atherogenesis, insulin sensitivity, and adipogenesis. The clinical outcomes of adipose tissue modulation by these drugs, as well as differences of major importance for clinical practice between drugs of the same class, were identified. Whether solutions to these issues will be found in further adjustments and combinations between drugs already in use or necessarily in new advances in pharmacology is not known. To better understand the effect of drugs used in dyslipidemia and obesity on adipose tissue not only is challenging for physicians but could also be the next step to tackle cardiovascular disease.

  16. Effect of conjugated linoleic acid isomers on lipoproteins and atherosclerosis in the Syrian Golden hamster.

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    Mitchell, Patricia L; Langille, Morgan A; Currie, Deborah L; McLeod, Roger S

    2005-06-01

    Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid (LA, C18:2 cis-9, cis-12) that are reported to have important biological activities, including protection against atherosclerosis. In this study, the potential role of the individual cis-9, trans-11 and trans-10, cis-12 isomers of CLA in atherogenesis were compared with LA in the Syrian Golden hamster. Supplementation of a high-fat, high-cholesterol diet (HFHC) with 1% (w/w) cis-9, trans-11 CLA or trans-10, cis-12 CLA did not significantly affect plasma cholesterol levels compared to supplementation with 1% (w/w) LA. Very low density lipoprotein cholesterol (VLDL-C) was lower and plasma triglycerides (TG) were higher in diets where C18:2 fatty acid was added to the HFHC diet, but neither the cis-9, trans-11 CLA group nor trans-10, cis-12 CLA group was significantly different from the LA control group. CLA supplementation did not significantly affect low density lipoprotein cholesterol (LDL-C). Trans-10, cis-12 CLA increased high density lipoprotein cholesterol (HDL-C) levels compared to LA or cis-9, trans-11 CLA (Phamster, but when compared to LA, the apparent atheroprotective effects do not correlate with beneficial changes in lipoprotein profile.

  17. Noradrenaline has opposing effects on the hydraulic conductance of arterial intima and media.

    Science.gov (United States)

    Chooi, K Y; Comerford, A; Sherwin, S J; Weinberg, P D

    2017-03-21

    The uptake of circulating macromolecules by the arterial intima is thought to be a key step in atherogenesis. Such transport is dominantly advective, so elucidating the mechanisms of water transport is important. The relation between vasoactive agents and water transport in the arterial wall is incompletely understood. Here we applied our recently-developed combination of computational and experimental methods to investigate the effects of noradrenaline (NA) on hydraulic conductance of the wall (Lp), medial extracellular matrix volume fraction (ϕECM) and medial permeability (K11) in the rat abdominal aorta. Experimentally, we found that physiological NA concentrations were sufficient to induce SMC contraction and produced significant decreases in Lp and increases in ϕECM. Simulation results based on 3D confocal images of the extracellular volume showed a corresponding increase in K11, attributed to the opening of the ECM. Conversion of permeabilities to layer-specific resistances revealed that although the total wall resistance increased, medial resistance decreased, suggesting an increase in intimal resistance upon application of NA. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. The effect of AVE 0991, nebivolol and doxycycline on inflammatory mediators in an apoE-knockout mouse model of atherosclerosis.

    Science.gov (United States)

    Jawien, Jacek; Toton-Zuranska, Justyna; Kus, Katarzyna; Pawlowska, Malgorzata; Olszanecki, Rafal; Korbut, Ryszard

    2012-10-01

    The aim of this study was to investigate whether the 3 different substances that can decrease the development of atherosclerosis--nebivolol, AVE 0991 and doxycycline--could at the same time diminish the level of inflammatory indicators interleukin-6 (IL-6), interleukin-12 (IL-12), serum amyloid A (SAA), and monocyte chemotactic protein-1 (MCP-1). Forty 8-week-old female apoE-knockout mice on the C57BL/6J background were divided into 4 groups and put on chow diet for 4 months. Three experimental groups received the same diet as a control group, mixed with AVE 0991 at a dose 0.58 µmol per kg of body weight per day, nebivolol at a dose 2.0 µmol per kg of body weight per day, and doxycycline at a dose 1.5 mg per kg of body weight per day. At the age of 6 months, the mice were sacrificed. All inflammatory indicators (MCP-1, IL-6, IL-12 and SAA) were diminished by AVE 0991. There was also a tendency to lower MCP-1, IL-6, IL-12 and SAA levels by nebivolol and doxycycline; however, it did not reach statistical significance. Of the 3 presented substances, only AVE 0991 was able to diminish the rise of inflammatory markers. Therefore, drug manipulations in the renin-angiotensin-aldosterone axis seem to be the most promising in the future treatment of atherogenesis.

  19. The influence of angiotensin-(1-7) peptidomimetic (AVE 0991) and nebivolol on angiotensin I metabolism in aorta of apoE-knockout mice.

    Science.gov (United States)

    Olszanecki, R; Suski, M; Gebska, A; Toton-Zuranska, J; Kus, K; Madej, J; Bujak-Gizycka, B; Jawien, J; Korbut, R

    2013-06-01

    The detrimental role of over activation of renin-angiotensin system (RAS) in atherogenesis is widely recognized. Recently, we have demonstrated that Ang-(1-7) peptidomimetic - AVE0991, as well as known beta-adrenolytic agent nebivolol, exert anti-atherogenic actions in mouse model of atherosclerosis - apoE-knockout mice. Here, using LC-ESI-MS ex vivo system, we tested whether prolonged treatment of apoE-knockout mice by these drugs can influence RAS in aorta of apoE-knockout mice in regard to generation of most active metabolites of Ang I-Ang II and Ang-(1-7). As compared to wild type animals there was increased generation of Ang II in aorta of apoE-knockout mice, while the formation of Ang-(1-7) did not differ between both groups. Either treatment with AVE0991 or nebivolol resulted in significant attenuation of Ang II production in aorta of apoE-knockout mice. In conclusion, for the first time we directly demonstrated that there is increase in ability of aortic tissue to generate Ang II in mouse model of atherosclerosis of apoE knockout mice, and that such effect could be efficiently attenuated either by treatment of nebivolol or Ang-(1-7) peptidomimetic - AVE0991. The exact mechanism(s) responsible for interference of both drugs with RAS require further investigation.

  20. MMP-1 serum levels predict coronary atherosclerosis in humans

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    Reiser Maximilian

    2009-09-01

    Full Text Available Background Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease. Methods 260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. Results In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85; p Conclusion MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.

  1. Dyslipidemia in dialysis patients

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    Ahmed H Mitwalli

    2011-01-01

    Full Text Available In order to evaluate the lipid profiles of dialysis patients, we retrospectively reviewed all the chronic kidney disease (CKD patients on chronic hemodialysis (HD or continuous ambulatory peritoneal dialysis (CAPD, followed up between June 2004 and May 2005, in two tertiary hospitals in Riyadh, Saudi Arabia. There were 380 patients including 206 (54.2% females and the mean age of the patients was 45.9 ± 15.8 years. The mean dialysis duration was 65.0 ± 58.3 months. Diabetes was present in 97 (25.5% of the patients and hypertension in 84 (22.1%. Younger patients had more disturbed lipid profile than elderly patients, and females had higher lipid values than males. The CAPD patients had worse lipid profile than those on HD, irrespective of age, sex and duration of dialysis. The presence of diabetes, hypertension, smoking and cardiovascular disease (CVD all contributed to the worsening of lipid profiles of our patients. Dialysis patients showed improvement in lipid profile initially followed by gradual deterioration. We conclude that dyslipidemia, which increases the risk of CVD by increasing atherogenesis, progresses over time in dialysis patients and becomes worse in CAPD patients.

  2. Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice.

    Science.gov (United States)

    Huang, LinZhang; Fan, BaoYan; Ma, Ang; Shaul, Philip W; Zhu, HaiBo

    2015-05-01

    ABCA1 plays a key role in the initial lipidation of apoA-I, which generates circulating HDL cholesterol. Whereas it is known that the transcriptional upregulation of ABCA1 promotes HDL formation and reverse cholesterol transport (RCT), it is not known how the inhibition of ABCA1 protein degradation impacts HDL function. Employing the small molecule triacetyl-3-hydroxyphenyladenosine (IMM-H007), we determined how the attenuation of ABCA1 protein degradation affects HDL cholesterol efflux capacity, RCT, and atherosclerotic lesion formation. Pulse-chase analysis revealed that IMM-H007 inhibits ABCA1 degradation and facilitates its cell-surface localization in macrophages, and additional studies in macrophages showed that IMM-H007 thereby promotes cholesterol efflux. IMM-H007 treatment of Paigen diet-fed mice caused an increase in circulating HDL level, it increased the cholesterol efflux capacity of HDL, and it enhanced in vivo RCT from macrophages to the plasma, liver, and feces. Furthermore, ABCA1 degradation suppression by IMM-H007 reduced atherosclerotic plaque formation in apoE(-/-) mice. Thus, via effects on both ABCA1-expressing cells and circulating HDL function, the inhibition of ABCA1 protein degradation by IMM-H007 promotes HDL cholesterol efflux capacity and RCT and attenuates atherogenesis. IMM-H007 potentially represents a lead compound for the development of agents to augment HDL function. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

  3. Effect of Antioxidant Mineral Elements Supplementation in the Treatment of Hypertension in Albino Rats

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    S. A. Muhammad

    2012-01-01

    Full Text Available Oxidative stress has been implicated in various pathologies, including hypertension, atherosclerosis, diabetes, and chronic renal disease. The current work was designed with the aim of investigating the potentials of antioxidants copper, manganese, and zinc in the treatment of hypertension in Wistar rats. The rats were fed 8% NaCl diet for 5 weeks and treatment with supplements in the presence of the challenging agent for additional 4 weeks. The supplementation significantly decreased the blood pressure as compared with hypertensive control. The result also indicated significant decreased in the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol, malondialdehyde, insulin and increase in the high-density lipoprotein cholesterol, total antioxidant activities, and nitric oxide of the supplemented groups relative to the hypertensive control. The average percentage protection against atherogenesis indicated 47.13 ± 9.60% for all the supplemented groups. The mean arterial blood pressure showed significant positive correlation with glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, atherogenic index, insulin resistance and malondialdehyde while high density lipoprotein-cholesterol and total antioxidant activities showed negative correlation. The result therefore indicated strong relationship between oxidative stress and hypertension and underscores the role of antioxidant minerals in reducing oxidative stress, dyslipidemia, and insulin resistance associated with hypertension.

  4. FY 1995 basic research to develop instruments for diagnosis of atherosclerosis on the basis of autofluorescence analysis of blood and vascular walls; 1995 nendo ketsueki oyobi kekkanheki no jiko keiko bunseki ni yoru domyaku koka shindan kiki kaiahtsu no tame no kisoteki kenkyu

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    NONE

    1997-03-01

    To obtain the basic data to develop instruments for diagnosis of atherosclerosis and to elucidate the mechanisms of atherogenesis by focusing on the autofluorescence of blood and vascular walls of atherosclerotic animal models and human patients. We have performed experiments to examine the relationships between autofluorescence of blood and vascular walls of guinea pig atherosclerotic model and human patients and obtained the following results. 1. The autofluorescence from human atherosclerotic aorta included the components with longer wave length than normal aorta, suggesting that diagnosis of atherosclerotic aortic walls will be possible using spectroscopic analysis through glass fiber catheter into vascular system. Further studies should be needed to the quantitative diagnosis. 2. The autofluorescence from blood plasma of human atherosclerotic patients has showed that the peak wave length was shorter than that of normal plasma. This phenomenon was mainly caused by the oxidization of plasma, especially lipoproteins, LDL and HDL. 3. Atherosclerotic model of the guinea pigs was quite similar to human atherosclerosis at the points of cholesterol levels and localization of lipid deposit to arterial walls, and showed to be useful for the studies of atherosclerosis. (NEDO)

  5. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009.

    Science.gov (United States)

    DeFronzo, R A

    2010-07-01

    Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients.

  6. Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia.

    Science.gov (United States)

    Yagyu, H; Kitamine, T; Osuga, J; Tozawa, R; Chen, Z; Kaji, Y; Oka, T; Perrey, S; Tamura, Y; Ohashi, K; Okazaki, H; Yahagi, N; Shionoiri, F; Iizuka, Y; Harada, K; Shimano, H; Yamashita, H; Gotoda, T; Yamada, N; Ishibashi, S

    2000-07-14

    Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes esterification of cellular cholesterol. To investigate the role of ACAT-1 in atherosclerosis, we have generated ACAT-1 null (ACAT-1-/-) mice. ACAT activities were present in the liver and intestine but were completely absent in adrenal, testes, ovaries, and peritoneal macrophages in our ACAT-1-/- mice. The ACAT-1-/- mice had decreased openings of the eyes because of atrophy of the meibomian glands, a modified form of sebaceous glands normally expressing high ACAT activities. This phenotype is similar to dry eye syndrome in humans. To determine the role of ACAT-1 in atherogenesis, we crossed the ACAT-1-/- mice with mice lacking apolipoprotein (apo) E or the low density lipoprotein receptor (LDLR), hyperlipidemic models susceptible to atherosclerosis. High fat feeding resulted in extensive cutaneous xanthomatosis with loss of hair in both ACAT-1-/-:apo E-/- and ACAT-1-/-:LDLR-/- mice. Free cholesterol content was significantly increased in their skin. Aortic fatty streak lesion size as well as cholesteryl ester content were moderately reduced in both double mutant mice compared with their respective controls. These results indicate that the local inhibition of ACAT activity in tissue macrophages is protective against cholesteryl ester accumulation but causes cutaneous xanthomatosis in mice that lack apo E or LDLR.

  7. Effect of the treatment with Euterpe oleracea Mart. oil in rats with Triton-induced dyslipidemia.

    Science.gov (United States)

    E Souza, Belmira S Faria; Carvalho, Helison O; Ferreira, Irlon M; da Cunha, Edilson L; Barros, Albenise Santana; Taglialegna, Talisson; Carvalho, José C T

    2017-06-01

    Dyslipidemias are defined as changes in lipid metabolism that have abnormal concentrations of lipids or lipoproteins in the bloodstream. Chronic increase in triglyceride and low-density lipoprotein (LDL-c) levels are known as risk factors for the atherogenesis process as well as other cardiovascular diseases (CVDs). The magnitude of the problems caused by dyslipidemias impels research by new agents that act in the prevention and control. Thus, products from the Amazonian biodiversity, such as Euterpe oleracea oil (OFEO), rich in unsaturated fatty acids (UFAs), constitutes a study source for the treatment of alterations in lipid metabolism. The present study aims to investigate the effect of OFEO treatment in rats with Triton-induced dyslipidemia (Tyloxapol WR1339). The physicochemical and chromatographic results confirmed the chemical composition of OFEO with a predominance of UFAs (67.83%), with Oleic acid being the majority (54.32%). At Triton-induced dyslipidemia, the animals treated with OFEO and Simvastatin showed a significant reduction in total cholesterol levels, with values ​​of 121.7±29.5 (pstudy had a beneficial effect on dyslipidemia, acting as antihypercholesterolemic and antihypertriglyceridemic, thus possibly contributing as a preventive agent for CVDs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. The role of platelet-endothelial cell adhesion molecule-1 in atheroma formation varies depending on the site-specific hemodynamic environment.

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    Harrison, Matthew; Smith, Emily; Ross, Ewan; Krams, Robert; Segers, Dolf; Buckley, Christopher D; Nash, Gerard B; Rainger, G Ed

    2013-04-01

    Polymorphisms in the platelet-endothelial cell adhesion molecule (PECAM-1)-1 gene are linked to increased risk of coronary artery disease. Because PECAM-1 has been demonstrated to form a mechanosensory complex that can modulate inflammatory responses in murine arterial endothelial cells, we hypothesized that PECAM-1 contributes to atherogenesis in a shear-dependent and site-specific manner. ApoE(-/-) mice that were wild-type, heterozygous, or deficient in PECAM-1 were placed on a high-fat diet. Detailed analysis of the aorta at sites with differing hemodynamics revealed that PECAM-1-deficient mice had reduced disease in areas of disturbed flow, whereas plaque burden was increased in areas of steady, laminar flow. In concordance with these observations, bone marrow chimera experiments revealed that hematopoietic PECAM-1 resulted in accelerated atheroma formation in areas of laminar and disturbed flow, however endothelial PECAM-1 moderated disease progression in areas of high sheer stress. Moreover, using shear stress-modifying carotid cuffs, PECAM-1 was shown to promote macrophage recruitment into lesions developing in areas of low shear stress. PECAM-1 on bone marrow cells is proatherogenic irrespective of the hemodynamic environment, however endothelial cell PECAM-1 is antiatherogenic in high shear environments. Thus, targeting this pathway therapeutically would require a cell-type and context-specific strategy.

  9. Monocytes initiate a cycle of leukocyte recruitment when cocultured with endothelial cells.

    Science.gov (United States)

    Tsouknos, Andreas; Nash, Gerard B; Rainger, G Ed

    2003-09-01

    During the development of atherosclerotic plaque, monocytes and T-lymphocytes are recruited to the arterial intima by endothelial cells (EC) lining the vessel. This process is associated with chronic arterial inflammation and requires the activation-dependent expression of adhesion receptors and chemokines on EC. Here we show that monocytes can activate cocultured EC so that they support the adhesion, activation and transmigration of a secondary bolus of flowing peripheral blood monocytes or lymphocytes. The number of adherent leukocytes and their behaviour was comparable to that seen on EC activated with tumour necrosis factor-alpha (TNF-alpha). Depending upon the duration of endothelial cell/monocyte coculture different patterns of adhesion receptors were utilised by leukocytes. After 4 h coculture, antibodies against E-selectin, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) reduced mononuclear leukocyte adhesion. After 24 h coculture, antibodies against E-selectin and VCAM-1 but not P-selectin were effective. Immunofluorescence analysis confirmed that monocyte coculture induced endothelial expression of E-selectin and VCAM-1, while P-selectin was at the limit of detection. We conclude that EC stimulated by monocytes can support the adhesion of flowing mononuclear leukocytes. We hypothesise that this mode of EC activation and leukocyte recruitment could initiate a self-perpetuating cycle of inflammation that could be relevant to atherogenesis and other chronic inflammatory disease states.

  10. Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption

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    Lampi, Marsha C.; Faber, Courtney J.; Huynh, John; Bordeleau, Francois; Zanotelli, Matthew R.; Reinhart-King, Cynthia A.

    2016-01-01

    Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening. PMID:26761203

  11. Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.

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    Marsha C Lampi

    Full Text Available Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.

  12. Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals

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    Kihara, Mikihiro; Schmelzer, J.D.; Poduslo, J.F.; Curran, G.L.; Nickander, K.K.; Low, P.A. (Mayo Foundation, Rochester, MN (United States))

    1991-07-15

    Since advanced glycosylation end products have been suggested to mediate hyperglycemia-induced microvascular atherogenesis and because aminoguanidine (AG) prevents their generation, the authors examined whether AG could prevent or ameliorate the physiologic and biochemical indices of streptozotocin (STZ)-induced experimental diabetic neuropathy. Four groups of adult Sprague-Dawley rats were studied: group I received STZ plus AG, group II received STZ plus AG, group III received STZ alone, and group IV was a control. They monitored conduction and action potential amplitudes serially in sciatic-tibial and caudal nerves, nerve blood flow, oxygen free radical activity (conjugated dienes and hydroperoxides), and the product of the permeability coefficient and surface area to {sup 125}I-labeled albumin. STZ-induced diabetes (group III) caused a 57% reduction in nerve blood flow and in abnormal nerve conduction and amplitudes and a 60% increase in conjugated dienes. Nerve blood flow was normalized by 8 weeks with AG (groups I and II) and conduction was significantly improved, in a dose-dependent manner, by 16 and 24 weeks in sciatic-tibial and caudal nerves, respectively. The permeability coefficient was not impaired, suggesting a normal blood-nerve barrier function for albumin, and the oxygen free-radical indices were not ameliorated by AG. They suggest that AG reverses nerve ischemia and more gradually improves their electrophysiology by an action on nerve microvessels. AG may have potential in the treatment of diabetic neuropathy.

  13. Plasma Gamma-Glutamyltransferase Is Strongly Determined by Acylation Stimulating Protein Levels Independent of Insulin Resistance in Patients with Acute Coronary Syndrome

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    Jumana Saleh

    2013-01-01

    Full Text Available Background. Steatosis is a manifestation of the metabolic syndrome often associated with release of liver enzymes and inflammatory adipocytokines linked to cardiovascular risk. Gamma-glutamyltransferase (GGT is one sensitive liver marker recently identified as an independent cardiovascular risk factor. Mechanisms involved in enhanced hepatic lipogenesis causing steatosis are not yet identified and are usually linked to insulin resistance (IR. Acylation stimulating protein (ASP, a potent lipogenic factor, was recently shown to increase in patients with steatosis and was implicated in its pathogenesis. Aim. To investigate the association of plasma ASP levels with liver and metabolic risk markers in acute coronary syndrome (ACS patients. Methods. 28 patients and 30 healthy controls were recruited. Their anthropometrics, lipid profile, liver markers, insulin, and ASP levels were measured. Results. In the patients, ASP, liver, and metabolic risk markers were markedly higher than in the controls. ASP strongly predicted GGT levels (B=0.75, P<0.0001, followed by triglycerides (B=0.403, P=0.017, together determining 57.6% variation in GGT levels. Insulin and IR correlated with metabolic risk components but not with liver enzymes. Conclusion. The strong association of ASP with GGT in ACS patients suggests that ASP, independent of IR, may contribute to a vicious cycle of hepatic lipogenic stimulation and GGT release promoting atherogenesis.

  14. Effects of Thyme Extract Oils (from Thymus vulgaris, Thymus zygis, and Thymus hyemalis on Cytokine Production and Gene Expression of oxLDL-Stimulated THP-1-Macrophages

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    A. Ocaña

    2012-01-01

    Full Text Available Properties of thyme extracts from three different species (Thymus vulgaris, Thymus zygis, and Thymus hyemalis were examined. Two oil fractions from each species were obtained by CO2 supercritical fluid extraction. Main compounds presented in the supercritical extracts of the three thyme varieties were 1,8 cineole, thymol, camphor, borneol, and carvacrol. As a cellular model of inflammation/atherogenesis, we use human macrophages derived from THP-1 monocytes and activated by oxidized LDLs. These cells were incubated with the thyme fraction oils, and the productions and gene expressions of the inflammatory mediators TNF-α, IL-1B, IL-6, and IL-10 were determined. Thyme extracts significantly reduced production and gene expression of the proinflammatory mediators TNF-α, IL-1B, and IL-6 and highly increased these parameters on the anti-inflammatory IL-10 cytokine. Changes on production and gene expressions were dose dependent and according to the thyme content of each species. Taken together, these results may suggest that thyme extracts could have anti-inflammatory effects.

  15. Rapeseed oil fortified with micronutrients reduces atherosclerosis risk factors in rats fed a high-fat diet

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    Yang Jin'e

    2011-06-01

    Full Text Available Abstract Background Micronutrients polyphenols, tocopherols and phytosterols in rapeseed exert potential benefit to cardiovascular system, but most of these micronutrients are removed by the refining process. The aim of this study was to determine the effect of rapeseed oil fortified with these micronutrients on the atherosclerosis risk factors in rats fed a high-fat diet. Methods The rodent diet contained 20% fat whose source was refined rapeseed oil (RRO or fortified refined rapeseed oil with low, middle and high quantities of these micronutrients (L-, M- and H-FRRO. Forty male SD rats were divided into four groups. One group received RRO diet and other groups received L-, M- and H-FRRO diet for 10 weeks. Results Micronutrients supplementation significantly increased plasma antioxidant defense capacities, as evaluated by the significant elevation in the activities of GPx, CAT and SOD as well as the level of GSH, and the significant decline in lipid peroxidation. These micronutrients also reduced the plasma contents of TG, TC and LDL-C and increased the ratio of HDL-C/LDL-C. In addition, in parallel with the enhancement of these micronutrients, plasma levels of IL-6 and CRP declined remarkably. Conclusion Rapeseed oil fortified with micronutrients polyphenols, tocopherols and phytosterols may contribute to prevent atherogenesis by ameliorating plasma oxidative stress, lipid profile and inflammation.

  16. SERUM GAMMA-GLUTAMYL TRANSPEPTIDASE AND LIPIDS IN YOUNG ADULTS WITH UNCOMPLICATED ESSENTIAL HYPERTENSION

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    Rajarajeswari D, Ramalingam, Sharmila T, Prasad Naidu M, Naidu JN

    2015-07-01

    Full Text Available Introduction: Gamma-glutamyl transpeptidase initially used as an indicator of alcohol ingestion is now viewed as a sensitive marker of sub clinical inflammation. Recent clinical studies have shown its association with blood pressure and lipid profile. As GGT degrades glutathione, an antioxidant GGT can be considered as a pro inflammatory marker playing a role in atherogenesis and hypertension. Materials and methods: 65 subjects with Essential hypertension and 50 age and sex matched healthy controls both male and female between 18-50 years of age were recruited from General Medicine department of Narayana Medical college and Hospital, Nellore, A.P. Serum GGT was measured by calorimetric kinetic assay. Fasting Serum Triglycerides, Total Cholesterol and HDL cholesterol by standard enzymatic procedures and LDL cholesterol by Friedwald equation. Results: GGT is significantly elevated in hypertensive subjects (Mean±SD 64.2±18.62IU/L compared to controls (Mean±SD 26.20±8.91IU/L (P value <0.001. GGT is significantly correlated with systolic BP (r= 0.26 p<0.01 and diastolic BP(r= 0.28 p<0.01. Conclusion: Our findings suggest that elevated GGT in young adults may contribute to their susceptibility to hypertension and provide an additional evidence of novel role of GGT in cardiovascular risk evaluation.

  17. Retinoid metabolism and its effects on the vasculature.

    Science.gov (United States)

    Rhee, Eun-Jung; Nallamshetty, Shriram; Plutzky, Jorge

    2012-01-01

    Retinoids, the metabolically-active structural derivatives of vitamin A, are critical signaling molecules in many fundamental biological processes including cell survival, proliferation and differentiation. Emerging evidence, both clinical and molecular, implicates retinoids in atherosclerosis and other vasculoproliferative disorders such as restenosis. Although the data from clinical trials examining effect of vitamin A and vitamin precursors on cardiac events have been contradictory, this data does suggest that retinoids do influence fundamental processes relevant to atherosclerosis. Preclinical animal model and cellular studies support these concepts. Retinoids exhibit complex effects on proliferation, growth, differentiation and migration of vascular smooth muscle cells (VSMC), including responses to injury and atherosclerosis. Retinoids also appear to exert important inhibitory effects on thrombosis and inflammatory responses relevant to atherogenesis. Recent studies suggest retinoids may also be involved in vascular calcification and endothelial function, for example, by modulating nitric oxide pathways. In addition, established retinoid effects on lipid metabolism and adipogenesis may indirectly influence inflammation and atherosclerosis. Collectively, these observations underscore the scope and complexity of retinoid effects relevant to vascular disease. Additional studies are needed to elucidate how context and metabolite-specific retinoid effects affect atherosclerosis. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved.

  18. Effects of rosiglitazone on contralateral iliac artery after vascular injury in hypercholesterolemic rabbits

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    Baroncini Liz

    2008-05-01

    Full Text Available Abstract Background The objective was to evaluate the effects of rosiglitazone on iliac arteries of hypercholesterolemic rabbits undergoing balloon catheter injury in the contralateral iliac arteries. Methods White male rabbits were fed a hypercholesterolemic diet for 6 weeks and divided into two groups as follows: rosiglitazone group, 14 rabbits treated with rosiglitazone (3 mg/Kg body weight/day during 6 weeks; and control group, 18 rabbits without rosiglitazone treatment. All animals underwent balloon catheter injury of the right iliac artery on the fourteenth day of the experiment. Results There was no significant difference in intima/media layer area ratio between the control group and the rosiglitazone group. Rosiglitazone did not reduce the probability of lesions types I, II, or III (72.73% vs. 92.31%; p = 0.30 and types IV or V (27.27% vs. 7.69%; p = 0.30. There were no differences in the extent of collagen type I and III deposition or in the percentage of animals with macrophages in the intima layer. The percentage of rabbits with smooth muscle cells in the intima layer was higher in rosiglitazone group (p = 0.011. Conclusion These findings demonstrate that rosiglitazone given for 6 weeks did not prevent atherogenesis at a vessel distant from the injury site.

  19. Plasma oxygen permeability may be a factor in atherosclerosis.

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    Heppner, Bradley T; Morgan, Louis Wm

    2004-01-01

    Plasma oxygen permeability measures how easily oxygen dissolves in and diffuses through blood plasma. There has long been evidence that artery wall hypoxia plays a role in atherogenesis. This paper reviews the influence that plasma oxygen permeability has on artery wall oxygenation and presents experimental evidence for a relationship between plasma oxygen permeability and clinically significant obstructive coronary artery disease. Thirty-eight inpatients referred for diagnostic cardiac catheterization were scored for active coronary artery disease, and their plasma oxygen permeabilities were measured. There was a statistically significant (p = 0.04) correlation between active coronary artery disease and plasma oxygen permeability. There were also statistically significant differences in mean plasma oxygen permeability both between patients who did and did not have actively progressing coronary artery disease (p = 0.01) and between patients who did and did not have clinically significant obstructive coronary artery disease, whether it was actively progressing or not (p = 0.02). These findings suggest that a decline in plasma oxygen permeability may be one of the many factors associated with progression of atherosclerosis and that substances which increase oxygen permeability might offer a useful adjunct to current therapeutic measures.

  20. Fasting Lipoprotein Lipase Protein Levels Can Predict a Postmeal Increment of Triglyceride Levels in Fasting Normohypertriglyceridemic Subjects.

    Science.gov (United States)

    Tsuzaki, Kokoro; Kotani, Kazuhiko; Yamada, Kazunori; Sakane, Naoki

    2016-09-01

    Although a postprandial increment in triglyceride (TG) levels is considered to be a risk factor for atherogenesis, tests (e.g., fat load) to assess postprandial changes in TG levels cannot be easily applied to clinical practice. Therefore, fasting markers that predict postprandial TG states are needed to be developed. One current candidate is lipoprotein lipase (LPL) protein, a molecule that hydrides TGs. This study investigated whether fasting LPL levels could predict postprandial TG levels. A total of 17 subjects (11 men, 6 women, mean age 52 ± 11 years) with normotriglyceridemia during fasting underwent the meal test. Several fasting parameters, including LPL, were measured for the area under the curve of postprandial TGs (AUC-TG). The subjects' mean fasting TG level was 1.30 mmol/l, and their mean LPL level was 41.6 ng/ml. The subjects' TG levels increased after loading (they peaked after two postprandial hours). Stepwise multiple regression analysis demonstrated that fasting TG levels were a predictor of the AUC-TG. In addition, fasting LPL mass levels were found to be a predictor of the AUC-TG (β = 0.65, P fasting TG levels. Fasting LPL levels may be useful to predict postprandial TG increment in this population. © 2015 Wiley Periodicals, Inc.

  1. Simultaneous measurement of flow over and transmigration through a cultured endothelial cell layer

    Science.gov (United States)

    Lambert, Lori; Pipinos, Iraklis; Baxter, Timothy; MacTaggart, Jason; Moormeier, Derek; Bayles, Kenneth; Wei, Timothy

    2014-11-01

    The measurement and analysis of fluid forces on endothelial cells at the cellular and subcellular levels is an essential component of understanding mechanotransduction and atherogenesis. The ultimate goal of this study is to examine and model the transport and transmigration of low-density lipoproteins across a confluent endothelial layer as a function of fluid loading and time. In this study, steady flow over a cultured endothelial cell layer at shear rates up to 20 dynes/cm2 in a 350 μm × 70 μm cross section mircrochannel was measured using μPTV measurements. By using multiple measurement planes parallel to the channel wall, wall shear stress and wall pressure were computed as well as the endothelial cell topography. The study was performed over a period of 18 hours in which the transport and transmigration of fluorescently tagged low-density lipoproteins through a cultured endothelial cell layer were examined as a function of fluid forces, cell topography, and time. The help of Dr. Richard Leighton is gratefully acknowledged.

  2. Control of the T follicular helper-germinal center B-cell axis by CD8⁺ regulatory T cells limits atherosclerosis and tertiary lymphoid organ development.

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    Clement, Marc; Guedj, Kevin; Andreata, Francesco; Morvan, Marion; Bey, Laetitia; Khallou-Laschet, Jamila; Gaston, Anh-Thu; Delbosc, Sandrine; Alsac, Jean-Marc; Bruneval, Patrick; Deschildre, Catherine; Le Borgne, Marie; Castier, Yves; Kim, Hye-Jung; Cantor, Harvey; Michel, Jean-Baptiste; Caligiuri, Giuseppina; Nicoletti, Antonino

    2015-02-10

    The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated. Here, we analyzed the contribution of Qa-1-restricted CD8(+) regulatory T cells to the control of the T follicular helper-germinal center B-cell axis during atherogenesis. Genetic disruption of CD8(+) regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper-germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs. This study is the first to demonstrate that the T follicular helper-germinal center B-cell axis is proatherogenic and that CD8(+) regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach. © 2014 American Heart Association, Inc.

  3. Prevention of cardiovascular events in early menopause: a possible role for hormone replacement therapy.

    Science.gov (United States)

    Antonicelli, Roberto; Olivieri, Fabiola; Morichi, Valeria; Urbani, Elisa; Mais, Valerio

    2008-11-12

    Heart disease is a major cause of illness and death in women. It is well known that there is an increase in cardiovascular disease and cardiovascular risk factors after the menopause, but it is still unclear whether the change in risk factors after the menopause is only related to the aging process or is principally due to estrogen deprivation. Observational studies suggest a protective role for estrogens, whereas recent randomized controlled trials report a negative effect of oral estrogens on primary and secondary prevention of cardiovascular events. The role of inflammation in the process of atherogenesis and in determining the cardiovascular disease risk in postmenopausal women has been focused only recently as well as the role of the estrogen receptor system in different tissues and the role of genetic susceptibility to adverse events during estrogen therapy. The objective of this work was to review the current understanding of the relationships between cardiovascular disease risk factors and hormonal age-related changes in postmenopausal women and particularly in early and surgical postmenopausal women, for a more appropriate evaluation of the expected effects of therapy with exogenous estrogens in a specific sample of the large population of postmenopausal women.

  4. Associations between periodontal disease and cardiovascular surrogate measures among Indigenous Australians.

    Science.gov (United States)

    Kapellas, Kostas; Jamieson, Lisa M; Do, Loc G; Bartold, P Mark; Wang, Hao; Maple-Brown, Louise J; Sullivan, David; O'Dea, Kerin; Brown, Alex; Celermajer, David S; Slade, Gary D; Skilton, Michael R

    2014-05-01

    Inflammation is a key pathogenetic factor in atherogenesis. Periodontitis is a chronic inflammatory source which can have systemic impacts. Indigenous Australians have a higher prevalence of periodontal disease and experience cardiovascular disease earlier than non-Indigenous Australians. The aim was to describe the association between severity of periodontal inflammatory disease and measures of arterial structure and function. Periodontal disease in a convenience sample of Indigenous Australians was assessed clinically; for those with periodontal disease, the extent of periodontal pockets ≥ 4 mm was stratified into quartiles. Vascular health was measured non-invasively via carotid-dorsalis pedis pulse-wave velocity (PWV), and via B-mode ultrasound of the common carotid intima-media (IMT). Non-fasting blood samples were collected for lipid and inflammatory marker evaluation. Linear regression models were constructed to determine the associations between extent of periodontal pocketing and vascular health, adjusting for traditional cardiovascular common risk factors. 273 Indigenous Australian adults were recruited and complete data was available for 269 participants (154 males), median age 39 years. Arterial stiffness (PWV) significantly increased with increasing extent of periodontal pocketing (p trend=0.001). By contrast, carotid IMT did not differ across quartiles. Periodontal pocketing was associated with central arterial stiffness, a marker of presymptomatic arterial dysfunction, in Indigenous Australian adults with periodontal disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Uric acid as one of the important factors in multifactorial disorders--facts and controversies.

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    Pasalic, Daria; Marinkovic, Natalija; Feher-Turkovic, Lana

    2012-01-01

    With considering serum concentration of the uric acid in humans we are observing hyperuricemia and possible gout development. Many epidemiological studies have shown the relationship between the uric acid and different disorders such are obesity, metabolic syndrome, hypertension and coronary artery disease. Clinicians and investigators recognized serum uric acid concentration as very important diagnostic and prognostic factor of many multifactorial disorders. This review presented few clinical conditions which are not directly related to uric acid, but the concentrations of uric acid might have a great impact in observing, monitoring, prognosis and therapy of such disorders. Uric acid is recognized as a marker of oxidative stress. Production of the uric acid includes enzyme xanthine oxidase which is involved in producing of radical-oxigen species (ROS). As by-products ROS have a significant role in the increased vascular oxidative stress and might be involved in atherogenesis. Uric acid may inhibit endothelial function by inhibition of nitric oxide-function under conditions of oxidative stress. Down regulation of nitric oxide and induction of endothelial dysfunction might also be involved in pathogenesis of hypertension. The most important and well evidenced is possible predictive role of uric acid in predicting short-term outcome (mortality) in acute myocardial infarction (AMI) patients and stroke. Nephrolithiasis of uric acid origin is significantly more common among patients with the metabolic syndrome and obesity. On contrary to this, uric acid also acts is an "antioxidant", a free radical scavenger and a chelator of transitional metal ions which are converted to poorly reactive forms.

  6. Maternal high-fat diet exaggerates atherosclerosis in adult offspring by augmenting periaortic adipose tissue-specific proinflammatory response.

    Science.gov (United States)

    Wakana, Noriyuki; Irie, Daisuke; Kikai, Masakazu; Terada, Kensuke; Yamamoto, Keita; Kawahito, Hiroyuki; Kato, Taku; Ogata, Takehiro; Ueyama, Tomomi; Matoba, Satoaki; Yamada, Hiroyuki

    2015-03-01

    Maternal obesity elicits offspring's metabolic disorders via developmental modifications of visceral adipose tissue; however, its effect on atherogenesis remains undefined. Perivascular adipose tissue has recently been implicated in vascular remodeling and vasoreactivity. We hypothesize that developmental modifications of perivascular adipose tissue by maternal high-fat diet (HFD) exposure promotes atherosclerosis in adult offspring. Eight-week-old female apolipoprotein E-deficient mice were fed an HFD or normal diet (ND) during gestation and lactation. Offspring were fed a high-cholesterol diet from 8 weeks of age. Twenty-week-old male offspring of HFD-fed dams (O-HFD) showed a 2.1-fold increase in atherosclerotic lesion of the entire aorta compared with those of ND-fed dams (O-ND). Although mRNA expressions of interleukin-6, tumor necrosis factor, and monocyte chemotactic protein-1 and accumulation of macrophages in epididymal white adipose tissue were less in O-HFD than in O-ND, thoracic periaortic adipose tissue (tPAT) showed an exaggerated inflammatory response in O-HFD. Intra-abdominal transplantation of tPAT from 8-week-old O-HFD alongside the distal abdominal aorta exaggerated atherosclerosis development of the infrarenal aorta in recipient apolipoprotein E-deficient mice compared with tPAT from O-ND (210%, Patherosclerosis development in offspring by augmenting tPAT-specific inflammatory response proceeded by an increased expression of macrophage colony-stimulating factor. © 2015 American Heart Association, Inc.

  7. Molecular mechanisms of felodipine suppressing atherosclerosis in high-cholesterol-diet apolipoprotein E-knockout mice.

    Science.gov (United States)

    Yao, Rui; Cheng, Xiang; Liao, Yu-Hua; Chen, Yong; Xie, Jiang-Jiao; Yu, Xian; Ding, Ying-Jun; Tang, Ting-Ting

    2008-02-01

    Oxidative stress and inflammation processes are key components of atherosclerosis, from fatty streak formation to plaque rupture and thrombosis. Evidence has revealed that calcium-channel blockers (CCB) could retard atherogenesis, but the exact mechanisms have not been fully elucidated. The present study was undertaken to investigate the potential effects and molecular mechanisms of the CCB felodipine on the process of atherosclerosis in high-cholesterol-diet (HCD) apolipoprotein E-knockout (ApoE KO) mice. Adult male ApoE KO mice were given a normal diet (ND) or HCD and were randomized to no treatment or felodipine (5 mg / kg per day for 12 weeks). The ApoE KO mice with HCD were associated with a marked increase in plasma lipid levels, atherosclerotic lesion area, and the expressions of NADPH oxidase subunits (p47 and Rac-1), nuclear factor-kappaB (NF-kappaB) in nucleus, phosphor-inhibitors of kappaB (p-IkappaB), tumor necrosis-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and vascular cell-adhesion molecule-1 (VCAM-1). These changes were suppressed in mice that were treated with felodipine (5 mg/kg per day for 12 weeks) concomitant with HCD administration, with no significant change in systolic blood pressure and plasma lipid levels. The results suggest that felodipine can attenuate atherosclerosis, and this effect is partly related to inhibition of oxidative stress and inflammatory signal-transduction pathways, which lead to decreases in the expression of inflammatory cytokines.

  8. Effects of Schistosoma mansoni worms and eggs on circulating cholesterol and liver lipids in mice.

    Science.gov (United States)

    Stanley, Ronald G; Jackson, Christopher L; Griffiths, Keith; Doenhoff, Michael J

    2009-11-01

    It has previously been shown that experimental infections of the parasitic trematode Schistosoma mansoni, the adult worms of which reside in the blood stream of the mammalian host, significantly reduced atherogenesis in apolipoprotein E gene knockout (apoE(-/-)) mice. These effects occurred in tandem with a lowering of serum total cholesterol levels in both apoE(-/-) and random-bred laboratory mice and a beneficial increase in the proportion of HDL to LDL cholesterol. To better understand how the parasitic infections induce these effects we have here investigated the involvement of adult worms and their eggs on lipids in the host. Our results indicate that the serum cholesterol-lowering effect is mediated by factors released from S. mansoni eggs, while the presence of adult worms seemed to have had little or no effect. It was also observed that high levels of lipids, particularly triacylglycerols and cholesteryl esters, present in the uninfected livers of both random-bred and apoE(-/-)mice fed a high-fat diet were not present in livers of the schistosome-infected mice.

  9. Effects of Thyme Extract Oils (from Thymus vulgaris, Thymus zygis, and Thymus hyemalis) on Cytokine Production and Gene Expression of oxLDL-Stimulated THP-1-Macrophages

    Science.gov (United States)

    Ocaña, A.; Reglero, G.

    2012-01-01

    Properties of thyme extracts from three different species (Thymus vulgaris, Thymus zygis, and Thymus hyemalis) were examined. Two oil fractions from each species were obtained by CO2 supercritical fluid extraction. Main compounds presented in the supercritical extracts of the three thyme varieties were 1,8 cineole, thymol, camphor, borneol, and carvacrol. As a cellular model of inflammation/atherogenesis, we use human macrophages derived from THP-1 monocytes and activated by oxidized LDLs. These cells were incubated with the thyme fraction oils, and the productions and gene expressions of the inflammatory mediators TNF-α, IL-1B, IL-6, and IL-10 were determined. Thyme extracts significantly reduced production and gene expression of the proinflammatory mediators TNF-α, IL-1B, and IL-6 and highly increased these parameters on the anti-inflammatory IL-10 cytokine. Changes on production and gene expressions were dose dependent and according to the thyme content of each species. Taken together, these results may suggest that thyme extracts could have anti-inflammatory effects. PMID:22577523

  10. Histopathological changes due to the effect of selenium in experimental cockerels

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    S.A.A Latheef

    2014-01-01

    Full Text Available Background & objectives: Selenium usually acts as an antioxidant at optimal levels in the body and increased levels are toxic. In this study an attempt was made to evaluate the effect of an optimum dose (0.14 mg of selenium on histopathological changes in experimental hypercholesterolemia in cockerels. Methods: The effect of selenium (0.14 mg was investigated on histopathological changes in four tissues namely liver, kidney, heart, and descending aorta in cockerel animal model. Animals were either fed with stock diet (group C, stock diet with cholesterol (group CH, stock diet with selenium (group Se, stock diet, selenium and cholesterol (group CH+Se for six months. Animals were sacrified and the tissues were isolated and subjected to histopathological study. Results: Xanthochromatic collections in liver were observed in group CH; hydropic degeneration in group Se and lobular disarray, hydropic degeneration and kuppfer cell hyperplasia in group CH+Se were observed. In kidney, mild mononuclear infiltration was observed in interstitium in groups CH, Se and CH+Se. myocyte disruption, and mononuclear infiltration in group CH and c0 H+Se, and disruption of muscle bundles with vascular congestion in group Se were observed. Smooth muscle proliferation in the media of blood vessel was observed in groups CH, Se and CH+Se. Interpretation & conclusions: The results of the present study suggested that the optimum dose of (140 ΅g/day feeding induced atherogenesis by inflammation and smooth muscle proliferation in cockerels with experimentally induced hypercholesterolaemia.

  11. Cross-reacting antibacterial auto-antibodies are produced within coronary atherosclerotic plaques of acute coronary syndrome patients.

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    Filippo Canducci

    Full Text Available Coronary atherosclerosis, the main condition predisposing to acute myocardial infarction, has an inflammatory component caused by stimuli that are yet unknown. We molecularly investigated the nature of the immune response within human coronary lesion in four coronary plaques obtained by endoluminal atherectomy from four patients. We constructed phage-display libraries containing the IgG1/kappa antibody fragments produced by B-lymphocytes present in each plaque. By immunoaffinity, we selected from these libraries a monoclonal antibody, arbitrarily named Fab7816, able to react both with coronary and carotid atherosclerotic tissue samples. We also demonstrated by confocal microscopy that this monoclonal antibody recognized human transgelin type 1, a cytoskeleton protein involved in atherogenesis, and that it co-localized with fibrocyte-like cells transgelin+, CD68+, CD45+ in human sections of coronary and carotid plaques. In vitro fibrocytes obtained by differentiating CD14+ cells isolated from peripheral blood mononuclear cells also interacted with Fab7816, thus supporting the hypothesis of a specific recognition of fibrocytes into the atherosclerotic lesions. Interestingly, the same antibody, cross-reacted with the outer membrane proteins of Proteus mirabilis and Klebsiella pneumoniae (and possibly with homologous proteins of other enterobacteriaceae present in the microbiota. From all the other three libraries, we were able to clone, by immunoaffinity selection, human monoclonal antibodies cross-reacting with bacterial outer membrane proteins and with transgelin. These findings demonstrated that in human atherosclerotic plaques a local cross-reactive immune response takes place.

  12. Dehydroepiandrosterone (DHEA) inhibition of monocyte binding by vascular endothelium is associated with sialylation of neural cell adhesion molecule.

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    Curatola, Anna-Maria; Huang, Kui; Naftolin, Frederick

    2012-01-01

    Adhesion of monocytes to vascular endothelium is necessary for atheroma formation. This adhesion requires binding of endothelial neural cell adhesion molecule (NCAM) to monocyte NCAM. NCAM:NCAM binding is blocked by sialylation of NCAM (polysialylated NCAM; PSA-NCAM). Since estradiol (E2) and dihydrotestosterone (DHT) induced PSA-NCAM and decreased monocyte adhesion, in consideration of possible clinical applications we tested whether their prohormone dehydroepiandrosterone (DHEA) has similar effects. (1) DHEA was administered to cultured human coronary artery endothelial cells (HCAECs) from men and women. Monocyte binding was assessed using fluorescence-labeled monocytes. (2) HCEACs were incubated with E2, DHT, DHEA alone, or with trilostane, fulvestrant or flutamide. Expression of PSA-NCAM was assessed by immunohistochemistry and Western blotting. Dehydroepiandrosterone inhibited monocyte adhesion to HCAECs by ≥50% (P DHEA's inhibition of monocyte binding appeared to be gender dependent. The DHEA-induced expression of PSA-NCAM was completely blocked by trilostane. In these preliminary in vitro studies, DHEA increased PSA-NCAM expression and inhibited monocyte binding in an estrogen- and androgen receptor-dependent manner. Dehydroepiandrosteroneappears to act via its end metabolites, E2 and DHT. Dehydroepiandrosterone could furnish clinical prevention against atherogenesis and arteriosclerosis.

  13. Effects of drospirenone on adhesion molecule expression and monocyte adherence in human endothelial cells.

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    Ito, Fumitake; Mori, Taisuke; Takaoka, Osamu; Tanaka, Yukiko; Koshiba, Akemi; Tatsumi, Hiroshi; Iwasa, Koichi; Kitawaki, Jo

    2016-06-01

    A major concern in hormone replacement therapy is the associated increased risk of cardiovascular diseases. A progestogen without the unfavorable effects on cardiovascular disease should be explored. Monocyte adhesion to endothelial cells is an important initial event in atherosclerosis. In this study, the effects of the alternative progestogen drospirenone (DRSP) on monocyte adhesion in human umbilical venous endothelial cells (HUVECs) were examined. In HUVECs treated with estrogens and progestogens, including DRSP and medroxyprogesterone acetate (MPA), the expression of the adhesion molecules E-selectin, P-selectin, ICAM-1, and VCAM-1 were examined by real-time PCR and using an enzyme-linked immunosorbent assay. A flow chamber system was used to investigate the effects of DRSP on U937 monocytoid cell adherence to HUVEC monolayers. All experimental data were compared using one-way Analysis of Variance. Upregulation of adhesion molecule mRNA or protein was not seen in HUVECs treated with DRSP alone or with 17β-estradiol+DRSP. DRSP alone, 17β-estradiol+DRSP or ethinylestradiol+DRSP did not increase the number of adherent monocytoid cells to HUVECs in the flow chamber system. However, MPA significantly enhanced the monocytoid cell adherence (Padhesion molecules or monocytoid cell adherence to endothelial cells, indicating that DRSP could reduce the risk of atherogenesis caused by MPA. These results suggest that DRSP may be an alternative to MPA in hormone replacement therapy. Copyright © 2016. Published by Elsevier Ireland Ltd.

  14. Dextromethorphan attenuates LPS-induced adhesion molecule expression in human endothelial cells.

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    Jiang, Shinn-Jong; Hsu, Sheng-Yao; Deng, Chuan-Rou; Huang, Huey-Chun; Liu, Shu-Lin; Shi, Guey-Yueh; Wu, Hua-Lin

    2013-02-01

    This study examines the effect of Dextromethorphan (d-3-methoxy-17-methylmorphinan; DXM), a commonly used cough-suppressing drug, on the expression of VCAM-1 and ICAM-1 in human umbilical vein endothelial cells (HUVECs) stimulated with lipopolysaccharide (LPS). The effect of DXM on expression of cell adhesion molecules induced by LPS was evaluated by monocyte bindings in vitro and ex vivo and transmigration assays. The signaling pathways involved in the inflammation inhibitory effect of DXM were analyzed by Western blot and immunofluorescent stain. Pretreatment of HUVECs with DXM inhibited LPS-induced adhesion of THP-1 cells in vitro and ex vivo, and reduced transendothelial migration of these cells. Furthermore, treatment of HUVECs with DXM can significantly decrease LPS-induced expression of ICAM-1 and VCAM-1. DXM abrogated LPS-induced phosphorylation of ERK and Akt. The translocation of early growth response gene-1 (Egr-1), a downstream transcription factor involved in the mitogen-activated kinase (MEK)-ERK signaling pathway, was suppressed by DXM treatment. Furthermore, DXM inhibited LPS-induced IκBα degradation and nuclear translocation of p65. Dextromethorphan inhibits the adhesive capacity of HUVECs by reducing the LPS-induced ICAM-1 and VCAM-1 expression via the suppression of the ERK, Akt, and NF-κB signaling pathways. Thus, DXM is a potential anti-inflammatory therapeutic that may modulate atherogenesis. © 2012 John Wiley & Sons Ltd.

  15. EVALUATION OF DIPYRIDAMOLE ON ACUTE AND SUBACUTE MODELS OF INFLAMMATION IN MALE WISTAR RATS: AN EXPERIMENTAL STUDY

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    Angadi Netravathi B, Hiremath Shrishail V , Suranagi Vijayalakshmi V.

    2015-07-01

    Full Text Available Background: Atherosclerosis and its complications remains the major cause of death and premature disability. Atherogenesis involves elements of inflammation, a process that now provides a unifying theme in the pathogenesis of the disease. Anti-platelet drugs are currently used in the treatment of atherosclerosis and its complications. Our study evaluated the influence of dipyridamole on acute and sub-acute models of inflammation in male Wistar rats. Methods: Male Wistar rats (150-200g were divided into three groups i.e. control, Aspirin and dipyridamole (n=6 animals in each group. The effect of dipyridamole, administered orally, on inflammation was studied using acute (carrageenan induced rat paw edema and sub-acute (cotton pellet granuloma and histopathological examination of grass piths models. Experiment was conducted according to the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA guidelines. Analysis was done using one way ANOVA followed by Post Hoc Test of Dunnets. P<0.05 was considered as statistically significant. Results: Dipyridamole showed significant inhibition of rat paw edema in acute model (P<0.01 and granuloma dry weight, in sub acute model of inflammation when compared to control (P<0.01. Histopathological examination of grass pith revealed markedly reduced fibroblasts, granulation tissue, fibrous tissue and collagen in dipyridamole group when compared to control. Conclusion: Dipyridamole exhibited a significant anti inflammatory activity in acute and sub-acute models of inflammation.

  16. Proteomic Analysis of Plasma-Purified VLDL, LDL, and HDL Fractions from Atherosclerotic Patients Undergoing Carotid Endarterectomy: Identification of Serum Amyloid A as a Potential Marker

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    Antonio J. Lepedda

    2013-01-01

    Full Text Available Apolipoproteins are very heterogeneous protein family, implicated in plasma lipoprotein structural stabilization, lipid metabolism, inflammation, or immunity. Obtaining detailed information on apolipoprotein composition and structure may contribute to elucidating lipoprotein roles in atherogenesis and to developing new therapeutic strategies for the treatment of lipoprotein-associated disorders. This study aimed at developing a comprehensive method for characterizing the apolipoprotein component of plasma VLDL, LDL, and HDL fractions from patients undergoing carotid endarterectomy, by means of two-dimensional electrophoresis (2-DE coupled with Mass Spectrometry analysis, useful for identifying potential markers of plaque presence and vulnerability. The adopted method allowed obtaining reproducible 2-DE maps of exchangeable apolipoproteins from VLDL, LDL, and HDL. Twenty-three protein isoforms were identified by peptide mass fingerprinting analysis. Differential proteomic analysis allowed for identifying increased levels of acute-phase serum amyloid A protein (AP SAA in all lipoprotein fractions, especially in LDL from atherosclerotic patients. Results have been confirmed by western blotting analysis on each lipoprotein fraction using apo AI levels for data normalization. The higher levels of AP SAA found in patients suggest a role of LDL as AP SAA carrier into the subendothelial space of artery wall, where AP SAA accumulates and may exert noxious effects.

  17. Rapeseed oil fortified with micronutrients reduces atherosclerosis risk factors in rats fed a high-fat diet

    Science.gov (United States)

    2011-01-01

    Background Micronutrients polyphenols, tocopherols and phytosterols in rapeseed exert potential benefit to cardiovascular system, but most of these micronutrients are removed by the refining process. The aim of this study was to determine the effect of rapeseed oil fortified with these micronutrients on the atherosclerosis risk factors in rats fed a high-fat diet. Methods The rodent diet contained 20% fat whose source was refined rapeseed oil (RRO) or fortified refined rapeseed oil with low, middle and high quantities of these micronutrients (L-, M- and H-FRRO). Forty male SD rats were divided into four groups. One group received RRO diet and other groups received L-, M- and H-FRRO diet for 10 weeks. Results Micronutrients supplementation significantly increased plasma antioxidant defense capacities, as evaluated by the significant elevation in the activities of GPx, CAT and SOD as well as the level of GSH, and the significant decline in lipid peroxidation. These micronutrients also reduced the plasma contents of TG, TC and LDL-C and increased the ratio of HDL-C/LDL-C. In addition, in parallel with the enhancement of these micronutrients, plasma levels of IL-6 and CRP declined remarkably. Conclusion Rapeseed oil fortified with micronutrients polyphenols, tocopherols and phytosterols may contribute to prevent atherogenesis by ameliorating plasma oxidative stress, lipid profile and inflammation. PMID:21663699

  18. DETECTION OF MODIFIED LIPOPROTEINS IN ATHEROSCLEROTIC LESIONS OF HUMAN AORTA

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    P. V. Pigarevsky

    2006-01-01

    Full Text Available Abstract. Specific autoantibodies against acetylated, maleylated and malonic dialdehyde-(MDA-modified lipoproteins are detectable in human plasma. Immunization of rabbits with autologous, correspondingly modified low-density lipoproteins (LDLs did induce autoantibodies against acetylated, maleylated and MDA-modified lipoproteins. In atherosclerotic lesions from hyman aorta, the epitopes have been detected that were recognized by the antibodies to acetylated, maleylated, and MDA-modified LDLs. Such antigens were detected at all atherogenesis stages, beginning with the earliest lesions (lipid spots, and their deposition pattern was quite variable.Rabbit and human autoantibodies against acetylated, maleylated and MDA-modified lipoproteins recognized antigens in human atherosclerotic aorta. Modified proteins were localized both intra- and extracellular in tectum, superficial and deep layers of the atherosclerotic lesions. The most typical mode of depositions for all modified proteins si represented by extracellular deposits in the cap of lipid streaks and fibrous plaques, especially in transitional “shoulder” area.The intimal deposits of modified proteins shared similar features with distribution of apo-B-containing lipoproteins, like as of lipids detectable by Oil Red staining. The areas where modified proteins and apo-B-containing lipoproteins were revealed did often coincide with foci of IgG deposits. Modified proteins were not detectable in the non-affected segments of aortic intima.

  19. Quantum dot mediated imaging of atherosclerosis

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    Jayagopal, Ashwath; Haselton, Frederick R [Department of Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, TN 37232 (United States); Su Yanru; Blakemore, John L; Linton, MacRae F; Fazio, Sergio [Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 (United States)], E-mail: rick.haselton@vanderbilt.edu

    2009-04-22

    The progression of atherosclerosis is associated with leukocyte infiltration within lesions. We describe a technique for the ex vivo imaging of cellular recruitment in atherogenesis which utilizes quantum dots (QD) to color-code different cell types within lesion areas. Spectrally distinct QD were coated with the cell-penetrating peptide maurocalcine to fluorescently-label immunomagnetically isolated monocyte/macrophages and T lymphocytes. QD-maurocalcine bioconjugates labeled both cell types with a high efficiency, preserved cell viability, and did not perturb native leukocyte function in cytokine release and endothelial adhesion assays. QD-labeled monocyte/macrophages and T lymphocytes were reinfused in an ApoE{sup -/-} mouse model of atherosclerosis and age-matched controls and tracked for up to four weeks to investigate the incorporation of cells within aortic lesion areas, as determined by oil red O (ORO) and immunofluorescence ex vivo staining. QD-labeled cells were visible in atherosclerotic plaques within two days of injection, and the two cell types colocalized within areas of subsequent ORO staining. Our method for tracking leukocytes in lesions enables high signal-to-noise ratio imaging of multiple cell types and biomarkers simultaneously within the same specimen. It also has great utility in studies aimed at investigating the role of distinct circulating leukocyte subsets in plaque development and progression.

  20. Inflammatory Mechanisms Linking Periodontal Diseases to Cardiovascular Diseases

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    Schenkein, Harvey A.; Loos, Bruno G.

    2015-01-01

    Aims In this paper, inflammatory mechanisms that link periodontal diseases to cardiovascular diseases (CVD) are reviewed. Materials and Methods and Results This paper is a literature review. Studies in the literature implicate a number of possible mechanisms that could be responsible for increased inflammatory responses in atheromatous lesions due to periodontal infections. These include increased systemic levels of inflammatory mediators stimulated by bacteria and their products at sites distant from the oral cavity, elevated thrombotic and hemostatic markers that promote a prothrombotic state and inflammation, cross-reactive systemic antibodies that promote inflammation and interact with the atheroma, promotion of dyslipidemia with consequent increases in proinflammatory lipid classes and subclasses, and common genetic susceptibility factors present in both disease leading to increased inflammatory responses. Conclusions Such mechanisms may be thought to act in concert to increase systemic inflammation in periodontal disease and to promote or exacerbate atherogenesis. However, proof that the increase in systemic inflammation attributable to periodontitis impacts inflammatory responses during atheroma development, thrombotic events, or myocardial infarction or stroke is lacking. PMID:23627334

  1. Nitric Oxide as a Unique Bioactive Signaling Messenger in Physiology and Pathophysiology

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    Tuteja Narendra

    2004-01-01

    Full Text Available Nitric oxide (NO is an intra- and extracellular messenger that mediates diverse signaling pathways in target cells and is known to play an important role in many physiological processes including neuronal signaling, immune response, inflammatory response, modulation of ion channels, phagocytic defense mechanism, penile erection, and cardiovascular homeostasis and its decompensation in atherogenesis. Recent studies have also revealed a role for NO as signaling molecule in plant, as it activates various defense genes and acts as developmental regulator. In plants, NO can also be produced by nitrate reductase. NO can operate through posttranslational modification of proteins (nitrosylation. NO is also a causative agent in various pathophysiological abnormalities. One of the very important systems, the cardiovascular system, is affected by NO production, as this bioactive molecule is involved in the regulation of cardiovascular motor tone, modulation of myocardial contractivity, control of cell proliferation, and inhibition of platelet activation, aggregation, and adhesion. The prime source of NO in the cardiovascular system is endothelial NO synthase, which is tightly regulated with respect to activity and localization. The inhibition of chronic NO synthesis leads to neurogenic and arterial hypertensions, which later contribute to development of myocardial fibrosis. Overall, the modulation of NO synthesis is associated with hypertension. This review briefly describes the physiology of NO, its synthesis, catabolism, and targeting, the mechanism of NO action, and the pharmacological role of NO with special reference to its essential role in hypertension.

  2. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009

    Science.gov (United States)

    2010-01-01

    Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients. PMID:20361178

  3. Noninvasive assessment of preclinical atherosclerosis

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    Helen A Lane

    2006-03-01

    Full Text Available Helen A Lane, Jamie C Smith, J Stephen DaviesDepartment of Endocrinology, University of Wales College of Medicine, Heath Park, Cardiff, Wales, UKAbstract: Initially considered as a semipermeable barrier separating lumen from vessel wall, the endothelium is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter, and blood flow; hemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intimamedia thickness, pulse wave analysis, pulse wave velocity, and plethysmography. This review outlines the various modalities, indications, and limitations of available methods to assess arterial dysfunction and vascular risk.Keywords: endothelial function, vascular risk, vascular stiffness

  4. Possible role of milk-derived bioactive peptides in the treatment and prevention of metabolic syndrome.

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    Ricci-Cabello, Ignacio; Herrera, Manuel Olalla; Artacho, Reyes

    2012-04-01

    The growing prevalence of metabolic syndrome as well as its impact on public health has garnered increased attention in recent years. As a result, metabolic syndrome is now considered one of the world's leading public health problems. Bioactive peptides deriving from milk proteins may play an important role in the prevention and treatment of metabolic syndrome and its complications via several mechanisms, such as the satiety response, the regulation of insulinemia levels and blood pressure, the uptake of free radicals, and alteration of the lipid profile. These peptides can be incorporated into functional foods or administered via nutraceuticals to decrease the risk of obesity, atherogenesis, arterial hypertension, and type 2 diabetes. Recent findings have generated considerable scientific and commercial interest in milk-derived bioactive peptides, leading to numerous publications on the effectiveness of these substances. This review summarizes the current knowledge on bioactive peptides derived from milk proteins and examines the potential value of these peptides in the treatment and prevention of metabolic syndrome and its complications. © 2012 International Life Sciences Institute.

  5. Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.

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    Singh, Rajesh K; Barbosa-Lorenzi, Valéria C; Lund, Frederik W; Grosheva, Inna; Maxfield, Frederick R; Haka, Abigail S

    2016-03-01

    Monocyte-derived cells use an extracellular, acidic, lytic compartment (a lysosomal synapse) for initial degradation of large objects or species bound to the extracellular matrix. Akin to osteoclast degradation of bone, extracellular catabolism is used by macrophages to degrade aggregates of low density lipoprotein (LDL) similar to those encountered during atherogenesis. However, unlike osteoclast catabolism, the lysosomal synapse is a highly dynamic and intricate structure. In this study, we use high resolution three dimensional imaging to visualize compartments formed by macrophages to catabolize aggregated LDL. We show that these compartments are topologically complex, have a convoluted structure and contain sub-regions that are acidified. These sub-regions are characterized by a close apposition of the macrophage plasma membrane and aggregates of LDL that are still connected to the extracellular space. Compartment formation is dependent on local actin polymerization. However, once formed, compartments are able to maintain a pH gradient when actin is depolymerized. These observations explain how compartments are able to maintain a proton gradient while remaining outside the boundaries of the plasma membrane. © 2016. Published by The Company of Biologists Ltd.

  6. Quantitative analysis of monocyte subpopulations in murine atherosclerotic plaques by multiphoton microscopy.

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    Abigail S Haka

    Full Text Available The progressive accumulation of monocyte-derived cells in the atherosclerotic plaque is a hallmark of atherosclerosis. However, it is now appreciated that monocytes represent a heterogeneous circulating population of cells that differ in functionality. New approaches are needed to investigate the role of monocyte subpopulations in atherosclerosis since a detailed understanding of their differential mobilization, recruitment, survival and emigration during atherogenesis is of particular importance for development of successful therapeutic strategies. We present a novel methodology for the in vivo examination of monocyte subpopulations in mouse models of atherosclerosis. This approach combines cellular labeling by fluorescent beads with multiphoton microscopy to visualize and monitor monocyte subpopulations in living animals. First, we show that multiphoton microscopy is an accurate and timesaving technique to analyze monocyte subpopulation trafficking and localization in plaques in excised tissues. Next, we demonstrate that multiphoton microscopy can be used to monitor monocyte subpopulation trafficking in atherosclerotic plaques in living animals. This novel methodology should have broad applications and facilitate new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.

  7. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.

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    Grosheva, Inna; Haka, Abigail S; Qin, Chunbo; Pierini, Lynda M; Maxfield, Frederick R

    2009-10-01

    Interaction of macrophages with aggregated matrix-anchored lipoprotein deposits is an important initial step in atherogenesis. Aggregated lipoproteins require different cellular uptake processes than those used for endocytosis of monomeric lipoproteins. In this study, we tested the hypothesis that engagement of aggregated LDL (agLDL) by macrophages could lead to local increases in free cholesterol levels and that these increases in free cholesterol regulate signals that control cellular actin. AgLDL resides for prolonged periods in surface-connected compartments. Although agLDL is still extracellular, we demonstrate that an increase in free cholesterol occurs at sites of contact between agLDL and cells because of hydrolysis of agLDL-derived cholesteryl ester. This increase in free cholesterol causes enhanced actin polymerization around the agLDL. Inhibition of cholesteryl ester hydrolysis results in decreased actin polymerization. We describe a novel process that occurs during agLDL-macrophage interactions in which local release of free cholesterol causes local actin polymerization, promoting a pathological positive feedback loop for increased catabolism of agLDL and eventual foam cell formation.

  8. Quantitative analysis of monocyte subpopulations in murine atherosclerotic plaques by multiphoton microscopy.

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    Haka, Abigail S; Potteaux, Stephane; Fraser, Haley; Randolph, Gwendalyn J; Maxfield, Frederick R

    2012-01-01

    The progressive accumulation of monocyte-derived cells in the atherosclerotic plaque is a hallmark of atherosclerosis. However, it is now appreciated that monocytes represent a heterogeneous circulating population of cells that differ in functionality. New approaches are needed to investigate the role of monocyte subpopulations in atherosclerosis since a detailed understanding of their differential mobilization, recruitment, survival and emigration during atherogenesis is of particular importance for development of successful therapeutic strategies. We present a novel methodology for the in vivo examination of monocyte subpopulations in mouse models of atherosclerosis. This approach combines cellular labeling by fluorescent beads with multiphoton microscopy to visualize and monitor monocyte subpopulations in living animals. First, we show that multiphoton microscopy is an accurate and timesaving technique to analyze monocyte subpopulation trafficking and localization in plaques in excised tissues. Next, we demonstrate that multiphoton microscopy can be used to monitor monocyte subpopulation trafficking in atherosclerotic plaques in living animals. This novel methodology should have broad applications and facilitate new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.

  9. Plasmin promotes foam cell formation by increasing macrophage catabolism of aggregated low density lipoprotein

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    Haka, Abigail S.; Grosheva, Inna; Singh, Rajesh K.; Maxfield, Frederick R.

    2013-01-01

    Objective The plasmin/plasminogen system is involved in atherosclerosis. However, the mechanisms by which it stimulates disease are not fully defined. A key event in atherogenesis is the deposition of LDL on arterial walls where it is modified, aggregated and retained. Macrophages are recruited to clear the lipoproteins, and they become foam cells. The goal of this study was to assess the role of plasmin in macrophage uptake of aggregated LDL and foam cell formation. Approach and Results Plasminogen treatment of macrophages catabolizing aggregated LDL significantly accelerated foam cell formation. Macrophage interaction with aggregated LDL increased the surface expression of urokinase-type plasminogen activator receptor and plasminogen activator activity, resulting in increased ability to generate plasmin at the cell surface. The high local level of plasmin cleaves cell-associated aggregated LDL, allowing a portion of the aggregate to become sequestered in a nearly sealed, yet extracellular, acidic compartment. The low pH in the plasmin-induced compartment allows lysosomal enzymes, delivered via lysosome exocytosis, greater activity, resulting in more efficient cholesteryl ester hydrolysis and delivery of a large cholesterol load to the macrophage, thereby promoting foam cell formation. Conclusion These findings highlight a critical role for plasmin in the catabolism of aggregated LDL by macrophages and provide a new context for considering the atherogenic role of plasmin. PMID:23702659

  10. Plasmin promotes foam cell formation by increasing macrophage catabolism of aggregated low-density lipoprotein.

    Science.gov (United States)

    Haka, Abigail S; Grosheva, Inna; Singh, Rajesh K; Maxfield, Frederick R

    2013-08-01

    The plasmin/plasminogen system is involved in atherosclerosis. However, the mechanisms by which it stimulates disease are not fully defined. A key event in atherogenesis is the deposition of low-density lipoprotein (LDL) on arterial walls where it is modified, aggregated, and retained. Macrophages are recruited to clear the lipoproteins, and they become foam cells. The goal of this study was to assess the role of plasmin in macrophage uptake of aggregated LDL and foam cell formation. Plasminogen treatment of macrophages catabolizing aggregated LDL significantly accelerated foam cell formation. Macrophage interaction with aggregated LDL increased the surface expression of urokinase-type plasminogen activator receptor and plasminogen activator activity, resulting in increased ability to generate plasmin at the cell surface. The high local level of plasmin cleaves cell-associated aggregated LDL, allowing a portion of the aggregate to become sequestered in a nearly sealed, yet extracellular, acidic compartment. The low pH in the plasmin-induced compartment allows lysosomal enzymes, delivered via lysosome exocytosis, greater activity, resulting in more efficient cholesteryl ester hydrolysis and delivery of a large cholesterol load to the macrophage, thereby promoting foam cell formation. These findings highlight a critical role for plasmin in the catabolism of aggregated LDL by macrophages and provide a new context for considering the atherogenic role of plasmin.

  11. Mechanotransduction at the basis of endothelial barrier function

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    Gulino-Debrac, Danielle

    2013-01-01

    Destabilization of cell-cell contacts involved in the maintenance of endothelial barrier function can lead to increased endothelial permeability. This increase in endothelial permeability results in an anarchical movement of fluid, solutes and cells outside the vasculature and into the surrounding tissues, thereby contributing to various diseases such as stroke or pulmonary edema. Thus, a better understanding of the molecular mechanisms regulating endothelial cell junction integrity is required for developing new therapies for these diseases. In this review, we describe the mechanotransduction mechanism at the basis of adherens junction strengthening at endothelial cell-cell contacts. More particularly, we report on the emerging role of α-catenin and EPLIN that act as a mechanotransmitter of myosin-IIgenerated traction forces. The interplay between α-catenin, EPLIN and the myosin-II machinery initiates the junctional recruitment of vinculin and α-actinin leading to a drastic remodeling of the actin cytoskeleton and to cortical actin ring reshaping. The pathways initiated by tyrosine phosphorylation of VE-cadherin at the basis of endothelial cell–cell junction remodeling is also reported, as it may be interrelated to α-catenin/ EPLIN-mediated mechanotransduction mechanisms. We also describe the junctional mechanosensory complex composed of PECAM-1, VE-cadherin and VEGFR2 that is able to transmit signaling pathway under the onset of shear stress. This mechanosensing mechanism, involved in the earliest events promoting atherogenesis, is required for endothelial cell alignment along flow direction. PMID:24665386

  12. Effects of Nebivolol on Endothelial Gene Expression during Oxidative Stress in Human Umbilical Vein Endothelial Cells

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    Ulisse Garbin

    2008-01-01

    Full Text Available The endothelium plays a key role in the development of atherogenesis and its inflammatory and proliferative status influences the progression of atherosclerosis. The aim of this study is to compare the effects of two beta blockers such as nebivolol and atenolol on gene expression in human umbilical vein endothelial cells (HUVECs following an oxidant stimulus. HUVECs were incubated with nebivolol or atenolol (10 micromol/L for 24 hours and oxidative stress was induced by the addition of oxidized (ox-LDL. Ox-LDL upregulated adhesion molecules (ICAM-1, ICAM-2, ICAM-3, E-selectin, and P-selectin; proteins linked to inflammation (IL-6 and TNFalpha, thrombotic state (tissue factor, PAI-1 and uPA, hypertension such as endothelin-1 (ET-1, and vascular remodeling such as metalloproteinases (MMP-2, MMP-9 and protease inhibitor (TIMP-1. The exposure of HUVECs to nebivolol, but not to atenolol, reduced these genes upregulated by oxidative stress both in terms of protein and RNA expression. The known antioxidant properties of the third generation beta blocker nebivolol seem to account to the observed differences seen when compared to atenolol and support the specific potential protective role of this beta blocker on the expression of a number of genes involved in the initiation and progression of atherosclerosis.

  13. Epigallocatechin Gallate Attenuates Proliferation and Oxidative Stress in Human Vascular Smooth Muscle Cells Induced by Interleukin-1β via Heme Oxygenase-1

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    Po-Len Liu

    2014-01-01

    Full Text Available Proliferation of vascular smooth muscle cells (VSMCs triggered by inflammatory stimuli and oxidative stress contributes importantly to atherogenesis. The association of green tea consumption with cardiovascular protection has been well documented in epidemiological observations, however, the underlying mechanisms remain unclear. This study aimed to elucidate the effects of the most active green tea catechin derivative, (−-epigallocatechin-3-gallate (EGCG, in human aortic smooth muscle cells (HASMCs, focusing particularly on the role of a potent anti-inflammatory and antioxidative enzyme heme oxygenase-1 (HO-1. We found that pretreatment of EGCG dose- and time-dependently induced HO-1 protein levels in HASMCs. EGCG inhibited interleukin- (IL-1β-induced HASMC proliferation and oxidative stress in a dose-dependent manner. The HO-1 inducer CoPPIX decreased IL-1β-induced cell proliferation, whereas the HO-1 enzyme inhibitor ZnPPIX significantly reversed EGCG-caused growth inhibition in IL-1β-treated HASMCs. At the molecular level, EGCG treatment significantly activated nuclear factor erythroid-2-related factor (Nrf2 transcription activities. These results suggest that EGCG might serve as a complementary and alternative medicine in the treatment of these pathologies by inducing HO-1 expression and subsequently decreasing VSMC proliferation.

  14. Epigallocatechin Gallate Attenuates Proliferation and Oxidative Stress in Human Vascular Smooth Muscle Cells Induced by Interleukin-1β via Heme Oxygenase-1

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    Liu, Po-Len; Kuo, Hsuan-Fu; Hsieh, Chong-Chao

    2014-01-01

    Proliferation of vascular smooth muscle cells (VSMCs) triggered by inflammatory stimuli and oxidative stress contributes importantly to atherogenesis. The association of green tea consumption with cardiovascular protection has been well documented in epidemiological observations, however, the underlying mechanisms remain unclear. This study aimed to elucidate the effects of the most active green tea catechin derivative, (−)-epigallocatechin-3-gallate (EGCG), in human aortic smooth muscle cells (HASMCs), focusing particularly on the role of a potent anti-inflammatory and antioxidative enzyme heme oxygenase-1 (HO-1). We found that pretreatment of EGCG dose- and time-dependently induced HO-1 protein levels in HASMCs. EGCG inhibited interleukin- (IL-)1β-induced HASMC proliferation and oxidative stress in a dose-dependent manner. The HO-1 inducer CoPPIX decreased IL-1β-induced cell proliferation, whereas the HO-1 enzyme inhibitor ZnPPIX significantly reversed EGCG-caused growth inhibition in IL-1β-treated HASMCs. At the molecular level, EGCG treatment significantly activated nuclear factor erythroid-2-related factor (Nrf2) transcription activities. These results suggest that EGCG might serve as a complementary and alternative medicine in the treatment of these pathologies by inducing HO-1 expression and subsequently decreasing VSMC proliferation. PMID:25386047

  15. Quantifying the influence of oscillatory flow disturbances on blood flow.

    Science.gov (United States)

    Gabriel, Sargon A; Ding, Yan; Feng, Yuqing

    2017-10-07

    Pulsatile blood flow is renowned for inducing localised flow disturbances that are characterised by significant oscillations. These flow disturbances are recognised to have a physiologic significance within the cardiovascular system, particularly with respect to their proatherogenic expression on endothelial cells. Flow disturbances also impart significant influence on the mechanics of cardiovascular flow and are formally shown in the present study to be coupled to the period-average behaviour of a pulsatile flow field, causing it to be misrepresented by its steady-equivalent; which is often used in models of atherogenesis and hence limits their reliability. It is demonstrated that a measure of the localised influence of flow disturbances on the period-average flow can be realised by the relative significance of their kinetic energy, which is quantified by the introduced Oscillatory Kinetic Energy Index (OKEI). A specific measure of direction-reversing oscillations is also developed with the introduction of the Oscillatory Flow Index (OFI), which is an extension of the wall-bound Oscillatory Shear Index (OSI) onto flow and wall spaces. A case study of a human carotid artery is made; wherein pulsatile flow is studied relative to its steady-equivalent state. The introduced indices are demonstrated to collectively identify oscillatory flow disturbances within the flow; quantifying their spatial distribution and influence on the flow field. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Differences in vascular reactivity between pregnant women with chronic hypertension and preeclampsia.

    Science.gov (United States)

    Mori, Toshitaka; Watanabe, Kazushi; Iwasaki, Ai; Kimura, Chiharu; Matsushita, Hiroshi; Shinohara, Koichi; Wakatsuki, Akihiko

    2014-02-01

    The purpose of this study was to evaluate the distinct pathogenic mechanisms underlying chronic hypertension in pregnancy and preeclampsia in terms of oxidative stress and vascular reactivity. A total of 17 women with uncomplicated pregnancies, 30 women with preeclampsia and 17 women with chronic hypertension were evaluated. We measured serum derivatives of reactive oxygen metabolites (d-ROMs; marker of oxygen free radicals), flow-mediated vasodilation (FMD; marker of endothelial function) and intima-media thickness in the carotid artery (IMT; marker of atherogenesis) during pregnancy and 1 month after delivery. Serum d-ROM concentrations were significantly higher in women with chronic hypertension and severe preeclampsia than in the control group during pregnancy. d-ROM concentrations in all groups significantly decreased to similar levels 1 month after delivery. FMD was significantly lower during pregnancy in preeclamptic and chronic hypertension groups compared with the control group. FMD in preeclamptic groups significantly increased and normalized to control levels after delivery. Similarly, FMD in the chronic hypertension group significantly increased after delivery but was still lower. IMT in the chronic hypertension group was significantly higher than that in control and preeclamptic groups. These findings suggest that endothelial dysfunction induced by enhanced oxidative stress is reversible in women with preeclampsia, whereas impaired vascular reactivity may be associated with atherosclerotic changes in women with chronic hypertension.

  17. Atherosclerosis and Cancer; A Resemblance with Far-reaching Implications.

    Science.gov (United States)

    Tapia-Vieyra, Juana Virginia; Delgado-Coello, Blanca; Mas-Oliva, Jaime

    2017-01-01

    Atherosclerosis and cancer are chronic diseases considered two of the main causes of death all over the world. Taking into account that both diseases are multifactorial, they share not only several important molecular pathways but also many ethiological and mechanistical processes from the very early stages of development up to the advanced forms in both pathologies. Factors involved in their progression comprise genetic alterations, inflammatory processes, uncontrolled cell proliferation and oxidative stress, as the most important ones. The fact that external effectors such as an infective process or a chemical insult have been proposed to initiate the transformation of cells in the artery wall and the process of atherogenesis, emphasizes many similarities with the progression of the neoplastic process in cancer. Deregulation of cell proliferation and therefore cell cycle progression, changes in the synthesis of important transcription factors as well as adhesion molecules, an alteration in the control of angiogenesis and the molecular similarities that follow chronic inflammation, are just a few of the processes that become part of the phenomena that closely correlates atherosclerosis and cancer. The aim of the present study is therefore, to provide new evidence as well as to discuss new approaches that might promote the identification of closer molecular ties between these two pathologies that would permit the recognition of atherosclerosis as a pathological process with a very close resemblance to the way a neoplastic process develops, that might eventually lead to novel ways of treatment. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  18. CTSS promoter -25G/A: not a risk factor for CHD in Chinese.

    Science.gov (United States)

    Sun, Aijun; Binay, Kumar Rauniyar; Xiang, Feiyu; Zhao, Ji; Wang, Ying; Xu, Lei; Ma, Huili; Wang, Keqiang; Zou, Yunzeng; Huang, Wei; Ge, Junbo

    2009-06-01

    Atherosclerosis is an inflammatory disease characterized by extensive remodelling of the extracellular matrix architecture of the arterial wall. Recent data suggested the participation of lysosomal cysteine proteases such as cathepsin S (CTSS) in atherogenesis. The G/A polymorphism at nucleotide -25 was reported to be located in the promoter of the CTSS gene. The aim of this study was to observe the association between CTSS -25G/A polymorphism and the risk of coronary heart disease (CHD) in a Chinese population sample. The polymerase chain reaction and restriction digestion methods were performed to screen the CTSS gene -25G/A polymorphism in a Chinese population sample with (n = 659) or without CHD (n = 352). Traditional risk factors for CHD were obtained simultaneously. The frequencies of the G and A allele in the total population was 0.630 and 0.370, respectively. The frequencies of -25G/A polymorphism in the CTSS gene (G: 0.626 vs. 0.633, P > 0.05; A: 0.374 vs. 0.367, P > 0.05) and the genotype distribution (G: 83.4 vs. 85.3, P > 0.05; A: 58.0 vs. 58.5, P > 0.05) were similar between CHD patients and control subjects. Moreover, CTSS genotype was not associated with severity of coronary stenosis (P > 0.05) in CHD patients. The CTSS -25G/A polymorphism was not related with CHD in our Chinese population sample.

  19. Truths and Controversies Concerning the Role of miRNAs in Atherosclerosis and Lipid Metabolism

    Science.gov (United States)

    Baldán, Ángel; Fernández-Hernando, Carlos

    2017-01-01

    Purpose of review Better tools are sorely needed for both the prevention and treatment of cardiovascular diseases, which account for more than one third of the deaths in Western countries. MicroRNAs typically regulate the expression of several mRNAs involved in the same biological process. Therapeutic manipulation of miRNAs could restore the expression of multiple players within the same physiologic pathway, and ideally offer better curative outcomes than conventional approaches that target only one single player within the pathway. This review summarizes available studies on the prospective value of targeting miRNAs to prevent dyslipidemia and atherogenesis. Recent findings Silencing the expression of miRNAs that target key genes involved in lipoprotein metabolism in vivo with antisense oligonucleotides (ASOs) results in the expected de-repression of target mRNAs in liver and atherosclerotic plaques. However, the consequences of long-term anti-miRNA treatment on both circulating lipoproteins and athero-protection are yet to be established. Summary A number of studies have demonstrated the efficacy of miRNA mimics and inhibitors as novel therapeutic tools for treating dyslipidemia and cardiovascular diseases. Nevertheless, concerns over unanticipated side effects related to de-repression of additional targets should not be overlooked for miRNA-based therapies. PMID:27755115

  20. Low Density Lipoprotein-Containing Circulating Immune Complexes: Role in Atherosclerosis and Diagnostic Value

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    Igor A. Sobenin

    2014-01-01

    Full Text Available It has been suggested that low density lipoprotein-containing circulating immune complexes (LDL-CIC play a role in atherogenesis and are involved in the formation of early atherosclerotic lesion. These complexes, as well as anti-LDL autoantibodies, have been found in the blood and in the atherosclerotic lesions of patients with different cardiovascular diseases, as well as in the blood of animals with experimental atherosclerosis. It can be suggested that the presence of anti-LDL antibodies in the blood is a result of immune response induced by lipoprotein modification. LDL-CIC differs from native LDL in many aspects. It has much lower sialic acid content, smaller diameter, and higher density and is more electronegative than native LDL. Fraction of LDL-CICs is fundamental to the serum atherogenicity manifested at the cellular level. LDL-CIC, unlike native LDL, is able to induce intracellular accumulation of neutral lipids, especially esterified cholesterol, in cells cultured from uninvolved human aortic intima and in macrophage cultures. After removal of LDL-CIC, the CHD patient’s sera lose their atherogenic properties. Titer of LDL-CIC in blood serum significantly correlates with progression of atherosclerosis in human in vivo and has the highest diagnostic value among other measured serum lipid parameters. Elevated CIC-cholesterol might well be a possible risk factor of coronary atherosclerosis.

  1. Cholesterol homeostasis in cardiovascular disease and recent advances in measuring cholesterol signatures.

    Science.gov (United States)

    Seo, Hong Seog; Choi, Man Ho

    2015-09-01

    Despite the biochemical importance of cholesterol, its abnormal metabolism has serious cellular consequences that lead to endocrine disorders such as cardiovascular disease (CVD). Nevertheless, the impact of blood cholesterol as a CVD risk factor is still debated, and treatment with cholesterol-lowering drugs remains controversial, particularly in older patients. Although, the prevalence of CVD increases with age, the underlying mechanisms for this phenomenon are not well understood, and metabolic changes have not been confirmed as predisposing factors of atherogenesis. The quantification of circulating biomarkers for cholesterol homeostasis is therefore warranted, and reference values for cholesterol absorption and synthesis should be determined in order to establish CVD risk factors. The traditional lipid profile is often derived rather than directly measured and lacks a universal standard to interpret the results. In contrast, mass spectrometry-based cholesterol profiling can accurately measure free cholesterol as a biologically active component. This approach allows to detect alterations in various metabolic pathways that control cholesterol homeostasis, by quantitative analysis of cholesterol and its precursors/metabolites as well as dietary sterols. An overview of the mechanism of cholesterol homeostasis under different physiological conditions may help to identify predictive biomarkers of concomitant atherosclerosis and conventional CVD risk factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. [Therapy of dyslipidemia in post-infarction: state of the art].

    Science.gov (United States)

    Borgia, M C; Nardi, M; Da Ros, S; Castellano, V

    2007-01-01

    Between the risks factors involved in the atherogenesis LDL-cholesterol is determinant because highly associated to cardiovascular events. The primary target for the prevention of coronary diseases is a reduction of LDL-cholesterol because that reduces the cardiovascular mortality and the total mortality. The NCEP ATP III 2004 guide-lines propose as therapeutic target for the high-risk patients the reduction of plasma levels of LDL-cholesterol under 100 mg/dl and according to new trials under 70 mg/dl. The dyslipidaemia treatments are based on two approaches, i.e., the therapeutic lifestyle change and the pharmacological therapy. The available drugs are statins, fibrates, anion exchange resins, nicotinic acid. In the acute coronary syndrome patients is desirable to start immediately a therapy with statins since the hospital phase and direct the treatment to aggressive therapy. Unfortunately, the statin doses used in the most secondary prevention trials allow to get LDL-cholesterol under 100 mg/dl in the only half high-risk patients. The innovative therapeutic approach to hypercholesterolemia today is based on a double inhibition of cholesterol synthesis and absorption combining a statin with ezetimibe.

  3. What is metabolic syndrome, and why are children getting it?

    Science.gov (United States)

    Weiss, Ram; Bremer, Andrew A; Lustig, Robert H

    2013-01-01

    Metabolic syndrome comprises a cluster of cardiovascular risk factors (hypertension, altered glucose metabolism, dyslipidemia, and abdominal obesity) that occur in obese children. However, metabolic syndrome can also occur in lean individuals, suggesting that obesity is a marker for the syndrome, not a cause. Metabolic syndrome is difficult to define, due to its nonuniform classification and reliance on hard cutoffs in the evaluation of disorders with non-Gaussian distributions. Defining the syndrome is even more difficult in children, owing to racial and pubertal differences and lack of cardiovascular events. Lipid partitioning among specific fat depots is associated with insulin resistance, which can lead to mitochondrial overload and dysfunctional subcellular energy use and drive the various elements of metabolic syndrome. Multiple environmental factors, in particular a typical Western diet, drive mitochondrial overload, while other changes in Western society, such as stress and sleep deprivation, increase insulin resistance and the propensity for food intake. These culminate in an adverse biochemical phenotype, including development of altered glucose metabolism and early atherogenesis during childhood and early adulthood. PMID:23356701

  4. POSSIBLE ROLE OF MITOCHONDRIAL GENOME MUTATIONS IN CORONARY HEART DISEASE

    Directory of Open Access Journals (Sweden)

    L. A. Egorova

    2014-07-01

    Full Text Available Mitochondria are not only the major producers of adenosine triphosphate, but also an endogenous source of reactive oxygen species. Mitochondrialdysfunction plays a key role in the trigger and progression of atherosclerotic lesion. Impaired function in the mitochondria due to their elevated level of oxidized oxygen species, the accumulation of mitochondrial DNA damages, and the exhaustion of respiratory chains induces dysfunction and apoptosis in the endothelial cells; activation of matrix metalloproteinases; growth of vascular smooth muscle cells and their migration into the intima; expression of adhesion molecules, and oxidation of low-density lipoproteins. Mitochondrial dysfunction may be an important unifying mechanism that accounts for the atherogenic effect of major cardiovascular risk factors. Small clinical pilot studies have shown an association of different mitochondrial genome mutations with atherosclerotic lesion in the artery. Taking into account the available data on the possible role of mitochondria in atherogenesis, novel drugs are now being designed to affect mitochondrial function.

  5. Adipoparacrinology: an Emerging Field in Biomedical Research

    Directory of Open Access Journals (Sweden)

    George N. Chaldakov

    2012-03-01

    Full Text Available White adipose tissue (WAT is a dynamic multicellular assembly composed of adipocytes and stromovascular cells, including fibroblasts, endothelial and immune cells, nerve fibers, and stem cells. In humans, WAT is a responsive and secretory (endocrine and paracrine tissue partitioned into two large depots (subcutaneous and visceral and many small depots associated with the heart, blood vessels, major lymph nodes, prostate gland, ovaries and mammary glands. This short review conceptualizes evidence for the paracrine activity of adipose tissue in founding a new research field, designated adipoparacrinology. Here we focus on (i epicardial and periadventitial adipose tissue in atherogenesis, (ii mammary gland-associated adipose tissue in breast cancer, and (iii periprostatic adipose tissue in prostate cancer. Other examples include: (i mesenteric adipose tissue in Crohn’s disease, (ii lymph node-associated (perinodal adipose tissue in Crohn’s disease and HIV-associated adipose redistribution syndrome, (iii infrapatellar fat pad (Hoffa’s fat pad in knee osteoarthritis, (iv orbital adipose tissue in thyroid-associated (Graves’ ophthalmopathy, and (v parasellar region-associated adipose tissue in brain disorders. The therapy aspect of adipoparacrinology is also discussed.

  6. Atherosclerosis of coronary blood vessels - local or systemic inflamation?

    Science.gov (United States)

    Pejkov, Hristo; Kedev, Sasko; Panov, Saso; Srbinovska-Kostovska, Elizabeta; Lang, Irene

    2013-01-01

    The presence of atherosclerotic lesions in the blood vessels is a predisposition for the development and occurrence of acute ischaemic attacks. Bigger atherosclerotic lesions in the coronary blood vessels cause lumen occlusion, which is a cause of acute myocardial infarction. Endothelial dysfunction is defined as an ability of the endothelium to produce vasorelaxing nitric oxide (NO), or deregulation of the other vasoactive substances, such as angiotensin II and endothelin [13]. This definition describes endothelial dysfunction as an improper vasomotor constriction of the vessel, that leads to lumen occlusion of the already existing atherosclerotic lesions. According to the modern model, the development of atherosclerotic plaque and inappropriate endothelial NO production have a synergistic role in patho-physiological and molecular processes in the blood vessels [14]. Lesions in the coronary arteries are deposits of huge quantities of foamy cells and fibrous plaques. The thin fibrous plaques are 10-20% of the total plaque population and are the cause of 80-90% of clinical cases due to their ability to rupture [48]. According to all the results from published studies by far, it has been pointed out that the plaque stability, not the absolute size influences the rupture potential. Elucidating the risk factors that may modify in the atherogenesis and the consequent atherothrombic effect is the first step to this goal.

  7. Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice.

    Science.gov (United States)

    MacLean, Paul S; Bower, Joseph F; Vadlamudi, Satyaprasad; Osborne, Jody N; Bradfield, John F; Burden, Hubert W; Bensch, William H; Kauffman, Raymond F; Barakat, Hisham A

    2003-08-01

    Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity. Transgenic mice expressing the human CETP minigene were crossed with db/db strain, and 3 groups of offspring (CETP, db, and db/CETP) were placed on an atherogenic diet for 16 weeks. The proximal aorta was then excised and examined for the presence of atherosclerotic plaques. In db mice, 9 of 11 had intimal lesions with a mean area of 26 098+/-7486 microm2. No lesions greater than 1000 microm2 were observed in db/CETP or CETP mice. CETP-expressing mice had lower circulating cholesterol concentrations than db mice. Fractionating plasma lipids by FPLC indicated that the difference in total cholesterol was primarily attributable to differences in VLDL and LDL. The expression of human CETP in db/db mice prevented the formation of diet-induced lesions, suggesting an antiatherogenic effect of CETP in the context of diabetic obesity.

  8. Insulin and Its Cardiovascular Effects: What Is the Current Evidence?

    Science.gov (United States)

    Dongerkery, Sahana Pai; Schroeder, Pamela R; Shomali, Mansur E

    2017-10-23

    In this article, we examine the nature of the complex relationship between insulin and cardiovascular disease. With metabolic abnormalities comes increased risk for cardiovascular complications. We discuss the key factors implicated in development and progression of cardiovascular disease, its relationship to insulin therapy, and what can be learned from large, recent cardiovascular outcome studies. Preclinical studies suggest that insulin has positive effects of facilitating glucose entry into cells and maintaining euglycemia and negative effects of favoring obesity and atherogenesis under certain conditions. Confounding this relationship is that cardiovascular morbidity is linked closely to duration and control of diabetes, and insulin is often used in patients with diabetes of longer duration. However, more recent clinical studies examining the cardiovascular safety of insulin therapy have been reassuring. Diabetes and cardiovascular outcomes are closely linked. Many studies have implicated insulin resistance and hyperinsulinemia as a major factor for poor cardiovascular outcomes. Additional studies link the anabolic effects of therapeutic insulin to weight gain, along with hypoglycemia, which may further aggravate cardiovascular risk in this population. Though good glycemic control has been shown to improve microvascular risks in type 1 and type 2 diabetes, what are the known cardiovascular effects of insulin therapy? The ORIGIN trial suggests at least a neutral effect of the basal insulin glargine on cardiovascular outcomes. Recent studies have demonstrated that ultra-long-acting insulin analogs like insulin degludec are non-inferior to insulin glargine with regard to cardiovascular outcomes.

  9. Thyroid and lipid metabolism.

    Science.gov (United States)

    Pucci, E; Chiovato, L; Pinchera, A

    2000-06-01

    Thyroid hormones influence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure obtained acting on protein, carbohydrate and lipid metabolism. With specific regard to lipid metabolism, thyroid hormones affect synthesis, mobilization and degradation of lipids, although degradation is influenced more than synthesis. The main and best-known effects on lipid metabolism include: (a) enhanced utilization of lipid substrates; (b) increase in the synthesis and mobilization of triglycerides stored in adipose tissue; (c) increase in the concentration of non-esterified fatty acids (NEFA); and (d) increase of lipoprotein-lipase activity. While severe hypothyroidism is usually associated with an increased serum concentration of total cholesterol and atherogenic lipoproteins, the occurrence of acute myocardial infarction (AMI) in hypothyroid patients is not frequent. However, hypothyroid patients appear to have an increased incidence of residual myocardial ischemia following AMI. Even in subclinical hypothyroidism, which is characterized by raised serum TSH levels with normal serum thyroid hormone concentrations, mild hyperlipidemia is present and may contribute to an increased risk of atherogenesis. Prudent substitution therapy with L-thyroxine is indicated in patients with both overt and subclinical hypothyroidism, with or without angina, to counteract the cardiovascular risk resulting from hyper-dyslipidemia.

  10. A regime map for secondary flow structures under physiological and multi-harmonic inflow through a bent tube model for curved arteries

    Science.gov (United States)

    Callahan, Shannon M.; Caldwell, Kirin; Bulusu, Kartik V.; Plesniak, Michael W.

    2012-11-01

    Secondary flow structures are known to affect wall shear stress, which is closely related to atherogenesis and drug particle deposition. A regime map provides a framework to examine phase-wise variations in secondary flow structures under physiological and multi-harmonic inflow waveforms under conditions of a fixed Womersley number (4.2) and curvature ratio (1/7). Experimental PIV data were acquired at the 90-degree location in a 180-degree curved test section of a bent tube model for curved arteries using a blood analog working fluid. Coherent structure detection was performed using a continuous wavelet transform algorithm (PIVlet 1.2) and further analysis was carried out by grouping similar secondary flow structures at a fixed secondary Reynolds numbers. Phase-locked, planar vorticity fields over one period of inflow waveform revealed size, structure and strength similarities in secondary flow morphologies during the acceleration and deceleration phases. The utility of the new regime map lies in the a priori identification of pulsatile secondary flow structures, eliminating the need for exhaustive experimentation or computing, requiring only flow rate measurements that are easily acquired under clinical conditions. Supported by the National Science Foundation, Grant No. CBET-0828903 and GW Center for Biomimetics and Bioinspired Engineering (COBRE).

  11. Race-ethnic variation in carotid bifurcation geometry.

    Science.gov (United States)

    Koch, Sebastian; Nelson, Donoffa; Rundek, Tatjana; Mandrekar, Jay; Rabinstein, Alejandro

    2009-01-01

    Disturbances in local blood flow influenced by arterial geometry contribute to atherogenesis. Carotid bifurcation hemodynamics depend on the relative sizes of the common carotid artery (CCA), internal carotid artery (ICA), and external carotid artery (ECA), which vary considerably among individuals. The prevalence of carotid bifurcation atherosclerosis differs among race-ethnic groups and is generally lower in African Americans despite a more adverse vascular risk factor profile. We here examine whether there are race-ethnic differences in carotid bifurcation anatomy. The diameters of the CCA, carotid bulb, ICA, and ECA were measured from consecutive cerebral angiograms of African American, white, and Caribbean Hispanic patients. The bulb/CCA, ICA/CCA, ECA/CCA, ECA/ICA, and total cross-sectional outflow/inflow ratio ([ICA(2) + ECA(2)]/CCA(2)) were calculated. The final analysis included 272 bifurcations of which 103 were among white, 87 Hispanic, and 82 African American patients. The mean age of the population was 59.8 +/- 15.8 years and 148 (54.4%) were men. African Americans had a lower ICA/CCA ratio (P ECA ratio (P ECA/CCA ratio (P groups. We found significant differences in the relative sizes of the ICA, ECA, and CCA among race-ethnic groups. African Americans had a proportionally smaller ICA and larger ECA in comparison with whites and Caribbean Hispanics.

  12. Cardiovascular effects of electronic cigarettes.

    Science.gov (United States)

    Benowitz, Neal L; Fraiman, Joseph B

    2017-08-01

    Cardiovascular safety is an important consideration in the debate on the benefits versus the risks of electronic cigarette (EC) use. EC emissions that might have adverse effects on cardiovascular health include nicotine, oxidants, aldehydes, particulates, and flavourants. To date, most of the cardiovascular effects of ECs demonstrated in humans are consistent with the known effects of nicotine. Pharmacological and toxicological studies support the biological plausibility that nicotine contributes to acute cardiovascular events and accelerated atherogenesis. However, epidemiological studies assessing Swedish smokeless tobacco, which exposes users to nicotine without combustion products, generally have not found an increased risk of myocardial infarction or stroke among users, but suggest that nicotine might contribute to acute cardiovascular events, especially in those with underlying coronary heart disease. The effects of aldehydes, particulates, and flavourants derived from ECs on cardiovascular health have not been determined. Although ECs might pose some cardiovascular risk to users, particularly those with existing cardiovascular disease, the risk is thought to be less than that of cigarette smoking based on qualitative and quantitative comparisons of EC aerosol versus cigarette smoke constituents. The adoption of ECs rather than cigarette smoking might, therefore, result in an overall benefit for public health.

  13. Impaired arterial smooth muscle cell vasodilatory function in methamphetamine users.

    Science.gov (United States)

    Nabaei, Ghaemeh; Oveisgharan, Shahram; Ghorbani, Askar; Fatehi, Farzad

    2016-11-15

    Methamphetamine use is a strong risk factor for stroke. This study was designed to evaluate arterial function and structure in methamphetamine users ultrasonographically. In a cross-sectional study, 20 methamphetamine users and 21 controls, aged between 20 and 40years, were enrolled. Common carotid artery intima-media thickness (CCA-IMT) marker of early atherogenesis, flow-mediated dilatation (FMD) determinants of endothelium-dependent vasodilation, and nitroglycerine-mediated dilatation (NMD) independent marker of vasodilation were measured in two groups. There were no significant differences between the two groups regarding demographic and metabolic characteristics. The mean (±SD) CCA-IMT in methamphetamine users was 0.58±0.09mm, versus 0.59±0.07mm in the controls (p=0.84). Likewise, FMD% was not significantly different between the two groups [7.6±6.1% in methamphetamine users vs. 8.2±5.1% in the controls; p=0.72], nor were peak flow and shear rate after hyperemia. However, NMD% was considerably decreased in the methamphetamine users [8.5±7.8% in methamphetamine users vs. 13.4±6.2% in controls; p=0.03]. According to our results, NMD is reduced among otherwise healthy methamphetamine users, which represents smooth muscle dysfunction in this group. This may contribute to the high risk of stroke among methamphetamine users. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Novel therapies targeting vascular endothelium.

    Science.gov (United States)

    Tousoulis, Dimitris; Antoniades, Charalambos; Koumallos, Nikolaos; Marinou, Kyriakoula; Stefanadi, Elli; Latsios, George; Stefanadis, Christodoulos

    2006-01-01

    Endothelial dysfunction has been identified as a major mechanism involved in all the stages of atherogenesis. Evaluation of endothelial function seems to have a predictive role in humans, and therapeutic interventions improving nitric oxide bioavailability in the vasculature may improve the long-term outcome in healthy individuals, high-risk subjects, or patients with advanced atherosclerosis. Several therapeutic strategies are now available, targeting both the synthesis and oxidative inactivation of nitric oxide (NO) in human vasculature. Statins seem to be currently the most powerful category of these agents, improving endothelial function and decreasing cardiovascular risk after long-term administration. Other cardiovascular agents improving endothelial function in humans are angiotensin-converting enzyme inhibitors/angiotensin receptors blockers, which increase NO bioavailability by modifying the rennin-angiotensin-aldosterone system. Newer therapeutic approaches targeting endothelial dysfunction in specific disease states include insulin sensitizers, L-arginine (the substrate for endothelial NO synthase [eNOS]) as well as substances that target eNOS "coupling," such as folates or tetrahydrobiopterin. Although there are a variety of strategies to improve NO bioavailability in human endothelium, it is still unclear whether they have any direct benefit at a clinical level.

  15. The burden of type 2 diabetes: strategies to prevent or delay onset

    Directory of Open Access Journals (Sweden)

    Nayyar Iqbal

    2007-09-01

    Full Text Available Nayyar IqbalDepartment of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania, Philadelphia VA Medical Center, PA, USAAbstract: Type 2 diabetes is widespread and its prevalence is increasing rapidly. In the US alone, approximately 41 million individuals have prediabetes, placing them at high risk for the development of diabetes. The pathogenesis of type 2 diabetes involves inadequate insulin secretion and resistance to the action of insulin. Suggestive data link insulin resistance and accompanying hyperglycemia to an excess of abdominal adipose tissue, a link that appears to be mediated partially by adipocyte secretion of multiple adipokines that mediate inflammation, thrombosis, atherogenesis, hypertension, and insulin resistance. The adipokine adiponectin has reduced expression in obesity and appears to be protective against the development of type 2 diabetes. Current recommendations to prevent type 2 diabetes center on lifestyle modifications, such as diet and exercise. Clinical trials have established the efficacy of lifestyle intervention, as well as pharmacologic interventions that target glycemic control or fat metabolism. However, diabetes did develop in a substantial percentage of individuals who received intensive intervention in these trials. Thus there is an unmet need for additional strategies in high-risk individuals. Recent data suggest thiazolidinediones and blockade of the endocannabinoid system represent novel therapeutic approaches that may be used for the prevention of diabetes.Keywords: cardiometabolic risk, abdominal obesity, dyslipidemia, diabetes, insulin resistance, endocannabinoid system

  16. Obesity-related inflammation & cardiovascular disease: Efficacy of a yoga-based lifestyle intervention

    Directory of Open Access Journals (Sweden)

    Kumar Sarvottam

    2014-01-01

    Full Text Available Obesity is a global health burden and its prevalence is increasing substantially due to changing lifestyle. Chronic adiposity is associated with metabolic imbalance leading to dyslipidaemia, diabetes, hypertension and cardiovascular diseases (CVD. Adipose tissue acts as an endocrine organ releasing several adipocytokines, and is associated with increased levels of tissue and circulating inflammatory biomolecules causing vascular inflammation and atherogenesis. Further, inflammation is also associated independently with obesity as well as CVD. Keeping this in view, it is possible that a reduction in weight may lead to a decrease in inflammation, resulting in CVD risk reduction, and better management of patients with CVD. Lifestyle intervention has been endorsed by several health authorities in prevention and management of chronic diseases. A yoga-based lifestyle intervention appears to be a promising option in reducing the risk for CVD as well as management of patients with CVD as it is simple to follow and cost-effective with high compliance. The efficacy of such lifestyle intervention programmes is multifaceted, and is achieved via reduction in weight, obesity-related inflammation and stress, thereby culminating into risk reduction towards several chronic diseases including CVD. In this review, the association between obesity-related inflammation and CVD, and the role of yoga-based lifestyle intervention in prevention and management of CVD are discussed.

  17. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARɣ and LXRα pathways

    Science.gov (United States)

    Chinetti-Gbaguidi, Giulia; Baron, Morgane; Bouhlel, Mohamed Amine; Vanhoutte, Jonathan; Copin, Corinne; Sebti, Yasmine; Derudas, Bruno; Mayi, Thérèse; Bories, Gael; Tailleux, Anne; Haulon, Stéphane; Zawadzki, Christophe; Jude, Brigitte; Staels, Bart

    2011-01-01

    Rationale A crucial step in atherogenesis is the infiltration of the sub-endothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells which adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, while Th2 cytokines trigger an “alternative” M2 phenotype. Objective We previously reported the presence of CD68+MR+ M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68+MR+ macrophages is still unknown. Methods and Results Histological analysis revealed that CD68+MR+ locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68+MR− macrophages. IL-4 polarized CD68+MR+ display a reduced capacity to handle and efflux cellular cholesterol due to low expression levels of the nuclear receptor Liver X Receptor (LXR)α and its target genes, ABCA1 and ApoE, caused by the high 15-lipoxygenase activity in CD68+MR+ macrophages. By contrast, CD68+MR+ highly express opsonins and receptors involved in phagocytosis resulting in high phagocytic activity. In M2 macrophages, Peroxisome Proliferator-Activated receptor (PPAR)γ activation enhances the phagocytic, but not the cholesterol trafficking pathways. Conclusions These data identify a distinct macrophage sub-population with a low susceptibility to become foam cells, but high phagocytic activity due to different regulatory activities of the PPARγ-LXRα pathways. PMID:21350215

  18. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways.

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    Chinetti-Gbaguidi, Giulia; Baron, Morgane; Bouhlel, Mohamed Amine; Vanhoutte, Jonathan; Copin, Corinne; Sebti, Yasmine; Derudas, Bruno; Mayi, Thérèse; Bories, Gael; Tailleux, Anne; Haulon, Stephane; Zawadzki, Christophe; Jude, Brigitte; Staels, Bart

    2011-04-15

    A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an "alternative" M2 phenotype. We previously reported the presence of CD68(+) mannose receptor (MR)(+) M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68(+)MR(+) macrophages is still unknown. Histological analysis revealed that CD68(+)MR(+) macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68(+)MR(-) macrophages. Interleukin (IL)-4-polarized CD68(+)MR(+) macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68(+)MR(+) macrophages. By contrast, CD68(+)MR(+) macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways. These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.

  19. Mast cells in atherosclerotic cardiovascular disease - Activators and actions.

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    Kovanen, Petri T; Bot, Ilze

    2017-10-12

    Mast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the site of atherogenesis, mast cells are activated to degranulate, and thereby triggered to release an abundance of preformed inflammatory mediators, notably histamine, heparin, neutral proteases and cytokines stored in their cytoplasmic secretory granules. Depending on the stimulus, mast cell activation may also launch prolonged synthesis and secretion of single bioactive molecules, such as cytokines and derivatives of arachidonic acid. The mast cell-derived mediators may impede the functions of different types of cells present in atherosclerotic lesions, and also compromise the structural and functional integrity of the intimal extracellular matrix. In the adventitial layer of atherosclerotic coronary arteries, mast cells locate next to peptidergic sensory nerve fibers, which, by releasing neuropeptides may activate mast cells to release vasoactive compounds capable of triggering local vasoconstriction. The concerted actions of arterial mast cells have the potential to contribute to the initiation and progression of atherosclerosis, and ultimately to destabilization and rupture of an advanced atherosclerotic plaque with ensuing atherothrombotic complications. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Vascular neuropeptide Y contributes to atherosclerotic plaque progression and perivascular mast cell activation.

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    Lagraauw, H Maxime; Westra, Marijke M; Bot, Martine; Wezel, Anouk; van Santbrink, Peter J; Pasterkamp, Gerard; Biessen, Erik A L; Kuiper, Johan; Bot, Ilze

    2014-07-01

    Neuropeptide Y is an abundantly expressed neurotransmitter capable of modulating both immune and metabolic responses related to the development of atherosclerosis. NPY receptors are expressed by a number of vascular wall cell types, among which mast cells. However, the direct effects of NPY on atherosclerotic plaque development and progression remain to be investigated. In this study we thus aimed to determine whether NPY is expressed in atherosclerotic plaques and to establish its role in atherosclerotic plaque development. NPY expression was seen to be increased up to 2-fold in unstable human endarterectomy plaques, as compared to stable plaques, and to be significantly upregulated during lesion progression in apoE(-/-) mice. In apoE(-/-) mice focal overexpression of NPY in the carotid artery significantly increased atherosclerotic plaque size compared to controls, while plaque composition was unaffected. Interestingly, perivascular mast cell activation was significantly higher in the NPY-overexpressing mice, suggesting that NPY may impact plaque progression in part via mast cell activation. Furthermore, in vitro NPY-induced murine mast cell activation resulted in the release of pro-atherogenic mediators including IL-6 and tryptase. Our data show that NPY expression is increased during atherogenesis and in particular in unstable plaques. Furthermore, perivascular overexpression of NPY promoted plaque development and perivascular mast cell activation, suggestive of a role for NPY-induced mast cell activation in lesion progression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Regional gene expression of LOX-1, VCAM-1, and ICAM-1 in aorta of HIV-1 transgenic rats.

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    Anne Mette Fisker Hag

    Full Text Available BACKGROUND: Increased prevalence of atherosclerotic cardiovascular disease in HIV-infected patients has been observed. The cause of this accelerated atherosclerosis is a matter of controversy. As clinical studies are complicated by a multiplicity of risk-factors and a low incidence of hard endpoints, studies in animal models could be attractive alternatives. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated gene expression of lectin-like oxidized-low-density-lipoprotein receptor-1 (LOX-1, vascular cell adhesion molecule-1 (VCAM-1, and intercellular adhesion molecule-1 (ICAM-1 in HIV-1 transgenic (HIV-1Tg rats; these genes are all thought to play important roles in early atherogenesis. Furthermore, the plasma level of sICAM-1 was measured. We found that gene expressions of LOX-1 and VCAM-1 were higher in the aortic arch of HIV-1Tg rats compared to controls. Also, the level of sICAM-1 was elevated in the HIV-1Tg rats compared to controls, but the ICAM-1 gene expression profile did not show any differences between the groups. CONCLUSIONS/SIGNIFICANCE: HIV-1Tg rats have gene expression patterns indicating endothelial dysfunction and accelerated atherosclerosis in aorta, suggesting that HIV-infection per se may cause atherosclerosis. This transgenic rat model may be a very promising model for further studies of the pathophysiology behind HIV-associated cardiovascular disease.

  2. Exercise and Dietary-Mediated Reductions in Postprandial Lipemia

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    Plaisance, Eric P.; Fisher, Gordon

    2014-01-01

    Postprandial hyperlipemia produces long-term derangements in lipid/lipoprotein metabolism, vascular endothelial dysfunction, hypercoagulability, and sympathetic hyperactivity which are strongly linked to atherogenesis. The purpose of this review is to (1) provide a qualitative analysis of the available literature examining the dysregulation of postprandial lipid metabolism in the presence of obesity, (2) inspect the role of adiposity distribution and sex on postprandial lipid metabolism, and (3) examine the role of energy deficit (exercise- and/or energy restriction-mediated), isoenergetic low-carbohydrate diets, and omega-3 (n-3) fatty acid supplementation on postprandial lipid metabolism. We conclude from the literature that central adiposity primarily accounts for sex-related differences in postprandial lipemia and that aerobic exercise attenuates this response in obese or lean men and women to a similar extent through potentially unique mechanisms. In contrast, energy restriction produces only mild reductions in postprandial lipemia suggesting that exercise may be superior to energy restriction alone as a strategy for lowering postprandial lipemia. However, isoenergetic very low-carbohydrate diets and n-3 fatty acid supplementation reduce postprandial lipemia indicating that macronutrient manipulations reduce postprandial lipemia in the absence of energy restriction. Therefore, interactions between exercise/energy restriction and alterations in macronutrient content remain top priorities for the field to identify optimal behavioral treatments to reduce postprandial lipemia. PMID:25061524

  3. Exercise and Dietary-Mediated Reductions in Postprandial Lipemia

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    Eric P. Plaisance

    2014-01-01

    Full Text Available Postprandial hyperlipemia produces long-term derangements in lipid/lipoprotein metabolism, vascular endothelial dysfunction, hypercoagulability, and sympathetic hyperactivity which are strongly linked to atherogenesis. The purpose of this review is to (1 provide a qualitative analysis of the available literature examining the dysregulation of postprandial lipid metabolism in the presence of obesity, (2 inspect the role of adiposity distribution and sex on postprandial lipid metabolism, and (3 examine the role of energy deficit (exercise- and/or energy restriction-mediated, isoenergetic low-carbohydrate diets, and omega-3 (n-3 fatty acid supplementation on postprandial lipid metabolism. We conclude from the literature that central adiposity primarily accounts for sex-related differences in postprandial lipemia and that aerobic exercise attenuates this response in obese or lean men and women to a similar extent through potentially unique mechanisms. In contrast, energy restriction produces only mild reductions in postprandial lipemia suggesting that exercise may be superior to energy restriction alone as a strategy for lowering postprandial lipemia. However, isoenergetic very low-carbohydrate diets and n-3 fatty acid supplementation reduce postprandial lipemia indicating that macronutrient manipulations reduce postprandial lipemia in the absence of energy restriction. Therefore, interactions between exercise/energy restriction and alterations in macronutrient content remain top priorities for the field to identify optimal behavioral treatments to reduce postprandial lipemia.

  4. Cardiovascular risk and subclinical cardiovascular disease in polycystic ovary syndrome.

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    Bajuk Studen, Katica; Jensterle Sever, Mojca; Pfeifer, Marija

    2013-01-01

    In addition to its effects on reproductive health, it is now well recognized that polycystic ovary syndrome (PCOS) is a metabolic disorder, characterized by decreased insulin sensitivity which leads to an excess lifetime risk of type 2 diabetes and cardiovascular disease. PCOS patients are often obese, hypertensive, dyslipidemic and insulin resistant; they have obstructive sleep apnea and have been reported to have higher aldosterone levels in comparison to normal healthy controls. These are all components of an adverse cardiovascular risk profile. Many studies exploring subclinical atherosclerosis using different methods (flow-mediated dilatation, intima media thickness, arterial stiffness, coronary artery calcification) as well as assessing circulating cardiovascular risk markers, point toward an increased cardiovascular risk and early atherogenesis in PCOS. The risk and early features of subclinical atherosclerosis can be reversed by non-medical (normalization of weight, healthy lifestyle) and medical (metformin, thiazolidinediones, spironolactone, and statins) interventions. However, the long-term risk for cardiovascular morbidity and mortality as well as the clinical significance of different interventions still need to be properly addressed in a large prospective study. Copyright © 2013 S. Karger AG, Basel.

  5. Central blood pressure and chronic kidney disease

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    Ohno, Yoichi; Kanno, Yoshihiko; Takenaka, Tsuneo

    2016-01-01

    In this review, we focused on the relationship between central blood pressure and chronic kidney diseases (CKD). Wave reflection is a major mechanism that determines central blood pressure in patients with CKD. Recent medical technology advances have enabled non-invasive central blood pressure measurements. Clinical trials have demonstrated that compared with brachial blood pressure, central blood pressure is a stronger risk factor for cardiovascular (CV) and renal diseases. CKD is characterized by a diminished renal autoregulatory ability, an augmented direct transmission of systemic blood pressure to glomeruli, and an increase in proteinuria. Any elevation in central blood pressure accelerates CKD progression. In the kidney, interstitial inflammation induces oxidative stress to handle proteinuria. Oxidative stress facilitates atherogenesis, increases arterial stiffness and central blood pressure, and worsens the CV prognosis in patients with CKD. A vicious cycle exists between CKD and central blood pressure. To stop this cycle, vasodilator antihypertensive drugs and statins can reduce central blood pressure and oxidative stress. Even in early-stage CKD, mineral and bone disorders (MBD) may develop. MBD promotes oxidative stress, arteriosclerosis, and elevated central blood pressure in patients with CKD. Early intervention or prevention seems necessary to maintain vascular health in patients with CKD. PMID:26788468

  6. Pathophysiological Role of Adiponectin, Leptin and Asymmetric Dimethylarginine in the Process of Atherosclerosis

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    Koleva Daniela Iv.

    2016-12-01

    Full Text Available Adipose tissue is recognized as a rich source of proinflammatory mediators that may directly contribute to vascular injury, insulin resistance, and atherogenesis. Many studies have shown that adiponectin has antiatherogenic and anti-inflammatory properties. Adiponectin acts not only as a factor increasing insulin sensitivity, and the protective effect may result from its ability to suppress production of proinflammatory cytokines. It negatively regulates the expression of TNF-alpha and C-reactive protein (CRP in adipose tissue; reduces expression of vascular and intracellular adhesion molecules (VCAM-1, ICAM-1, E-selectin, interleukin-8 (IL-8. Hyperleptinemia has been linked with the development of hypertension and endothelial dysfunction/atherosclerosis, two main pathophysiological conditions associated with cardiovascular disease development. Leptin-mediated increases in sympathetic nervous system activity may be among the principal mechanisms evoking obesity related hypertension. Leptin stimulates the secretion of proinflammatory cytokines, and increases the release of endothelin-1 (ET-1, which may promote hypertension. Increased serum levels of asymmetric dimethylarginine (ADMA, a physiological regulator of the biosynthesis of nitric oxide (NO, promote the process of atherosclerosis, leading to the occurrence of endothelial dysfunction and cardiovascular disease.

  7. The influence of perivascular adipose tissue on vascular homeostasis.

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    Szasz, Theodora; Bomfim, Gisele Facholi; Webb, R Clinton

    2013-01-01

    The perivascular adipose tissue (PVAT) is now recognized as an active contributor to vascular function. Adipocytes and stromal cells contained within PVAT are a source of an ever-growing list of molecules with varied paracrine effects on the underlying smooth muscle and endothelial cells, including adipokines, cytokines, reactive oxygen species, and gaseous compounds. Their secretion is regulated by systemic or local cues and modulates complex processes, including vascular contraction and relaxation, smooth muscle cell proliferation and migration, and vascular inflammation. Recent evidence demonstrates that metabolic and cardiovascular diseases alter the morphological and secretory characteristics of PVAT, with notable consequences. In obesity and diabetes, the expanded PVAT contributes to vascular insulin resistance. PVAT-derived cytokines may influence key steps of atherogenesis. The physiological anticontractile effect of PVAT is severely diminished in hypertension. Above all, a common denominator of the PVAT dysfunction in all these conditions is the immune cell infiltration, which triggers the subsequent inflammation, oxidative stress, and hypoxic processes to promote vascular dysfunction. In this review, we discuss the currently known mechanisms by which the PVAT influences blood vessel function. The important discoveries in the study of PVAT that have been made in recent years need to be further advanced, to identify the mechanisms of the anticontractile effects of PVAT, to explore the vascular-bed and species differences in PVAT function, to understand the regulation of PVAT secretion of mediators, and finally, to uncover ways to ameliorate cardiovascular disease by targeting therapeutic approaches to PVAT.

  8. The Role of Adipocytokines in Coronary Atherosclerosis.

    Science.gov (United States)

    Liberale, Luca; Bonaventura, Aldo; Vecchiè, Alessandra; Matteo, Casula; Dallegri, Franco; Montecucco, Fabrizio; Carbone, Federico

    2017-02-01

    The aim of this review is to overview the pathophysiological role of adipocytokines in atherogenesis, focusing on their potential role as biomarkers of coronary disease. Several lines of evidence indicated adipose tissue not only as depot but rather as an endocrine organ. In this context, the balance between pro- and anti-inflammatory adipocytokines has been shown to critically regulate vascular homeostasis in both physiological and pathophysiological conditions. Overweight and obesity are characterized by dysfunctional adipose tissue and then the prevalence of pro-inflammatory mediators, with a detrimental effect on vascular health. As opposite to adiponectin, pro-inflammatory adipocytokines, such as leptin and resistin, promote endothelial dysfunction and inflammatory processes involved in atherosclerotic plaque progression and vulnerability. Therefore, many adipocytokines have been investigated as potential biomarkers of cardiovascular (CV) risk, but their role has not yet been clearly established. Furthermore, the perivascular adipose tissue recently emerged as a critical modulator of atherosclerotic processes, due to the close interaction with the underlying vascular tissue. The ongoing discovery of new adipocytokines and the complex pathophysiological role of the different adipose tissue depots strongly contribute to define the complexity of adipocytokines network. Understanding those complex interactions may allow determining new potential biomarkers of CV risk and potential therapeutic targets.

  9. Di-(2-ethylhexyl) phthalate accelerates atherosclerosis in apolipoprotein E-deficient mice.

    Science.gov (United States)

    Zhao, Jin-Feng; Hsiao, Sheng-Huang; Hsu, Ming-Hua; Pao, Kuan-Chuan; Kou, Yu Ru; Shyue, Song-Kun; Lee, Tzong-Shyuan

    2016-01-01

    Di-(2-ethylhexyl) phthalate (DEHP) is associated with atherosclerosis-related cardiovascular disease complications, but we lack direct evidence of its unfavorable effect on atherogenesis. In this study, we aimed to clarify in vivo and in vitro the contribution of DEHP to the development of atherosclerosis and its underlying mechanisms. Apolipoprotein E-deficient (apoE(-/-)) mice chronically treated with DEHP for 4 weeks showed exacerbated hyperlipidemia, systemic inflammation, and atherosclerosis. In addition, DEHP promoted low-density lipoprotein (LDL) oxidation, which led to inflammation in endothelial cells as evidenced by increased protein expression of pro-inflammatory mediators. Furthermore, chronic DEHP treatment increased hepatic cholesterol accumulation by downregulating the protein expression of key regulators in cholesterol clearance including LDL receptor, cholesterol 7α-hydrolase, ATP-binding cassette transporter G5 and G8, and liver X receptor α. Moreover, the adiposity and inflammation of white adipose tissues were promoted in DEHP-treated apoE(-/-) mice. In conclusion, DEHP may disturb cholesterol homeostasis and deregulate the inflammatory response, thus leading to accelerated atherosclerosis.

  10. Tanshindiol C inhibits oxidized low-density lipoprotein induced macrophage foam cell formation via a peroxiredoxin 1 dependent pathway.

    Science.gov (United States)

    Yang, Yuyu; Li, Xueyan; Peng, Liying; An, Lin; Sun, Ningyuan; Hu, Xuewen; Zhou, Ping; Xu, Yong; Li, Ping; Chen, Jun

    2018-03-01

    NF-E2-related factor 2 (Nrf2) has been shown to be protective in atherosclerosis. The loss of Nrf2 in macrophages enhances foam cell formation and promotes early atherogenesis. Tanshindiol C (Tan C) is isolated from the root of Salvia miltiorrhiza Bge., a traditional Chinese medicine that has been used for the treatment of several cardiovascular diseases for many years. This study was aimed to test the potential role of Tan C against macrophage foam cell formation and to explore the underlying mechanism. Firstly, we observed that Tan C markedly suppressed oxidized low-density lipoprotein (oxLDL) induced macrophage foam cell formation. Then, we found that Tan C was an activator of both Nrf2 and Sirtuin 1 (Sirt1) in macrophages. Nrf2 and Sirt1 synergistically activated the transcription of anti-oxidant peroxiredoxin 1 (Prdx1) after Tan C treatment. More important, we demonstrated that silencing of Prdx1 promoted oxLDL-induced macrophage foam cell formation. Prdx1 upregulated adenosine triphosphate-binding cassette (ABC) transporter A1 (ABCA1) expression and decreased intracellular lipid accumulation. Furthermore, Tan C ameliorated oxLDL induced macrophage foam cell formation in a Prdx1-dependent manner. These observations suggest that Tan C protects macrophages from oxLDL induced foam cell formation via activation of Prdx1/ABCA1 signaling and that Prdx1 may be a novel target for therapeutic intervention of atherosclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. A review about biomarkers for the investigation of vascular function and impairment in diabetes mellitus

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    Derosa G

    2016-11-01

    Full Text Available Giuseppe Derosa,1 Pamela Maffioli2 1Centre of Diabetes and Metabolic Diseases, Department of Internal Medicine and Therapeutics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, 2School in Experimental Medicine, University of Pavia, Pavia, Italy Abstract: The aim of this review was to analyze the main biomarkers of vascular function and impairment in patients with type 2 diabetes. Medline, SCOPUS, Web of Science, and Google Scholar databases were searched. We concluded that proatherogenic adhesion molecules (soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and soluble E selectin and inflammatory cytokines (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α were elevated in type 2 diabetes mellitus. Their increased expression and release contribute to the accelerated atherogenesis typical of these patients. For these reasons, the early identification of high levels of these biomarkers will help to establish new strategies to reduce cardiovascular complications. Keywords: biomarkers, vascular function, type 2 diabetes mellitus

  12. Soluble FcγRIIIaMφ Levels in Plasma Correlate with Carotid Maximum Intima-Media Thickness (IMT) in Subjects Undergoing an Annual Medical Checkup

    Science.gov (United States)

    Masuda, Midori; Amano, Katsuya; Hong, Shi Yan; Nishimura, Noriko; Fukui, Masayoshi; Yoshika, Masamichi; Komiyama, Yutaka; Masaki, Hiroya; Iwasaka, Toshiji; Takahashi, Hakuo

    2008-01-01

    Macrophages play a major role in the development of vascular lesions in atherogenesis. The cells express FcγRIIIa (CD16) identical to that in NK cells, but with a cell type-specific glycosylation, and these soluble forms (sFcγRIIIa) are present in plasma. We measured sFcγRIIIaMφ derived from macrophages in plasma from subjects undergoing an annual medical checkup. The levels of sFcγRIIIaMφ increased with age, and correlated positively with body mass index, blood pressure, LDL cholesterol to HDL cholesterol ratio, triglycerides, hemoglobin A1c, and creatinine, but negatively with HDL-cholesterol levels. The sFcγRIIIaMφ levels were related to the number of risk factors for atherosclerosis: such as aging, current smoking, diabetes, hypertension, hyper-LDL-cholesterolemia, hypo-HDL-cholesterolemia, and family history of atherosclerotic diseases. In addition, the sFcγRIIIaMφ levels were correlated with carotid maximum intima-media thickness (IMT). These findings indicate the macrophages are activated during the incipient stage of atherosclerosis, and suggest sFcγRIIIaMφ may be used as a predictive marker for atherosclerosis. PMID:18475309

  13. Soluble FcgammaRIIIa(Mphi) levels in plasma correlate with carotid maximum intima-media thickness (IMT) in subjects undergoing an annual medical checkup.

    Science.gov (United States)

    Masuda, Midori; Amano, Katsuya; Hong, Shi Yan; Nishimura, Noriko; Fukui, Masayoshi; Yoshika, Masamichi; Komiyama, Yutaka; Masaki, Hiroya; Iwasaka, Toshiji; Takahashi, Hakuo

    2008-01-01

    Macrophages play a major role in the development of vascular lesions in atherogenesis. The cells express FcgammaRIIIa (CD16) identical to that in NK cells, but with a cell type-specific glycosylation, and these soluble forms (sFcgammaRIIIa) are present in plasma. We measured sFcgammaRIIIa(Mphi) derived from macrophages in plasma from subjects undergoing an annual medical checkup. The levels of sFcgammaRIIIa(Mphi) increased with age, and correlated positively with body mass index, blood pressure, LDL cholesterol to HDL cholesterol ratio, triglycerides, hemoglobin A1c, and creatinine, but negatively with HDL-cholesterol levels. The sFcgammaRIIIa(Mphi) levels were related to the number of risk factors for atherosclerosis: such as aging, current smoking, diabetes, hypertension, hyper-LDL-cholesterolemia, hypo-HDL-cholesterolemia, and family history of atherosclerotic diseases. In addition, the sFcgammaRIIIa(Mphi) levels were correlated with carotid maximum intima-media thickness (IMT). These findings indicate the macrophages are activated during the incipient stage of atherosclerosis, and suggest sFcgammaRIIIa(Mphi) may be used as a predictive marker for atherosclerosis.

  14. Molecular characterization of Chlamydia pneumoniae associated to atherosclerosis.

    Science.gov (United States)

    Yazouli, Loubna El; Criscuolo, Alexis; Hejaji, Hicham; Bouaaza, Mohamed; Elmdaghri, Naima; Alami, Aziz Aroussi; Amraoui, Abderahim; Dakka, Nadia; Radouani, Fouzia

    2017-04-06

    Chlamydia pneumoniae is a respiratory pathogen associated with chronic inflammatory diseases such as asthma and atherosclerosis, and its detection in human carotid and coronary atheroma suggests some support for its involvement in atherogenesis. The main objective of our study was to evaluate the association between Chlamydia pneumoniae and atherosclerosis in Moroccan patients through a case/control approach and detected strain genotyping. A total of 137 cases and 124 controls were enrolled, nested PCR was performed for Chlamydia pneumoniae screening of the peripheral blood mononuclear cells (PBMCs) of both cases and controls as well as atheroma plaques from 37 cases, and positive samples were subjected to sequencing for genotyping and phylogenetic analysis. The results showed 54% and 18%, respectively, for positivity in cases and control PBMCs and 86.5% in atheroma plaques, the difference being significant between the two groups (pChlamydia pneumoniae in atherosclerosis in the studied population and genotyping revealed that detected strains were identical to human strains circulating worldwide. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Chlamydia pneumoniae and atherosclerosis. Identification of bacterial DNA in the arterial wall

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    Coutinho Mário Sérgio Soares de Azeredo

    2000-01-01

    Full Text Available OBJECTIVE: The intracellular Gram-negative bacterium Chlamydia pneumoniae has been associated with atherosclerosis. The presence of Chlamydia pneumoniae has been investigated in fragments of the arterial wall with a technique for DNA identification. METHODS: Arterial fragments obtained from vascular surgical procedures in 58 patients were analyzed. From these patients, 39 were males and the mean age was 65±6 years. The polymerase chain reaction was used to identify the bacterial DNA with a pair of primers that codify the major outer membrane protein (MOMP of Chlamydia pneumoniae. The amplified product was visualized by electrophoresis in the 2% agarose gel stained with ethidium bromide, and it was considered positive when migrating in the band of molecular weight of the positive controls. RESULTS: Seven (12% out of the 58 patients showed positive results for Chlamydia pneumoniae. CONCLUSION: DNA from Chlamydia pneumoniae was identified in the arterial wall of a substantial number of patients with atherosclerosis. This association, which has already been described in other countries, corroborates the evidence favoring a role played by Chlamydia pneumoniae in atherogenesis.

  16. Biophysical and biochemical outcomes of Chlamydia pneumoniae infection promotes pro-atherogenic matrix microenvironment

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    Shankar J. Evani

    2016-08-01

    Full Text Available Multiple studies support the hypothesis that infectious agents may be involved in the pathogenesis of atherosclerosis. Chlamydia pneumoniae is strongly implicated in atherosclerosis, but the precise role has been underestimated and poorly understood due to the complexity of the disease process. In this work, we test the hypothesis that C. pneumoniae-infected macrophages lodged in the subendothelial matrix contribute to atherogenesis through pro-inflammatory factors and by cell-matrix interactions. To test this hypothesis, we used a 3D infection model with freshly isolated PBMC infected with live C. pneumoniae and chlamydial antigens encapsulated in a collagen matrix, and analyzed the inflammatory responses over 7 days. We observed that infection significantly upregulates the secretion of cytokines TNF-, IL-1, IL-8, MCP-1, MMP, oxidative stress, transendothelial permeability, and LDL uptake. We also observed that infected macrophages form clusters, and substantially modify the microstructure and mechanical properties of the extracellular matrix to an atherogenic phenotype. Together, our data demonstrates that C. pneumoniae-infection drives a low-grade, sustained inflammation that may predispose in the transformation to atherosclerotic foci.

  17. The Immune Response Is Involved in Atherosclerotic Plaque Calcification: Could the RANKL/RANK/OPG System Be a Marker of Plaque Instability?

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    Fabrizio Montecucco

    2007-01-01

    Full Text Available Atherogenesis is characterized by an intense inflammatory process, involving immune and vascular cells. These cells play a crucial role in all phases of atherosclerotic plaque formation and complication through cytokine, protease, and prothrombotic factor secretion. The accumulation of inflammatory cells and thus high amounts of soluble mediators are responsible for the evolution of some plaques to instable phenotype which may lead to rupture. One condition strongly associated with plaque rupture is calcification, a physiopathological process orchestrated by several soluble factors, including the receptor activator of nuclear factor NFκB ligand (RANKL/receptor activator of nuclear factor NFκB (RANK/osteoprotegerin (OPG system. Although some studies showed some interesting correlations with acute ischemic events, at present, more evidences are needed to evaluate the predictive and diagnostic value of serum sRANKL and OPG levels for clinical use. The major limitation is probably the poor specificity of these factors for cardiovascular disease. The identification of tissue-specific isoforms could increase the importance of sRANKL and OPG in predicting calcified plaque rupture and the dramatic ischemic consequences in the brain and the heart.

  18. Osteoprotegerin in Chronic Kidney Disease: Associations with Vascular Damage and Cardiovascular Events.

    Science.gov (United States)

    Yilmaz, Mahmut Ilker; Siriopol, Dimitrie; Saglam, Mutlu; Unal, Hilmi Umut; Karaman, Murat; Gezer, Mustafa; Kilinc, Ali; Eyileten, Tayfun; Guler, Ahmet Kerem; Aydin, İbrahim; Vural, Abdulgaffar; Oguz, Yusuf; Covic, Adrian; Ortiz, Alberto; Kanbay, Mehmet

    2016-08-01

    Vascular injury and dysfunction contribute to cardiovascular disease, the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG) is a soluble member of the tumor necrosis factor receptor superfamily that has been linked to atherogenesis and endothelial dysfunction. Elevated circulating OPG levels predict future cardiovascular events (CVE). Our aim was to evaluate the determinants of circulating OPG levels, to investigate the relationship between OPG and markers of vascular damage and to test whether OPG improves risk stratification for future CVE beyond traditional and renal-specific risk factors in a CKD population. 291 patients with CKD stage 1-5 not on dialysis were included in the study. In the multivariate analysis, OPG was a significant predictor for flow-mediated dilatation, but not for carotid intima media thickness levels. During follow-up (median 36 months, IQR = 32-42 months), 87 patients had CVE. In the Cox survival analysis, OPG levels were independently associated with CVE even after adjustment for traditional and renal-specific cardiovascular risk factors. The addition of OPG to a model based on commonly used cardiovascular factors significantly improved the reclassification abilities of the model for predicting CVE. We show for the first time that OPG improves risk stratification for CVE in a non-dialysis CKD population, above and beyond a model with established traditional and renal-specific cardiovascular risk factors, including estimated glomerular filtration rate and fibroblast growth factor 23.

  19. Thioredoxin attenuates oxidized low-density lipoprotein induced oxidative stress in human umbilical vein endothelial cells by reducing NADPH oxidase activity.

    Science.gov (United States)

    Chen, Beidong; Meng, Li; Shen, Tao; Gong, Huan; Qi, Ruomei; Zhao, Yanyang; Sun, Jie; Bao, Li; Zhao, Gexin

    2017-09-02

    Oxidative stress is recognized as one of the most important contributing factors to the development of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) can induce vascular reactive oxygen species (ROS) production, trigger endothelial dysfunction and initiate the progression of atherosclerosis. Previous studies have demonstrated that thioredoxin-1 (Trx) is one of the key regulators of intracellular redox, which is pivotal in atherogenesis. However, the regulation mechanism is still unclear. In this study, we investigated the effects of Trx1 on NADPH oxidase in human umbilical vein endothelial cells (HUVECs), whose ROS level is mainly produced by NADPH oxidase, especially Nox4 isoform. Our data demonstrated that Trx decreased NADPH oxidase activity, ROS production and ICAM-1 expression in ox-LDL treated HUVECs. Genetic gain-of-function and loss-of-function studies showed that Trx1 suppressed ox-LDL-induced Nox4 and p22phox expression. A co-immunoprecipitation assay indicated that Trx1 decreased Nox4-p22phox complex level during ox-LDL stimulation. Transient transfection of Nox4 and p22phox significantly increased intracellular ROS generation, which could be blocked by Trx overexpression. In addition, Trx overexpression also prevented ox-LDL-induced Nox2 and Rac1 protein levels. These results suggest that Trx suppresses NADPH oxidase activity in vascular endothelia under pathological conditions and may prevent the initiation of atherosclerosis by attenuating exceeding ROS production. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells.

    Science.gov (United States)

    Miao, LiXia; Okoro, Emmanuel U; Cao, ZhiJan; Yang, Hong; Motley-Johnson, Evangeline; Guo, Zhongmao

    2015-09-18

    Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI-mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition of PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCG1 and SR-B1 but not involving PI3K and Akt. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Exposure of mice to cigarette smoke and/or light causes DNA alterations in heart and aorta

    Energy Technology Data Exchange (ETDEWEB)

    Izzotti, Alberto; D' Agostini, Francesco [Department of Health Sciences, University of Genoa, Genoa (Italy); Balansky, Roumen [Department of Health Sciences, University of Genoa, Genoa (Italy); National Center of Oncology, Sofia 1756 (Bulgaria); Degan, Paolo [Cancer Research Institute (IST), Genoa (Italy); Pennisi, Tanya M. [Department of Health Sciences, University of Genoa, Genoa (Italy); Steele, Vernon E. [National Cancer Institute, Rockville, MD (United States); De Flora, Silvio [Department of Health Sciences, University of Genoa, Genoa (Italy)], E-mail: sdf@unige.it

    2008-09-26

    Cigarette smoke (CS) is a major risk factor for cardiovascular diseases, cancer, and other chronic degenerative diseases. UV-containing light is the most ubiquitous DNA-damaging agent existing in nature, but its possible role in cardiovascular diseases had never been suspected before, although it is known that mortality for cardiovascular diseases is increased during periods with high temperature and solar irradiation. We evaluated whether exposure of Swiss CD-1 mice to environmental CS (ECS) and UV-C-covered halogen quartz lamps, either individually or in combination, can cause DNA damage in heart and aorta cells. Nucleotide alterations were evaluated by {sup 32}P postlabeling methods and by HPLC-electrochemical detection. The whole-body exposure of mice to ECS considerably increased the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and of bulky DNA adducts in both heart and aorta. Surprisingly, even exposure to a light that simulated solar irradiation induced oxidatively generated damage in both tissues. The genotoxic effects of UV light in internal organs is tentatively amenable to formation of unidentified long-lived mutagenic products in the skin of irradiated mice. Nucleotide alterations were even more pronounced when the mice were exposed to smoke and/or light during the first 5 weeks of life rather than during adulthood for an equivalent period of time. Although the pathogenetic meaning is uncertain, DNA damage in heart and aorta may tentatively be related to cardiomyopathies and to the atherogenesis process, respectively.

  2. Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic Cigarettes: Clinical Perspectives From the Prevention of Cardiovascular Disease Section Leadership Council and Early Career Councils of the American College of Cardiology.

    Science.gov (United States)

    Morris, Pamela B; Ference, Brian A; Jahangir, Eiman; Feldman, Dmitriy N; Ryan, John J; Bahrami, Hossein; El-Chami, Mikhael F; Bhakta, Shyam; Winchester, David E; Al-Mallah, Mouaz H; Sanchez Shields, Monica; Deedwania, Prakash; Mehta, Laxmi S; Phan, Binh An P; Benowitz, Neal L

    2015-09-22

    Cardiovascular morbidity and mortality as a result of inhaled tobacco products continues to be a global healthcare crisis, particularly in low- and middle-income nations lacking the infrastructure to develop and implement effective public health policies limiting tobacco use. Following initiation of public awareness campaigns 50 years ago in the United States, considerable success has been achieved in reducing the prevalence of cigarette smoking and exposure to secondhand smoke. However, there has been a slowing of cessation rates in the United States during recent years, possibly caused by high residual addiction or fatigue from cessation messaging. Furthermore, tobacco products have continued to evolve faster than the scientific understanding of their biological effects. This review considers selected updates on the genetics and epigenetics of smoking behavior and associated cardiovascular risk, mechanisms of atherogenesis and thrombosis, clinical effects of smoking and benefits of cessation, and potential impact of electronic cigarettes on cardiovascular health. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  3. Second-hand tobacco smoke and cardiovascular disease risk: an epidemiological review.

    Science.gov (United States)

    Dunbar, Andrew; Gotsis, William; Frishman, William

    2013-01-01

    In this review, we have sought to examine the epidemiological, basic science, and public health data regarding the association between second-hand smoke (SHS) exposure and the development of coronary heart disease (CHD). SHS increases the risk of CHD by 25-30% according to multiple cohort, case-control, and meta-analytical studies. Physiologic and basic science research suggest that the mechanisms by which SHS affects the cardiovascular system are multiple and include increased thrombogenesis and low-density lipoprotein oxidation, decreased exercise tolerance, dysfunctional flow-mediated vasodilatation, and activation of inflammatory pathways with concomitant oxidative damage and impaired vascular repair. As a result, chronic exposure promotes atherogenesis and the development of cardiovascular disease, increasing the risk of having an acute coronary syndrome (ACS). With the implementation of statewide and nationwide public smoke-free legislation across the United States and Europe, respectively, over the last 10-15 years, there has been a significant and reciprocal decline in the incidence of emergency admissions for ACS by an average 17% despite persistent attempts on the part of the tobacco industry to diminish the correlation between SHS exposure and CHD. These findings underscore the importance of the effects of smoking legislation on community health.

  4. Pathogenesis of Cognitive Decline Following Therapeutic Irradiation for Head and Neck Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Abayomi, Olubunmi K. [Virginia Commonwealth Univ., Richmond, VA (United States). Dept. of Radiation Oncology

    2002-08-01

    Cognitive decline is a significant but largely unrecognized sequela following irradiation for several head and neck tumors, particularly cancer of the nasopharynx and paranasal sinuses. In this article the cellular mechanisms of radiation-induced vascular damage in the temporal lobe and its effects on the medial temporal lobe memory systems are described. Recognition of the mechanisms and site of the injury should permit the use of treatment planning systems, such as 3-dimensional (3-D) conformal and intensity-modulated radiotherapy (IMRT) techniques, to spare large volumes of the temporal lobe from receiving a high dose. Furthermore, the emerging concepts of vascular irradiation damage as an inflammatory fibroproliferative response to endothelial injury may permit the application of measures directed at inhibiting the expression of proinflammatory genes and thus mitigate the inflammatory response. Moreover, comorbid factors such as hypertension, diabetes, lipidemia, obesity and smoking are known to promote atherogenesis and therefore may exacerbate radiation-induced vascular damage. Control of these factors may also reduce the incidence and severity of this sequela.

  5. Reduced Paraoxonase 1 Activity as a Marker for Severe Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Chiyan Zhou

    2013-01-01

    Full Text Available Paraoxonase-1 (PON1, a high-density-lipoprotein- (HDL- associated enzyme, has the potential to protect against atherogenesis. We examine the relationships between plasma PON1 activity and the progression of atherosclerosis as well as coronary artery disease (CAD. Fasting blood samples were collected from female apolipoprotein E-deficient (apoE−/− mice and 149 patients undergoing coronary angiography for the biochemical parameters measurement. The severity of CAD was defined using angiographic Gensini score (GSS. Compared to 3-month-old apoE−/− mice, aged mice had significantly lower PON1 activity, which is negatively correlated with the size of atherosclerotic lesion and plasma interleukin-6 (IL-6 and tumor necrosis factor α (TNF-α levels. In study patients, PON1 activity was correlated with age, sex, and HDL-cholesterol, apolipoprotein AI, and high-sensitivity C-reactive protein (hs-CRP levels and was significantly lower in CAD group than that in non-CAD control group. Interestingly, PON1 activity in severe CAD group (GSS > 40 was further significantly reduced compared to those in mild and moderate subgroups (GSS  ≤ 40 (P<0.01. There is a significant correlation between PON1 activity and the severity of CAD as assessed by GSS (r=-0.393, P<0.001. PON1 activity may be a potential biomarker for the severity of CAD.

  6. Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE−/− Mice

    Directory of Open Access Journals (Sweden)

    Jaime Gonzalez

    2015-01-01

    Full Text Available Cardiovascular Diseases (CVD represent about 30% of all causes of death worldwide. The development of CVD is related in many cases with the previous existence of metabolic syndrome (MS. It is known that apple consumption has a cardiovascular protecting effect, containing phenolic compounds with antioxidant effect, which are concentrated in the fruit peel. The objective of this study was to test the effect of apple peel consumption in a murine model of MS and apoE−/− mice. Apple supplemented diets reduced the biochemical parameters (glycaemia, total cholesterol, HDL-cholesterol, LDL-cholesterol, ureic nitrogen, triglycerides, insulin, and asymmetric dimethylarginine (ADMA of MS model in CF1 mice significantly. The model apoE−/− mouse was used to evaluate the capacity of the apple peel to revert the progression of the atherogenesis. FD with HAP reverts cholesterol significantly and slows down the progression of the plate diminishing the cholesterol accumulation area. With these results, it can be concluded that the consumption of apple peel reduces several MS parameters and the atherogenic progression in mice.

  7. Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice.

    Science.gov (United States)

    Cazita, Patrícia M; Berti, Jairo A; Aoki, Carolina; Gidlund, Magnus; Harada, Lila M; Nunes, Valéria S; Quintão, Eder C R; Oliveira, Helena C F

    2003-01-01

    Reduced estrogen levels result in loss of protection from coronary heart disease in postmenopausal women. Enhanced and diminished atherosclerosis have been associated with plasma levels of cholesteryl ester transfer protein (CETP); however, little is known about the role of CETP-ovarian hormone interactions in atherogenesis. We assessed the severity of diet-induced atherosclerosis in ovariectomized (OV) CETP transgenic mice crossbred with LDL receptor knockout mice. Compared with OV CETP expressing ((+)), OV CETP non-expressing ((-)) mice had higher plasma levels of total, VLDL-, LDL-, and HDL-cholesterol, as well as higher antibodies titers against oxidized LDL. The mean aortic lesion area was 2-fold larger in OV CETP(-) than in OV CETP(+) mice (147 +/- 90 vs. 73 +/- 42 x 10(3) micro m(2), respectively). Estrogen therapy in OV mice blunted the CETP dependent differences in plasma lipoproteins, oxLDL antibodies, and atherosclerosis severity. Macrophages from OV CETP(+) mice took up less labeled cholesteryl ether (CEt) from acetyl-LDL than macrophages from OV CETP(-) mice. Estrogen replacement induced a further reduction in CEt uptake and an elevation in HDL mediated cholesterol efflux from pre-loaded OV CETP(+) as compared with OV CETP(-) macrophages. These findings support the proposed anti-atherogenic role of CETP in specific metabolic settings.

  8. Endothelial C-type natriuretic peptide maintains vascular homeostasis

    Science.gov (United States)

    Moyes, Amie J.; Khambata, Rayomand S.; Villar, Inmaculada; Bubb, Kristen J.; Baliga, Reshma S.; Lumsden, Natalie G.; Xiao, Fang; Gane, Paul J.; Rebstock, Anne-Sophie; Worthington, Roberta J.; Simone, Michela I.; Mota, Filipa; Rivilla, Fernando; Vallejo, Susana; Peiró, Concepción; Sánchez Ferrer, Carlos F.; Djordjevic, Snezana; Caulfield, Mark J.; MacAllister, Raymond J.; Selwood, David L.; Ahluwalia, Amrita; Hobbs, Adrian J.

    2014-01-01

    The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor–C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders. PMID:25105365

  9. Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke: implications in comorbidities of COPD

    Directory of Open Access Journals (Sweden)

    Yao Hongwei

    2010-07-01

    Full Text Available Abstract Background Chronic obstructive pulmonary disease is associated with numerous vascular effects including endothelial dysfunction, arterial stiffness and atherogenesis. It is also known that a decline in lung function is associated with increased cardiovascular comorbidity in smokers. The mechanism of this cardiopulmonary dual risk by cigarette smoke (CS is not known. We studied the molecular mechanisms involved in development of emphysema in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/- mice in response to CS exposure. Methods Adult male and female wild-type (WT mice of genetic background C57BL/6J and ApoE-/- mice were exposed to CS, and lung inflammatory responses, oxidative stress (lipid peroxidation products, mechanical properties as well as airspace enlargement were assessed. Results and Discussion The lungs of ApoE-/- mice showed augmented inflammatory response and increased oxidative stress with development of distal airspace enlargement which was accompanied with decline in lung function. Interestingly, the levels and activities of matrix metalloproteinases (MMP-9 and MMP-12 were increased, whereas the level of eNOS was decreased in lungs of CS-exposed ApoE-/- mice as compared to air-exposed ApoE-/- mice or CS-exposed WT mice. Conclusion These findings suggest that CS causes premature emphysema and a decline of lung function in mice susceptible to cardiovascular abnormalities via abnormal lung inflammation, increased oxidative stress and alterations in levels of MMPs and eNOS.

  10. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.

    Science.gov (United States)

    Fagman, Johan B; Wilhelmson, Anna S; Motta, Benedetta M; Pirazzi, Carlo; Alexanderson, Camilla; De Gendt, Karel; Verhoeven, Guido; Holmäng, Agneta; Anesten, Fredrik; Jansson, John-Olov; Levin, Malin; Borén, Jan; Ohlsson, Claes; Krettek, Alexandra; Romeo, Stefano; Tivesten, Åsa

    2015-04-01

    Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism. © FASEB.

  11. Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells.

    Science.gov (United States)

    Wang, Chen; Chen, Han; Zhu, Wei; Xu, Yinchuan; Liu, Mingfei; Zhu, Lianlian; Yang, Fan; Zhang, Ling; Liu, Xianbao; Zhong, Zhiwei; Zhao, Jing; Jiang, Jun; Xiang, Meixiang; Yu, Hong; Hu, Xinyang; Lu, Hong; Wang, Jian'an

    2017-01-01

    Cigarette smoking is an independent risk factor for atherosclerosis. Nicotine, the addictive component of cigarettes, induces mast cell (MC) release and contributes to atherogenesis. The purpose of this study was to determine whether nicotine accelerates atherosclerosis through MC-mediated mechanisms and whether MC stabilizer prevents this pathological process. Nicotine administration increased the size of atherosclerotic lesions in apolipoprotein E-deficient (Apoe-/-) mice fed a fat-enriched diet. This was accompanied by enhanced intraplaque macrophage content and lipid deposition but reduced collagen and smooth muscle cell contents. MC deficiency in Apoe-/- mice (Apoe-/-KitW-sh/W-sh) diminished nicotine-induced atherosclerosis. Nicotine activated bone marrow-derived MCs in vitro, which was inhibited by a MC stabilizer disodium cromoglycate or a nonselective nicotinic acetylcholine receptor blocker mecamylamine. Further investigation revealed that α7 nicotinic acetylcholine receptor was a target for nicotine activation in MCs. Nicotine did not change atherosclerotic lesion size of Apoe-/-KitW-sh/W-sh mice reconstituted with MCs from Apoe-/-α7nAChR-/- animals. Activation of α7 nicotinic acetylcholine receptor on MCs is a mechanism by which nicotine enhances atherosclerosis. © 2016 American Heart Association, Inc.

  12. Supercritical fluid extraction of oregano (Origanum vulgare) essentials oils: anti-inflammatory properties based on cytokine response on THP-1 macrophages.

    Science.gov (United States)

    Ocaña-Fuentes, A; Arranz-Gutiérrez, E; Señorans, F J; Reglero, G

    2010-06-01

    Two fractions (S1 and S2) of an oregano (Origanum vulgare) extract obtained by supercritical fluid extraction have been used to test anti-inflammatory effects on activated human THP-1 cells. The main compounds present in the supercritical extract fractions of oregano were trans-sabinene hydrate, thymol and carvacrol. Fractions toxicity was assessed using the mitochondrial-respiration-dependent 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction method for several concentrations during 24 and 48 h of incubation. Concentrations higher than 30 microg/mL of both supercritical S1 and S2 oregano fractions caused a reduction in cell viability in a dose-dependent manner. Oxidized-LDLs (oxLDLs) activated THP-1 macrophages were used as cellular model of atherogenesis and the release/secretion of cytokines (TNT-alpha, IL-1beta, IL-6 and IL-10) and their respective mRNA expressions were quantified both in presence or absence of supercritical oregano extracts. The results showed a decrease in pro-inflammatory TNF-alpha, IL-1beta and IL-6 cytokines synthesis, as well as an increase in the production of anti-inflammatory cytokine IL-10. These results may suggest an anti-inflammatory effect of oregano extracts and their compounds in a cellular model of atherosclerosis. Copyright 2010 Elsevier Ltd. All rights reserved.

  13. Quantum dot mediated imaging of atherosclerosis

    Science.gov (United States)

    Jayagopal, Ashwath; Su, Yan Ru; Blakemore, John L.; Linton, MacRae F.; Fazio, Sergio; Haselton, Frederick R.

    2009-04-01

    The progression of atherosclerosis is associated with leukocyte infiltration within lesions. We describe a technique for the ex vivo imaging of cellular recruitment in atherogenesis which utilizes quantum dots (QD) to color-code different cell types within lesion areas. Spectrally distinct QD were coated with the cell-penetrating peptide maurocalcine to fluorescently-label immunomagnetically isolated monocyte/macrophages and T lymphocytes. QD-maurocalcine bioconjugates labeled both cell types with a high efficiency, preserved cell viability, and did not perturb native leukocyte function in cytokine release and endothelial adhesion assays. QD-labeled monocyte/macrophages and T lymphocytes were reinfused in an ApoE-/- mouse model of atherosclerosis and age-matched controls and tracked for up to four weeks to investigate the incorporation of cells within aortic lesion areas, as determined by oil red O (ORO) and immunofluorescence ex vivo staining. QD-labeled cells were visible in atherosclerotic plaques within two days of injection, and the two cell types colocalized within areas of subsequent ORO staining. Our method for tracking leukocytes in lesions enables high signal-to-noise ratio imaging of multiple cell types and biomarkers simultaneously within the same specimen. It also has great utility in studies aimed at investigating the role of distinct circulating leukocyte subsets in plaque development and progression.

  14. Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems.

    Science.gov (United States)

    Girotti, Albert W; Korytowski, Witold

    2017-12-01

    Cholesterol is like other unsaturated lipids in being susceptible to peroxidative degradation upon exposure to strong oxidants like hydroxyl radical or peroxynitrite generated under conditions of oxidative stress. In the eukaryotic cell plasma membrane, where most of the cellular cholesterol resides, peroxidation leads to membrane structural and functional damage from which pathological states may arise. In low density lipoprotein, cholesterol and phospholipid peroxidation have long been associated with atherogenesis. Among the many intermediates/products of cholesterol oxidation, hydroperoxide species (ChOOHs) have a number of different fates and deserve special attention. These fates include (a) damage-enhancement via iron-catalyzed one-electron reduction, (b) damage containment via two-electron reduction, and (c) inter-membrane, inter-lipoprotein, and membrane-lipoprotein translocation, which allows dissemination of one-electron damage or off-site suppression thereof depending on antioxidant location and capacity. In addition, ChOOHs can serve as reliable and conveniently detected mechanistic reporters of free radical-mediated reactions vs. non-radical (e.g., singlet oxygen)-mediated reactions. Iron-stimulated peroxidation of cholesterol and other lipids underlies a newly discovered form of regulated cell death called ferroptosis. These and other deleterious consequences of radical-mediated lipid peroxidation will be discussed in this review.

  15. Testing of serum atherogenicity in cell cultures: questionable data published

    Directory of Open Access Journals (Sweden)

    Sergei V. Jargin

    2012-01-01

    Full Text Available In a large series of studies was reported that culturing of smooth muscle cells with serum from atherosclerosis patients caused intracellular lipid accumulation, while serum from healthy controls had no such effect. Cultures were used for evaluation of antiatherogenic drugs. Numerous substances were reported to lower serum atherogenicity: statins, trapidil, calcium antagonists, garlic derivatives etc. On the contrary, beta-blockers, phenothiazines and oral hypoglycemics were reported to be pro-atherogenic. Known antiatherogenic agents can influence lipid metabolism and cholesterol synthesis, intestinal absorption or endothelium-related mechanisms. All these targets are absent in cell monocultures. Inflammatory factors, addressed by some antiatherogenic drugs, are also not reproduced. In vivo, relationship between cholesterol uptake by cells and atherogenesis must be inverse rather than direct: in familial hypercholesterolemia, inefficient clearance of LDL-cholesterol by cells predisposes to atherosclerosis. Accordingly, if a pharmacological agent reduces cholesterol uptake by cells in vitro, it should be expected to elevate cholesterol in vivo. Validity of clinical recommendations, based on serum atherogenicity testing in cell monocultures, is therefore questionable. These considerations pertain also to the drugs developed on the basis of the cell culture experiments.

  16. Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis.

    Science.gov (United States)

    Fernández-Hernando, Carlos; Yu, Jun; Suárez, Yajaira; Rahner, Christoph; Dávalos, Alberto; Lasunción, Miguel A; Sessa, William C

    2009-07-01

    The accumulation of LDL-derived cholesterol in the artery wall is the initiating event that causes atherosclerosis. However, the mechanisms that lead to the initiation of atherosclerosis are still poorly understood. Here, by using endothelial cell-specific transgenesis of the caveolin-1 (Cav-1) gene in mice, we show the critical role of Cav-1 in promoting atherogenesis. Mice were generated lacking Cav-1 and apoE but expressing endothelial-specific Cav-1 in the double knockout background. Genetic ablation of Cav-1 on an apoE knockout background inhibits the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promotes lesion expansion. Mechanistically, the loss of Cav-1 reduces LDL infiltration into the artery wall, promotes nitric oxide production, and reduces the expression of leukocyte adhesion molecules, effects completely reversed in transgenic mice. In summary, this unique model provides physiological evidence supporting the important role of endothelial Cav-1 expression in regulating the entry of LDL into the vessel wall and the initiation of atherosclerosis.

  17. Detection of macrophage activity in atherosclerosis in vivo using multichannel, high-resolution laser scanning fluorescence microscopy

    Science.gov (United States)

    Pande, Ashvin N.; Kohler, Rainer; Aikawa, Elena; Weissleder, Ralph; Jaffer, Farouc

    2006-03-01

    Molecular and cellular mechanisms of atherogenesis and its treatment are largely being unraveled by in vitro techniques. We describe methodology to directly image macrophage cell activity in vivo in a murine model of atherosclerosis using laser scanning fluorescence microscopy (LSFM) and a macrophage-targeted, near-infrared fluorescent (NIRF) magnetofluorescent nanoparticle (MFNP). Atherosclerotic apolipoprotein E deficient (apoE -/-) mice (n=10) are injected with MFNP or 0.9% saline, and wild-type mice (n=4) are injected with MFNP as additional controls. After 24 h, common carotid arteries are surgically exposed and prepared for LSFM. Multichannel LSFM of MFNP-enhanced carotid atheroma (5×5-µm in-plane resolution) shows a strong focal NIRF signal, with a plaque target-to-background ratio of 3.9+/-1.8. Minimal NIRF signal is observed in control mice. Spectrally resolved indocyanine green (ICG) fluorescence angiograms confirm the intravascular location of atheroma. On ex vivo fluorescence reflectance imaging, greater NIRF plaque signal is seen in apoE -/- MFNP mice compared to controls (p<0.01). The NIRF signal correlates well with immunostained macrophages, both by stained surface area (r=0.77) and macrophage number (r=0.86). The validated experimental methodology thus establishes a platform for investigating macrophage activity in atherosclerosis in vivo, and has implications for the detection of clinical vulnerable plaques.

  18. Drinking modulates monocyte migration in healthy subjects: a randomised intervention study of water, ethanol, red wine and beer with or without alcohol.

    Science.gov (United States)

    Imhof, Armin; Blagieva, Roza; Marx, Nikolaus; Koenig, Wolfgang

    2008-03-01

    Moderate alcohol consumption is associated with reduced cardiovascular mortality compared to non-consumption of alcohol and heavy drinking. Experimental data suggest a direct effect of alcohol on atherosclerotic lesion development. We assessed the effect of consumption of moderate amounts of alcoholic and non-alcoholic beverages on monocyte migration, a crucial step in atherogenesis. Forty-nine healthy men and women (aged 22-56 years) were enrolled in this randomised controlled trial. After wash-out, participants were assigned to either ethanol (concentration 12.5%), beer (5.6%) or red wine (12.5%) equivalent to 30 grams of ethanol per day (g/d) for men and 20 g/d for women, or to the same amount of de-alcoholised beer or red wine, or to water. Monocyte migration was evaluated ex vivo using a modified Boyden chamber. Intake of ethanol or de-alcoholised red wine significantly reduced monocyte chemoattractant protein-1 (MCP-1)-induced monocyte migration by 58% (palcoholic beverages lower cardiovascular risk.

  19. Effects of Diesel Exhaust on Cardiovascular Function and Oxidative Stress.

    Science.gov (United States)

    Wilson, Simon J; Miller, Mark R; Newby, David E

    2017-07-14

    Air pollution is a major global health concern with particulate matter (PM) being especially associated with increases in cardiovascular morbidity and mortality. Diesel exhaust emissions are a particularly rich source of the smallest sizes of PM ("fine" and "ultrafine") in urban environments, and it is these particles that are believed to be the most detrimental to cardiovascular health. Recent Advances: Controlled exposure studies to diesel exhaust in animals and man demonstrate alterations in blood pressure, heart rate, vascular tone, endothelial function, myocardial perfusion, thrombosis, atherogenesis, and plaque stability. Oxidative stress has emerged as a highly plausible pathobiological mechanism by which inhalation of diesel exhaust PM leads to multiple facets of cardiovascular dysfunction. Diesel exhaust inhalation promotes oxidative stress in several biological compartments that can be directly associated with adverse cardiovascular effects. Further studies with more sensitive and specific in vivo human markers of oxidative stress are required to determine if targeting oxidative stress pathways involved in the actions of diesel exhaust PM could be of therapeutic value. Antioxid. Redox Signal. 00, 000-000.

  20. Buddleja officinalis suppresses high glucose-induced vascular smooth muscle cell proliferation: role of mitogen-activated protein kinases, nuclear factor-kappaB and matrix metalloproteinases.

    Science.gov (United States)

    Lee, Yun Jung; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

    2010-02-01

    Diabetes mellitus is a well-established risk factor for vascular diseases caused by atherosclerosis. In the development of diabetic atherogenesis, vascular smooth muscle cell proliferation is recognized as a key event. Thus, we aimed to investigate whether an ethanol extract of Buddleja officinalis (EBO) suppresses high glucose-induced proliferation in primary cultured human aortic smooth muscle cells (HASMC). [(3)H]-thymidine incorporation revealed that incubation of HASMC with a high concentration of glucose (25 mmol/L) increased cell proliferation. The expression levels of cell cycle protein were also increased by treatment with high glucose concentration. Pretreatment of HASMC with EBO significantly attenuated the increase of high glucose-induced cell proliferation as well as p38 mitogen-activated protein kinases (MAPK) and JNK phosphorylation. EBO suppressed high glucose-induced matrix metalloproteinase (MMP)-9 activity in a dose-dependent manner. In addition, EBO suppressed nuclear factor-kappaB (NF-kappaB) nuclear translocation and transcriptional activity in high glucose conditions. Taken together, the present data suggest that EBO could suppress high glucose-induced atherosclerotic processes through inhibition of p38, JNK, NF-kappaB and MMP signal pathways in HASMC.

  1. Noncoding RNAs regulate NF-κB signaling to modulate blood vessel inflammation

    Directory of Open Access Journals (Sweden)

    Henry S. Cheng

    2014-12-01

    Full Text Available Cardiovascular diseases such as atherosclerosis are one of the leading causes of morbidity and mortality worldwide. The clinical manifestations of atherosclerosis, which include heart attack and stroke, occur several decades after initiation of the disease and become more severe with age. Inflammation of blood vessels plays a prominent role in atherogenesis. Activation of the endothelium by inflammatory mediators leads to the recruitment of circulating inflammatory cells, which drives atherosclerotic plaque formation and progression. Inflammatory signaling within the endothelium is driven predominantly by the pro-inflammatory transcription factor, NF-κB. Interestingly, activation of NF-κB is enhanced during the normal aging process and this may contribute to the development of cardiovascular disease. Importantly, studies utilizing mouse models of vascular inflammation and atherosclerosis are uncovering a network of noncoding RNAs, particularly microRNAs, which impinge on the NF-κB signaling pathway. Here we summarize the literature regarding the control of vascular inflammation by microRNAs, and provide insight into how these microRNA-based pathways might be harnessed for therapeutic treatment of disease. We also discuss emerging areas of endothelial cell biology, including the involvement of long noncoding RNAs and circulating microRNAs in the control of vascular inflammation.

  2. The Different Facets of Dyslipidemia and Hypertension in Atherosclerosis.

    Science.gov (United States)

    Hurtubise, Jessica; McLellan, Krystie; Durr, Kevin; Onasanya, Oluwadara; Nwabuko, Daniel; Ndisang, Joseph Fomusi

    2016-12-01

    Atherosclerosis is the narrowing of arteries due to the accumulation of macrophages overloaded with lipids resulting in foam cell formation, and these events occur preferentially at the branching points of arteries which are particularly susceptible to hyperlipidemic stress-induced inflammation and oxidative stress. The different stages of atherogenesis rely on oxidative stress, endothelial dysfunction, and inflammation, and hypertension or dyslipidemia can independently trigger these stages. Dyslipidemia and hypertension are pathological conditions that damage the endothelium, triggering cell proliferation, vascular remodeling, apoptosis, and increased cellular permeability with increased adhesion molecules that bind monocytes and T lymphocytes to create a vicious cocktail of pathophysiological factors. Correspondingly, the factors are redirected by chemo-attractants and pro-inflammatory cytokines into the intima of the vasculature, where monocytes differentiate into macrophages taking up oxidized LDL uncontrollably to form foam cells and atherosclerotic lesions. Moreover, endothelial damage also causes loss of vasomotor activity, disproportionate vascular contractility, and elevation of blood pressure in dyslipidemic patients, while in hypertensive patients, further elevation of blood pressure occurs, creating a self-perpetuating vicious cycle that aggravates the development and progression of atherosclerotic lesions. This review offers an in-depth analysis of atherosclerosis and the related interplay between dyslipidemia/hypertension and critically appraises the current diagnosis, etiology, and therapeutic options.

  3. Datasets for the validation of the "in vivo" siRNA-silencing of CD40 and for the detection of new markers of atherosclerosis progression in ApoE-deficient mice

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    Miguel Hueso

    2016-12-01

    Full Text Available Data presented in this Data in Brief article correspond to the article "in vivo" silencing of CD40 reduces progression of experimental atherogenesis through a NFκB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis" (M. Hueso, L. De Ramon, E. Navarro, E. Ripoll, J.M. Cruzado, J.M. Grinyo, J. Torras, 2016 [1]. Here, we describe the validation of the silencing of CD40 expression with a specific siRNA in ApoE−/− mouse aortas, and its systemic effects on splenic lymphocytic subpopulations as well as on the infiltration of aortic intima by F4/80+, galectin-3+ macrophages or by NF-κB+ cells. We also show the output of a Gene Ontology and TLDA analysis which allowed the detection of potential mediators of atherosclerosis progression. We provide the scientific community with a set of genes whose expression is increased during atherosclerosis progression but downregulated upon CD40 silencing.

  4. MicroRNA-1185 Induces Endothelial Cell Apoptosis by Targeting UVRAG and KRIT1

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    Haoyuan Deng

    2017-04-01

    Full Text Available Background/Aims: Atherosclerosis is a multifactorial chronic disease and is the main cause of death and impairment in the world. Endothelial injury and apoptosis play a crucial role in the onset and development of atherosclerosis. MicroRNAs (miRNAs have been proven to be involved in the pathogenesis of atherosclerosis. However, studies of the functional role of apoptosis-related miRNAs in the endothelium during atherogenesis are limited. Methods: Cell injury and apoptosis were measured in five types of cells transfected with miR-1185 or co-transfected with miR-1185 and its inhibitor. Bioinformatics analysis and a luciferase reporter assay were used to confirm the targets of miR-1185. The effects of the targets of miR-1185 on endothelial apoptosis were determined using small-interfering RNA. Results: In this study, we first report that miR-1185 significantly promoted apoptosis in endothelial cells but not in vascular smooth muscle cells and macrophages. A mechanistic analysis showed that ultraviolet irradiation resistance-associated gene (UVRAG and krev1 interaction trapped gene 1 (KRIT1, targets of miR-1185, mediated miR-1185-induced endothelial cell apoptosis. Conclusion: The results revealed the impact of miR-1185 on endothelial apoptosis, suggesting that miR-1185 may be a potential target for the prevention and treatment of atherosclerosis.

  5. Impaired Arterial Smooth Muscle Cell Vasodilatory Function In Methamphetamine Users

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    Ghaemeh Nabaei

    2017-02-01

    Full Text Available Objectives: Methamphetamine use is a strong risk factor for stroke. This study was designed to evaluate arterial function and structure in methamphetamine users ultrasonographically. Methods: In a cross-sectional study, 20 methamphetamine users and 21 controls, aged between 20 and 40years, were enrolled. Common carotid artery intima-media thickness (CCA-IMT marker of early atherogenesis, flow-mediated dilatation (FMD determinants of endothelium-dependent vasodilation, and nitroglycerine-mediated dilatation (NMD independent marker of vasodilation were measured in two groups. Results: There were no significant differences between the two groups regarding demographic and metabolic characteristics. The mean (±SD CCA-IMT in methamphetamine users was 0.58±0.09mm, versus 0.59±0.07mm in the controls (p=0.84. Likewise, FMD% was not significantly different between the two groups [7.6±6.1% in methamphetamine users vs. 8.2±5.1% in the controls; p=0.72], nor were peak flow and shear rate after hyperemia. However, NMD% was considerably decreased in the methamphetamine users [8.5±7.8% in methamphetamine users vs. 13.4±6.2% in controls; p=0.03]. Conclusion: According to our results, NMD is reduced among otherwise healthy methamphetamine users, which represents smooth muscle dysfunction in this group. This may contribute to the high risk of stroke among methamphetamine users.

  6. Supression of hemin-mediated oxidation of low-density lipoprotein and subsequent endothelial reactions by hydrogen sulfide (H(2)S).

    Science.gov (United States)

    Jeney, Viktória; Komódi, Edina; Nagy, Emõke; Zarjou, Abolfazl; Vercellotti, Gregory M; Eaton, John W; Balla, György; Balla, József

    2009-03-01

    Heme-mediated oxidative modification of low-density lipoprotein (LDL) plays a crucial role in early atherogenesis. It has been shown that hydrogen sulfide (H(2)S) produced by vascular smooth muscle cells is present in plasma at a concentration of about 50 micromol/L. H(2)S is a strong reductant which can react with reactive oxygen species like superoxide anion and hydrogen peroxide. The current study investigated the effect of H(2)S on hemin-mediated oxidation of LDL and oxidized LDL (oxLDL)-induced endothelial reactions. H(2)S dose dependently delayed the accumulation of lipid peroxidation products-conjugated dienes, lipid hydroperoxides (LOOH), and thiobarbituric acid reactive substances-during hemin-mediated oxidation. Moreover, H(2)S decreased the LOOH content of both oxidized LDL and lipid extracts derived from soft atherosclerotic plaque, which was accompanied by reduced cytotoxicity. OxLDL-mediated induction of the oxidative stress responsive gene, heme oxygenase-1, was also abolished by H(2)S. Finally we have shown that H(2)S can directly protect endothelium against hydrogen peroxide and oxLDL-mediated endothelial cytotoxicity. These results demonstrate novel functions of H(2)S in preventing hemin-mediated oxidative modification of LDL, and consequent deleterious effects, suggesting a possible antiatherogenic action of H(2)S.

  7. CD47 blocking antibodies restore phagocytosis and prevent atherosclerosis

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    Kojima, Yoko; Volkmer, Jens-Peter; McKenna, Kelly; Civelek, Mete; Lusis, A. Jake; Miller, Clint; Direnzo, Daniel; Nanda, Vivek; Ye, Jianqin; Connolly, Andrew; Schadt, Eric; Quertermous, Thomas; Betancur, Paola; Maegdefessel, Lars; Perisic, Ljubica; Hedin, Ulf; Weissman, Irv; Leeper, Nicholas J.

    2016-01-01

    Summary Atherosclerosis is the disease process underlying heart attack and stroke1. Advanced lesions at risk for rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris2. Why these cells are not cleared remains unknown3. Here we show that atherogenesis is associated with upregulation of CD47, a key ‘don’t eat me’ molecule known to render malignant cells resistant to programmed cell removal (PrCR), or ‘efferocytosis’4–7. We find that administration of CD47 blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired PrCR, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer5, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target. PMID:27437576

  8. Modulation of enzymatic activities by n-3 polyunsaturated fatty acids to support cardiovascular health.

    Science.gov (United States)

    Siddiqui, Rafat A; Harvey, Kevin A; Zaloga, Gary P

    2008-07-01

    Epidemiological evidence from Greenland Eskimos and Japanese fishing villages suggests that eating fish oil and marine animals can prevent coronary heart disease. Dietary studies from various laboratories have similarly indicated that regular fish oil intake affects several humoral and cellular factors involved in atherogenesis and may prevent atherosclerosis, arrhythmia, thrombosis, cardiac hypertrophy and sudden cardiac death. The beneficial effects of fish oil are attributed to their n-3 polyunsaturated fatty acid (PUFA; also known as omega-3 fatty acids) content, particularly eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3). Dietary supplementation of DHA and EPA influences the fatty acid composition of plasma phospholipids that, in turn, may affect cardiac cell functions in vivo. Recent studies have demonstrated that long-chain omega-3 fatty acids may exert beneficial effects by affecting a wide variety of cellular signaling mechanisms. Pathways involved in calcium homeostasis in the heart may be of particular importance. L-type calcium channels, the Na+-Ca2+ exchanger and mobilization of calcium from intracellular stores are the most obvious key signaling pathways affecting the cardiovascular system; however, recent studies now suggest that other signaling pathways involving activation of phospholipases, synthesis of eicosanoids, regulation of receptor-associated enzymes and protein kinases also play very important roles in mediating n-3 PUFA effects on cardiovascular health. This review is therefore focused on the molecular targets and signaling pathways that are regulated by n-3 PUFAs in relation to their cardioprotective effects.

  9. Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells

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    Sabrina Gruber

    2016-03-01

    Full Text Available Atherosclerosis is initiated and sustained by hypercholesterolemia, which results in the generation of oxidized LDL (OxLDL and other metabolic byproducts that trigger inflammation. Specific immune responses have been shown to modulate the inflammatory response during atherogenesis. The sialic acid-binding immunoglobulin-like lectin G (Siglec-G is a negative regulator of the functions of several immune cells, including myeloid cells and B-1 cells. Here, we show that deficiency of Siglec-G in atherosclerosis-prone mice inhibits plaque formation and diet-induced hepatic inflammation. We further demonstrate that selective deficiency of Siglec-G in B cells alone is sufficient to mediate these effects. Levels of B-1 cell-derived natural IgM with specificity for OxLDL were significantly increased in the plasma and peritoneal cavity of Siglec-G-deficient mice. Consistent with the neutralizing functions of OxLDL-specific IgM, Siglec-G-deficient mice were protected from OxLDL-induced sterile inflammation. Thus, Siglec-G promotes atherosclerosis and hepatic inflammation by suppressing protective anti-inflammatory effector functions of B cells.

  10. The atherosclerotic heart disease and protecting properties of garlic: contemporary data.

    Science.gov (United States)

    Gorinstein, Shela; Jastrzebski, Zenon; Namiesnik, Jacek; Leontowicz, Hanna; Leontowicz, Maria; Trakhtenberg, Simon

    2007-11-01

    This article reviews the contemporary data concerning atherosclerosis and protecting properties of garlic. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis and garlic properties. Numerous in vitro studies have confirmed the ability of garlic to reduce the parameters of the risk of atherosclerosis: total cholesterol, LDL, triglycerides, oxidized LDL. Bioactive compounds and antioxidant potentials in fresh, cooked, boiled and commercial garlic from different regions are presented, using beta-carotene, 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide (NO), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) with K2S2O8 or MnO2, ferric-reducing/antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC) and others assays for antioxidant status. In vivo studies were reviewed on with garlic and cholesterol supplemented diets. The positive influences of garlic on plasma lipids, proteins, antioxidant activity, and some indices of blood coagulation are dose dependent. Garlic could be a valuable component of atherosclerosis-preventing diets only in optimal doses. Many recently published reports show that garlic possesses plasma lipid-lowering and plasma anticoagulant and antioxidant properties and improves impaired endothelial function.

  11. Agent Based Modeling of Atherosclerosis: A Concrete Help in Personalized Treatments

    Science.gov (United States)

    Pappalardo, Francesco; Cincotti, Alessandro; Motta, Alfredo; Pennisi, Marzio

    Atherosclerosis, a pathology affecting arterial blood vessels, is one of most common diseases of the developed countries. We present studies on the increased atherosclerosis risk using an agent based model of atherogenesis that has been previously validated using clinical data. It is well known that the major risk in atherosclerosis is the persistent high level of low density lipoprotein (LDL) concentration. However, it is not known if short period of high LDL concentration can cause irreversible damage and if reduction of the LDL concentration (either by life style or drug) can drastically or partially reduce the already acquired risk. We simulated four different clinical situations in a large set of virtual patients (200 per clinical scenario). In the first one the patients lifestyle maintains the concentration of LDL in a no risk range. This is the control case simulation. The second case is represented by patients having high level of LDL with a delay to apply appropriate treatments; The third scenario is characterized by patients with high LDL levels treated with specific drugs like statins. Finally we simulated patients that are characterized by several oxidative events (smoke, sedentary life style, assumption of alcoholic drinks and so on so forth) that effective increase the risk of LDL oxidation. Those preliminary results obviously need to be clinically investigated. It is clear, however, that SimAthero has the power to concretely help medical doctors and clinicians in choosing personalized treatments for the prevention of the atherosclerosis damages.

  12. Lipoprotein-associated phospholipase A2 and coronary heart disease.

    Science.gov (United States)

    Sofogianni, Areti; Alkagiet, Stelina; Tziomalos, Konstantinos

    2018-01-10

    In the last decades, the role of inflammation in the pathogenesis of atherosclerosis has been the topic of intense research. Several markers of inflammation have shown predictive value for first and recurrent coronary events in patients without and with established coronary heart disease (CHD). Among these markers, lipoprotein-associated phospholipase A2 (Lp-PLA2) has recently received considerable attention. In the present review, the potential role of Lp-PLA2 as a marker of CHD risk and as a therapeutic target is discussed. Elevated Lp-PLA2 mass and activity appears to be associated with increased risk for CHD, both in the general population and in patients with established CHD. However, it is unclear whether the measurement of Lp-PLA2 improves risk discrimination when incorporated in models that include traditional cardiovascular risk factors. Moreover, the lack of effect on CHD events of darapladib, a potent, selective Lp-PLA2 inhibitor, in two large, randomized, placebo-controlled trials and the mostly negative findings of genetic association studies suggest that Lp-PLA2 is unlikely to represent a causal factor in atherogenesis. Therefore, it is doubtful whether Lp-PLA2 will constitute a therapeutic target for the prevention of CHD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Diabetes mellitus and coronary heart disease in the elderly.

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    Vokonas, P S; Kannel, W B

    1996-02-01

    Data from epidemiologic studies document the role of clinically manifest diabetes mellitus as a powerful risk determinant for an array of atherosclerotic cardiovascular outcomes including coronary heart disease (CHD), stroke, and peripheral arterial disease, particularly in the elderly. Although dyslipidemias and hypertension are quite prevalent in persons with diabetes mellitus and contribute heavily to the underlying atherosclerotic process, other factors involving alternative pathogenetic mechanisms are necessary to explain for the dramatic acceleration of atherogenesis observed in this condition. Myocardial ischemia may be silent and myocardial infarction (MI) may be either painless or atypical in presentation which further complicates both the diagnostic and therapeutic management of CHD in older diabetic patients. MI, in this context, is confounded by dual prognostic disadvantages of higher risk for MI-related complications attributable to both advanced age and diabetes mellitus. Because available evidence has yet to demonstrate that control of hyperglycemia, either by oral agents or by insulin, effectively forestalls either the development or complications of atherosclerosis, preventive management in older patients with diabetes requires critical attention to correcting coexisting cardiovascular risk factors.

  14. Measurement of Low-Abundance Intracellular mRNA Using Amplified FISH Staining and Image-Based Flow Cytometry.

    Science.gov (United States)

    Henning, Andrea L; Sampson, Jill N Best; McFarlin, Brian Keith

    2016-04-01

    Recent advances in instrument design and reagent development have enabled the rapid progression in available measurement techniques in the field of flow cytometry. In particular, image-based flow cytometry extends the analysis capacity found in traditional flow cytometry. Until recently, it was not possible to measure intracellular mRNA in specific phenotypes of cells by flow cytometry. In this protocol, a method of completing simultaneous intracellular measurement of mRNA and protein for PPAR-gamma in peripheral blood monocytes, which have been exposed in vitro to modified LDL, is described. The process of PPAR-gamma activation following uptake of modified LDL is believed to play a role in the development of atherogenesis. PPAR-gamma mRNA measurement was made possible using an amplified FISH technique (PrimeFlow RNA Assay) that allowed for detection of low-abundant intracellular mRNA expression. This protocol represents a continued effort by the authors' laboratory to establish and validate new techniques to assess the role of the immune system in chronic disease. Copyright © 2016 John Wiley & Sons, Inc.

  15. Chylomicrons metabolism in patients with coronary artery disease; Metabolismo de quilomicrons em pacientes portadores de doenca arterial coronaria

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    Brandizzi, Laura Ines Ventura

    2002-07-01

    Chylomicrons are the triglyceride-rich lipoproteins that carry dietary lipids absorbed in the intestine. In the bloodstream , chylomicron triglycerides are broken-down by lipoprotein lipase using apoliprotein (apo) CII as co factor. Fatty acids and glycerol resulting from the enzymatic action are absorbed and stored in the body tissues mainly adipose and muscle for subsequent utilizations energy source. The resulting triglycerides depleted remnants are taken-up by liver receptor such as the LDL receptor using mainly apo E as ligand. For methodological reasons, chylomicron metabolism has been unfrequently studied in subjects despite its pathophysiological importance, and this metabolism was not evaluated in the great clinical trials that established the link between atherosclerosis and lipids. In studies using oral fat load tests, it has been shown that in patients with coronary artery disease there is a trend to accumulation of post-prandial triglycerides, vitamin A or apo B-48 , suggesting that in those patients chylomicrons and their remnants are slowly removed from the circulation. A triglyceride-rich emulsion marked radioisotopic which mimics chylomicron metabolism when injected into the bloodstream has been described that can offer a more straight forward approach to evaluate chylomicrons. In coronary artery disease patients both lipolysis and remnant removal from the plasma of the chylomicron-like emulsions were found slowed-down compared with control subjects without the disease. The introduction of more practical techniques to assess chylomicron metabolism may be new mechanisms underlying atherogenesis. (author)

  16. Antiatherogenic effects of n-3 fatty acids - evidence and mechanisms

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    Antonella Zampolli

    2006-12-01

    Full Text Available N-3 (omega-3 (polyunsaturated fatty acids are thought to display a variety of beneficial effects for human health. Clues to the occurrence of cardiovascular protective effects have been, however, the spur for the first biomedical interest in these compounds, and are the best documented. Historically, the epidemiologic association between dietary consumption of n-3 fatty acids and cardiovascular protection was first suggested by Bang and Dyerberg, who identified the high consumption of fish, and therefore, of fish oil-derived n-3 fatty acids, as the likely explanation for the strikingly low rate of coronary heart disease events reported in the Inuit population. Since their initial reports, research has proceeded in parallel to provide further evidence for their cardioprotection and to understand underlying mechanisms. Decreased atherogenesis is currently thought to be a part of the cardiovascular protection by n-3 fatty acids. This article summarizes the evidence for such a claim and the mechanisms putatively involved. (Heart International 2006; 3-4: 141-54

  17. Association of whole blood viscosity with non-alcoholic fatty liver disease.

    Science.gov (United States)

    Yu, Xin-Yang; Li, Ying; Liu, Tiemin; Wang, Rui-Tao

    2015-09-25

    Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for increased cardiovascular disease. Altered hemorheological parameters have also been shown to play a crucial role in atherogenesis. Moreover, increased viscosity is observed in insulin resistance, metabolic syndrome, hypertension, diabetes, ischemic heart disease, and stroke. A recent study confirmed that whole blood viscosity (WBV) is a predictor of cardiovascular events. This study aimed to investigate the association of WBV with NAFLD. In this cross-sectional study, we investigated the relationship between WBV and NAFLD in 1329 subjects (962 men and 367 women) in a general health examination. WBV at low shear stress was elevated in patients with NAFLD. In addition, the prevalence of metabolic syndrome and NAFLD increased as WBV quartiles increased both in men and in women. Multiple regression analysis further identified WBV as an independent and significant determinant for NAFLD. The findings showed that WBV at low shear stress is increased in NAFLD. Moreover, WBV at low shear stress is independently associated with NAFLD even after adjusting other cardiovascular risk factors.

  18. Genetic Markers of Cardiovascular Disease in Rheumatoid Arthritis

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    Luis Rodríguez-Rodríguez

    2012-01-01

    Full Text Available Cardiovascular (CV disease is the most common cause of premature mortality in patients with rheumatoid arthritis (RA. It is the result of an accelerated atherosclerotic process. Both RA and atherosclerosis are complex polygenic diseases. Besides traditional CV risk factors and chronic inflammation, a number of studies have confirmed the role of genetic factors in the development of the atherogenesis observed in RA. In this regard, besides a strong association between the HLA-DRB1*04 shared epitope alleles and both endothelial dysfunction, an early step in the atherosclerotic process, and clinically evident CV disease, other polymorphisms belonging to genes implicated in inflammatory and metabolic pathways, located inside and outside the HLA region, such as the 308 variant (G>A, rs1800629 of the TNFA locus, the rs1801131 polymorphism (A>C; position + 1298 of the MTHFR locus, or a deletion of 32 base pairs on the CCR5 gene, seem to be associated with the risk of CV disease in patients with RA. Despite considerable effort to decipher the genetic basis of CV disease in RA, further studies are required to better establish the genetic influence in the increased risk of CV events observed in patients with RA.

  19. [Significance of Toll-like receptors in the pathophysiology of surgical sepsis].

    LENUS (Irish Health Repository)

    Romics, Laszlo Jr

    2012-02-03

    The discovery of Toll-like receptors has substantially changed our knowledge of pathogen recognition. 11 Toll-like receptors have so far been described in humans. These recognize distinct pathogen associated molecular patterns, as well as endogenous ligands and small molecular synthetic compounds. TLRs have a multifunctional role in pathogen-triggered immune responses and represent an important connection between the "innate" and "adaptive" immunity. The role of the TLRs in the recognition of pathogens renders them a key figure in the activation of the immune response during surgical sepsis. However, emerging evidence points to a fundamental role in tumorigenesis, transplantation, wound healing, atherogenesis and inflammatory bowel disease. The aim hence was to review experimental data pertaining to the activation of TLR signalling pathways in conditions associated with surgical sepsis. A systematic review of the literature was undertaken by searching the MEDLINE database for the period 1966-2004 without language restriction. The paper also analyses the possible therapeutic utilization of the TLR signalling pathways in surgical sepsis.

  20. Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects--a monozygotic twin study.

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    Kirsi H Pietiläinen

    Full Text Available Both genetic and environmental factors are involved in the etiology of obesity and the associated lipid disturbances. We determined whether acquired obesity is associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic (MZ twins. 14 healthy MZ pairs discordant for obesity (10 to 25 kg weight difference and ten weight concordant control pairs aged 24-27 years were identified from a large population-based study. Insulin sensitivity was assessed by the euglycemic clamp technique, and body composition by DEXA (% body fat and by MRI (subcutaneous and intra-abdominal fat. Global characterization of lipid molecular species in serum was performed by a lipidomics strategy using liquid chromatography coupled to mass spectrometry. Obesity, independent of genetic influences, was primarily related to increases in lysophosphatidylcholines, lipids found in proinflammatory and proatherogenic conditions and to decreases in ether phospholipids, which are known to have antioxidant properties. These lipid changes were associated with insulin resistance, a pathogonomic characteristic of acquired obesity in these young adult twins. Our results show that obesity, already in its early stages and independent of genetic influences, is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance.

  1. Angiopoietin-1 promotes atherosclerosis by increasing the proportion of circulating Gr1+ monocytes

    Science.gov (United States)

    Fujisawa, Takeshi; Wang, Keqing; Niu, Xi-Lin; Egginton, Stuart; Ahmad, Shakil; Hewett, Peter; Kontos, Christopher D.; Ahmed, Asif

    2017-01-01

    Aims Atherosclerosis is a chronic inflammatory disease occurring within the artery wall. A crucial step in atherogenesis is the infiltration and retention of monocytes into the subendothelial space of large arteries induced by chemokines and growth factors. Angiopoietin-1 (Ang-1) regulates angiogenesis and reduces vascular permeability and has also been reported to promote monocyte migration in vitro. We investigated the role of Ang-1 in atherosclerosis-prone apolipoprotein-E (Apo-E) knockout mouse. Methods and results Apo-E knockout (Apo-E-/-) mice fed a western or normal chow diet received a single iv injection of adenovirus encoding Ang-1 or control vector. Adenovirus-mediated systemic expression of Ang-1 induced a significant increase in early atherosclerotic lesion size and monocyte/macrophage accumulation compared with control animals receiving empty vector. Ang-1 significantly increased plasma MCP-1 and VEGF levels as measured by ELISA. FACS analysis showed that Ang-1 selectively increased inflammatory Gr1+ monocytes in the circulation, while the cell-surface expression of CD11b, which mediates monocyte emigration, was significantly reduced. Conclusions Ang-1 specifically increases circulating Gr1+ inflammatory monocytes and increases monocyte/macrophage retention in atherosclerotic plaques, thereby contributing to development of atherosclerosis. PMID:28069704

  2. Effect of herbal polyphenols on atherogenic transcriptome.

    Science.gov (United States)

    Kaul, Deepak; Shukla, Akshay R; Sikand, Kavleen; Dhawan, Veena

    2005-10-01

    The ancient Indian system of medicine supports the antiatherogenic properties of some herbs. The crosstalk amongst the genes coding for LDLR, LXRalpha, PPARs (alpha,gamma), CD-36 and c-myc may be important in atherogenesis because these genes control lipid metabolism, cytokine production and cellular activity within the arterial wall. Hence, we attempted for the first time to explore whether or not the polyphenols extracted from medicinal herbs had any effect on the transcription of these genes. Normal human mononuclear cells were cultured in the presence of polyphenols (and their HPLC purified sub-fractions) extracted from Green tea (Camellia sinensis), Neem (Azadirachta indica) and Tulsi (Ocimum sanctum). Transcriptional expression of these genes was measured by using RT-PCR and SCION IMAGE analysis software. These polyphenolic extracts were found to have the inherent capacity to inhibit the transcriptional expression of genes having direct involvement in atherogenic process. On the basis of these results, we propose for the first time that HPLC purified polyphenolic fraction IV of Tulsi may have a profound antiatherogenic effect.

  3. Nutrient-Induced Inflammation in Polycystic Ovary Syndrome: Role in the Development of Metabolic Aberration and Ovarian Dysfunction.

    Science.gov (United States)

    González, Frank

    2015-07-01

    A pathophysiology paradigm shift has emerged with the discovery that polycystic ovary syndrome (PCOS) is a proinflammatory state. Despite the dogma that the compensatory hyperinsulinemia of insulin resistance is the promoter of hyperandrogenism, physiological insulin infusion has no effect on androgen levels in PCOS. The dogma also does not explain the cause of hyperandrogenism and ovarian dysfunction in the 30 to 50% of women with PCOS who are of normal weight and lack insulin resistance. Inflammation is the underpinning of insulin resistance in obesity and type 2 diabetes, and may also be the cause of insulin resistance when present in PCOS. The origin of inflammation in PCOS has been ascribed to excess abdominal adiposity or frank obesity. However, nutrients such as glucose and saturated fat can incite inflammation from circulating mononuclear cells (MNC) of women with PCOS independent of excess adiposity and insulin resistance, and can also promote atherogenesis. Hyperandrogenism activates MNC in the fasting state to increase MNC sensitivity to nutrients, and is a potential mechanism for initiating inflammation in PCOS. However, chronic ovarian androgen suppression does not reduce inflammation in normal-weight women with PCOS. Direct exposure of ovarian theca cells to proinflammatory stimuli in vitro increases androgen production. These findings may be corroborated in vivo with anti-inflammatory therapy to normal-weight insulin-sensitive women with PCOS without abdominal adiposity to observe for amelioration of ovarian dysfunction. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  4. Dietary α-linolenic acid increases the platelet count in ApoE-/- mice by reducing clearance.

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    Stivala, Simona; Reiner, Martin F; Lohmann, Christine; Lüscher, Thomas F; Matter, Christian M; Beer, Juerg H

    2013-08-08

    Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces atherogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein Ib (GPIb) shedding, exposure of P-selectin, and activated integrin αIIbβ3 upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo-endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-α-converting enzyme and reduced platelet activation/expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders.

  5. Genistein prevents the glucose autoxidation mediated atherogenic modification of low density lipoprotein.

    Science.gov (United States)

    Exner, M; Hermann, M; Hofbauer, R; Kapiotis, S; Quehenberger, P; Speiser, W; Held, I; Gmeiner, B M

    2001-01-01

    Hyperglycemia has been assumed to be responsible for oxidative stress in diabetes. In this respect, glucose autoxidation and advanced glycation end products (AGE) may play a causal role in the etiology of diabetic complications as e.g. atherosclerosis. There is now growing evidence that the oxidative modification of LDL plays a potential role in atherogenesis. Glucose derived oxidants have been shown to peroxidise LDL. In the present study, genistein, a compound derived from soy with a flavonoid chemical structure (4', 5, 7-trihydroxyisoflavone) has been evaluated for its ability to act as an antioxidant against the atherogenic modification of LDL by glucose autoxidation radical products. Daidzein, (4',7-dihydroxyisoflavone) an other phytoestrogen of soy, was tested in parallel. Genistein--in contrast to daidzein--effectively prevented the glucose mediated LDL oxidation as measured by thiobarbituric acid-reactive substance formation (TBARS), alteration in electrophoretic mobility, lipid hydroperoxides and fluorescence quenching of tryptophan residues of the lipoprotein. In addition the potential of glucose-oxidized LDL to increase tissue factor (TF) synthesis human endothelial cells (HUVEC) was completely inhibited when genistein was present during LDL oxidative modification by glucose. Both phytoestrogens did not influence the nonenzymatic protein glycation reaction as measured by the in vitro formation of glycated LDL. As the protective effect of genistein on LDL atherogenic modification was found at glucose/genistein molar ratios which may occur in vivo, our findings support the suggested beneficial action of a soy diet in preventing chronic vascular diseases and early atherogenic events.

  6. Genistein supplementation inhibits atherosclerosis with stabilization of the lesions in hypercholesterolemic rabbits.

    Science.gov (United States)

    Lee, Choong-Sik; Kwon, Su-Jin; Na, Sun-Young; Lim, Seung-Pyung; Lee, Jung-Hee

    2004-10-01

    The effect of genistein on aortic atherosclerosis was studied by immunohistochemistry with RAM-11 and HHF-35 antibodies and western blotting for matrix metalloproteinase-3 (MMP-3) in New Zealand White rabbits. After provocation of atherosclerosis with hyperlipidemic diet, the rabbits were divided as hyperlipidemic diet group (HD), normal diet group (ND) and hyperlipidemic plus genistein diet group (HD+genistein) for 4 and half months. The average cross sectional area of atherosclerotic lesion was 0.269 mm2 after provocation. The lesion was progressed by continuous hyperlipidemic diet (10.06 mm2) but was increased mildly by genistein (0.997 mm2), and decreased by normal diet (0.228 mm2). The ratio of macrophages to smooth muscle cells in the lesion was not changed by genistein supplementation. The western blotting showed reduction of MMP-3 expression in HD+genistein and ND groups than HD group. The inhibition of atherogenesis by genistein was might be due to improve the endothelial dysfunction rather than direct action on macrophages and/or smooth muscle cells in the lesion, since endothelial dysfunction by lipid peroxidation was the main atherogenic factor in the hypercholesterolemic rabbits. The genistein supplementation also suggests that it helps the stabilization of the atherosclerotic lesion by inhibition of MMP-3 expression.

  7. Divergent action of calcium channel blockers on ATP-binding cassette protein expression.

    Science.gov (United States)

    Hasegawa, Kazuhiro; Wakino, Shu; Kanda, Takeshi; Yoshioka, Kyoko; Tatematsu, Satoru; Homma, Koichiro; Takamatsu, Ichiro; Sugano, Naoki; Hayashi, Koichi

    2005-12-01

    Calcium channel blockers (CCBs) are widely used in clinical practice, and have been reported to be effective in preventing the progression of atherosclerosis. We examined whether various types of calcium channel blockers affected the expression of ATP binding cassette transporter A1 (ABCA1), a factor contributing to anti-atherogenesis. Undifferentiated monocytic cell line, THP-1 cells were maintained in RPMI 1640 medium and treated with different kinds of calcium channel blockers. Among the calcium channel blockers tested, aranidipine and efonidipine increased ABCA1 protein expression without an increase in ABCA1 mRNA expression, whereas other calcium channel blockers (eg, nifedipine, amlodipine, and nicardipine) or T-type calcium channel blockers (eg, mibefradil and nickel chloride) failed to upregulate ABCA1 expression. H89, a protein kinase A inhibitor inhibited the aranidipine-induced ABCA1 protein expression, whereas genistein (a tyrosine kinase inhibitor), or AG490 (a JAK-2 inhibitor) had no effects. Neither of these inhibitors suppressed the efonidipine-induced ABCA1 protein expression. Intracellular cAMP levels were elevated only by aranidipine, but not by efonidipine. In conclusion, aranidipine and efonidipine have the ability to induce ABCA1 protein by distinct mechanisms; protein kinase A is involved in the aranidipine-induced ABCA1 upregulation. This non-class effect of calcium channel blockers may potentially offer beneficial action in the treatment of hypertensive subjects with atherosclerosis.

  8. Animal Models of Atherosclerosis

    Science.gov (United States)

    Getz, Godfrey S.; Reardon, Catherine A.

    2012-01-01

    Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Both cells of the vessel wall and cells of the immune system participate in atherogenesis. This process is heavily influenced by plasma lipoproteins, genetics and the hemodynamics of the blood flow in the artery. A variety of small and large animal models have been used to study the atherogenic process. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis or lipoprotein profile. Useful large animal models include pigs, rabbits and non-human primates. Due in large part to the relative ease of genetic manipulation and the relatively short time frame for the development of atherosclerosis, murine models are currently the most extensively used. While not all aspects of murine atherosclerosis are identical to humans, studies using murine models have suggested potential biological processes and interactions that underlie this process. As it becomes clear that different factors may influence different stages of lesion development, the use of mouse models with the ability to turn on or delete proteins or cells in tissue specific and temporal manner will be very valuable. PMID:22383700

  9. Novel anti-inflammatory therapies for the treatment of atherosclerosis.

    Science.gov (United States)

    Khan, Razi; Spagnoli, Vincent; Tardif, Jean-Claude; L'Allier, Philippe L

    2015-06-01

    The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1β (IL-1β), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Fruitflow(®): the first European Food Safety Authority-approved natural cardio-protective functional ingredient.

    Science.gov (United States)

    O'Kennedy, Niamh; Raederstorff, Daniel; Duttaroy, Asim K

    2017-03-01

    Hyperactive platelets, in addition to their roles in thrombosis, are also important mediators of atherogenesis. Antiplatelet drugs are not suitable for use where risk of a cardiovascular event is relatively low. It is therefore important to find alternative safe antiplatelet inhibitors for the vulnerable population who has hyperactive platelets in order to reduce the risk of cardiovascular disease. Potent antiplatelet factors were identified in water-soluble tomato extract (Fruitflow(®)), which significantly inhibited platelet aggregation. Human volunteer studies demonstrated the potency and bioavailability of active compounds in Fruitflow(®). Fruitflow(®) became the first product in Europe to obtain an approved, proprietary health claim under Article 13(5) of the European Health Claims Regulation 1924/2006 on nutrition and health claims made on foods. Fruitflow(®) is now commercially available in different countries worldwide. In addition to its reduction in platelet reactivity, Fruitflow(®) contains anti-angiotensin-converting enzyme and anti-inflammatory factors, making it an effective and natural cardio-protective functional food.

  11. Chronic inhalation of carbon monoxide: effects on the respiratory and cardiovascular system at doses corresponding to tobacco smoking.

    Science.gov (United States)

    Sørhaug, Sveinung; Steinshamn, Sigurd; Nilsen, Odd G; Waldum, Helge L

    2006-12-07

    Carbon monoxide (CO) is a dangerous poison in high concentrations, but the long-term effects of low doses of CO, as in the gaseous component of tobacco smoke, are not well known. The aims of our study were to evaluate the long-term effects of inhaled CO on the respiratory and cardiovascular system at doses corresponding to tobacco smoking and its effect on tumourigenesis and pulmonary neuroendocrine (NE) cells. Female Wistar rats were exposed to either CO (200 ppm) for 20 h/day (n=51) or air (n=26) for 72 weeks. Carboxyhaemoglobin was 14.7+/-0.3% in CO exposed animals and 0.3+/-0.1% in controls. In the lungs, no signs of pathology similar to that associated with cigarette smoking were observed, and no differences in number of pulmonary NE cells were observed between the groups. Chronic CO inhalation induced a 20% weight increase of the right ventricle (p=0.001) and a 14% weight increase of the left ventricle and interventricular septum (prespiratory pathology associated with tobacco smoking. The effects on the cardiovascular system seem to involve myocardial hypertrophy, but not atherogenesis.

  12. Macrophage migration inhibitory factor (MIF in Clinical Kidney Disease - review

    Directory of Open Access Journals (Sweden)

    Annette eBruchfeld

    2016-01-01

    Full Text Available Macrophage migration inhibitory factor (MIF is a pro-inflammatory cytokine implicated in acute and chronic inflammatory conditions including sepsis, autoimmune disease, atherogenesis, plaque instability and pulmonary arterial hypertension (PAH. MIF in plasma and urine is significantly elevated in patients with Acute Kidney injury (AKI and elevated MIF in serum is associated with markers of oxidative stress, endothelial dysfunction, arterial stiffness and markers of myocardial damage in Chronic Kidney disease (CKD. Furthermore MIF seems to be involved in vascular processes and cardiovascular disease associated with CKD, glomerulonephritis, autosomal dominant polycystic kidney disease and possibly also in progression to renal failure. Moreover, in active ANCA-associated vasculitis plasma MIF-levels have been shown to be significantly elevated as compared with samples from patients in remission. A significant difference in the genotype frequency of high production MIF -173 G/C genotype has been found in end-stage renal disease (ESRD, compared to controls. Inhibition of MIF in a diabetic nephropathy model ameliorated blood glucose and albuminuria and in a model of adult polycystic kidney disease cyst growth was delayed. Preclinical studies support a potential therapeutic role for MIF in AKI and in a number of chronic kidney diseases whereas these data in human disease are still observational. Future interventional studies are needed to delineate the role of MIF as a treatment target in clinical kidney disease. Keywords: MIF, , AKI, CKD, glomerulonephritis, vasculitis, MIF gene polymorphism, diabetic nephropathy, ADPKD

  13. Obesity-related inflammation & cardiovascular disease: efficacy of a yoga-based lifestyle intervention.

    Science.gov (United States)

    Sarvottam, Kumar; Yadav, Raj Kumar

    2014-06-01

    Obesity is a global health burden and its prevalence is increasing substantially due to changing lifestyle. Chronic adiposity is associated with metabolic imbalance leading to dyslipidaemia, diabetes, hypertension and cardiovascular diseases (CVD). Adipose tissue acts as an endocrine organ releasing several adipocytokines, and is associated with increased levels of tissue and circulating inflammatory biomolecules causing vascular inflammation and atherogenesis. Further, inflammation is also associated independently with obesity as well as CVD. Keeping this in view, it is possible that a reduction in weight may lead to a decrease in inflammation, resulting in CVD risk reduction, and better management of patients with CVD. Lifestyle intervention has been endorsed by several health authorities in prevention and management of chronic diseases. A yoga-based lifestyle intervention appears to be a promising option in reducing the risk for CVD as well as management of patients with CVD as it is simple to follow and cost-effective with high compliance. The efficacy of such lifestyle intervention programmes is multifaceted, and is achieved via reduction in weight, obesity-related inflammation and stress, thereby culminating into risk reduction towards several chronic diseases including CVD. In this review, the association between obesity-related inflammation and CVD, and the role of yoga-based lifestyle intervention in prevention and management of CVD are discussed.

  14. The epigenetic memory of monocytes and macrophages as a novel drug target in atherosclerosis.

    Science.gov (United States)

    Bekkering, Siroon; Joosten, Leo A B; van der Meer, Jos W M; Netea, Mihai G; Riksen, Niels P

    2015-04-01

    Atherosclerosis is characterized by a persistent inflammation of the arterial wall. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. After stimulation, monocytes can adopt a long-term proinflammatory phenotype. This nonspecific memory of innate immune cells is mediated by epigenetic reprogramming and has recently been termed "trained innate immunity." The goal of this study was to describe the potential role of trained immunity in the development of atherosclerosis and to discuss the potential clinical implications of this concept. We performed a comprehensive literature search (PubMed) on the role of epigenetic programming of histones, and of trained immunity in particular, in atherogenesis. In vitro studies demonstrate that modified LDL particles can induce a long-term proinflammatory phenotype in monocytes/macrophages by epigenetic reprogramming at the level of histone methylation. This scenario is associated with increased production of proatherogenic cytokines and chemokines and increased formation of foam cells. Preclinical evidence suggests that trained innate immunity may contribute to vascular wall inflammation in patients with risk factors for atherosclerosis. Epigenetic reprogramming is regulated by enzymes that are amenable to pharmacologic modulation. Therefore, this mechanism could be used to develop novel pharmacologic targets for the prevention or treatment of atherosclerotic vascular disease. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

  15. [Caveolae membrane domains, specialized transmembrane exchange zones implicated in cell signalling].

    Science.gov (United States)

    Roch-Arveiller, M; Couderc, R

    2000-01-01

    Caveolae are small pockets or invaginations localized at the plasma membrane. They are enriched in glycosphingolipids, cholesterol, sphingomyelin and lipid-enchored membrane proteins, and they are characterized by a light buoyant density and resistance to solubilization by Triton X-100 at 4 C. Caveolins are the principal protein components of caveolae and play an important structural role in the formation of caveolae membranes. Numerous molecules involved in cell signalling have been identified in caveolae, suggesting that these structures may serve to compartimentalize, modulate and integrate signalling events at the cell surface. Depletion of membrane cholesterol disrupts the formation and function of caveolae, suggesting that these membrane microdomains are involved in a range of biological processes. Moreover, exposure of endothelial cells to high levels of cholesterol upregulates the caveolin abundance in caveolae, and decreases nitric oxide synthesis, suggesting that this may be an early event in atherogenesis. Alteration in the expression of caveolin genes has also been implicated in human diseases such as cancers, diabetes, Alzheimer's disease and muscular distrophy.

  16. Aging and endothelial barrier function in culture: effects of chronic exposure to fatty acid hydroperoxides and vitamin E.

    Science.gov (United States)

    Boissonneault, G A; Hennig, B; Wang, Y; Wood, C L

    1990-10-01

    As the endothelium ages it may become more susceptible to damage by atherogenic plasma components such as toxic lipid oxidation products. Vitamin E (vit E) might prove to be anti-atherogenic by reducing oxidative injury. This study investigated the effects of age and chronic exposure to fatty acid hydroperoxides (OFA) and/or vit E on endothelial barrier function (EBF) and cell growth characteristics. Chronic exposure to 5 microM OFA for 40 passages resulted in an age-related decrease in EBF, while supplementation of OFA-treated cultures with 25 microM vit E protected against the OFA-mediated decrease in EBF, independent of cell age. Vit E treatment alone had no significant effect on EBF relative to control cultures. No changes in growth characteristics, i.e., total DNA or protein per culture, were noted, regardless of treatment, although total DNA per culture decreased with increasing culture passage. These results suggest that chronic oxidative stress decreases EBF, predisposing the artery to infiltration by blood components and subsequent atherogenesis and that vit E delays cumulative changes in EBF related to chronic OFA exposure.

  17. THE MICROBIOTA OF UPPER PARTS OF GASTROINTESTINAL TRACT AND ITS ROLE IN THE DEVELOPMENT OF OBESITY IN CHILDREN

    Directory of Open Access Journals (Sweden)

    T. A. Bokova

    2016-01-01

    Full Text Available Evaluation of qualitative and quantitative composition of microflora of different habitats of the human body and definition of their role in the development of metabolic disorders are of great interest for investigators worldwide. The gut mi-crobiota is an obligatory contributor to the synthesis, recirculation and metabolism of steroid hormones, lipids, and bile acids. Infectious agents and their biologically active compounds initiate the atherogenesis. Disorders of lipid metabolism are associated with a change in bacterial entero-types. Microbiotal colonization of gastrointestinal tract starts at birth. Its composition in a newborn depends on a variety of environmental and nutritional factors, maternal health, the course of pregnancy and delivery. Infants born by cesarean section have a higher incidence of obesity, which is thought to be associated with a delay of bifido-bacterial colonization of gastrointestinal tract.Reduction of bifidobacteria counts in the gut in infants below 12 months of age predisposes to obesity in later life. Children born to mothers with obesity have significant differences in the composition of the gut microflora, compared to children born to normal weight mothers. This review presents the data on the association between metabolic disorders, such as obesity and type 2 diabetes, and persistence of Helicobacter pylori infection. Further in-depth research in this area would increase the knowledge on the mechanisms of hormonal and metabolic disorders in childhood and may help to develop algorithms for effective treatment and preventive measures.

  18. Multiplexed single-molecule force proteolysis measurements using magnetic tweezers.

    Science.gov (United States)

    Adhikari, Arjun S; Chai, Jack; Dunn, Alexander R

    2012-07-25

    The generation and detection of mechanical forces is a ubiquitous aspect of cell physiology, with direct relevance to cancer metastasis(1), atherogenesis(2) and wound healing(3). In each of these examples, cells both exert force on their surroundings and simultaneously enzymatically remodel the extracellular matrix (ECM). The effect of forces on ECM has thus become an area of considerable interest due to its likely biological and medical importance(4-7). Single molecule techniques such as optical trapping(8), atomic force microscopy(9), and magnetic tweezers(10,11) allow researchers to probe the function of enzymes at a molecular level by exerting forces on individual proteins. Of these techniques, magnetic tweezers (MT) are notable for their low cost and high throughput. MT exert forces in the range of ~1-100 pN and can provide millisecond temporal resolution, qualities that are well matched to the study of enzyme mechanism at the single-molecule level(12). Here we report a highly parallelizable MT assay to study the effect of force on the proteolysis of single protein molecules. We present the specific example of the proteolysis of a trimeric collagen peptide by matrix metalloproteinase 1 (MMP-1); however, this assay can be easily adapted to study other substrates and proteases.

  19. Recent advances in lipoprotein and atherosclerosis: A nutrigenomic approach

    Directory of Open Access Journals (Sweden)

    López, Sergio

    2009-03-01

    Full Text Available Atherosclerosis is a disease in which multiple factors contribute to the degeneration of the vascular wall. Many risk factors have been identified as having influence on the progression of atherosclerosis among them, the type of diet. Multifactorial interaction among lipoproteins, vascular wall cells, and inflammatory mediators has been recognised as the basis of atherogenesis. Dietary intake affects lipoprotein concentration and composition providing risk or protection at several stages of atherosclerosis. More intriguingly, it has been demonstrated that the extent to which each lipid or lipoprotein is associated with cardiovascular disease depends on the time to last meal; thus, postprandial lipoproteins, main lipoproteins in blood after a high-fat meal, have been shown to strongly influence atherogenesis. As a complex biological process, the full cellular and molecular characterization of atherosclerosis derived by diet, calls for application of the newly developing “omics” techniques of analysis. This review will considered recent studies using high-throughput technologies and a nutrigenomic approach to reveal the patho-physiological effects that the fasting and postprandial lipoproteins may exert on the vascular wall.La aterosclerosis es una enfermedad en la que múltiples factores, entre los que se encuentra la dieta, contribuyen a la degradación de la pared vascular. En la etiología de la aterogénesis son determinantes las lipoproteínas plasmáticas y los distintos tipos celulares de la pared vascular, incluyendo una respuesta inflamatoria. La ingesta de alimentos afecta la concentración y composición de las lipoproteínas, ejerciendo un papel de riesgo o protector durante las diferentes etapas del proceso aterosclerótico. Es importante destacar que la naturaleza de las lipoproteínas y por lo tanto su papel en la enfermedad cardiovascular, también depende del tiempo transcurrido entre comidas. Por ejemplo, las lipoprote

  20. Childhood obesity, adipose tissue distribution, and the pediatric practitioner.

    Science.gov (United States)

    Slyper, A H

    1998-07-01

    coronary disease tend to be obese. Very low-density lipoprotein and intermediate-density lipoprotein particles, which are small in size, may be important in atherogenesis but they cannot be identified in a fasting lipid panel. The propensity to atherogenesis cannot be interpreted readily from a fasting lipid panel, which therefore should be interpreted in conjunction with a family history for coronary risk factors. Hypertriglyceridemia may be indicative of increased visceral fat, familial combined hyperlipidemia, familial dyslipidemic hypertension, impaired glucose tolerance, or diabetes. Almost half of adult females with polycystic ovary syndrome are obese and many have a central distribution of body fat. This condition frequently has its origins in adolescence. It is associated with increased androgen secretion, hirsutism, menstrual abnormalities, and infertility, although these may not be present in every case. Adults with polycystic ovary syndrome adults are hyperlipidemic, have a high incidence of impaired glucose tolerance and noninsulin-dependent diabetes, and are at increased risk for coronary artery disease. Weight reduction and lipid lowering therefore are an important part of therapy. Obstructive sleep apnea with daytime somnolence is a common problem in obese adults. Pediatric studies suggest that obstructive sleep apnea occurs in approximately 17% of obese children and adolescents. Sleep disorders in the obese may be a major cause of learning disability and school failure, although this remains to be confirmed. Symptoms suggestive of a sleep disorder include snoring, restlessness at night with difficulty breathing, arousals and sweating, nocturnal enuresis, and daytime somnolence. Questions to exclude obstructive sleep apnea should be part of the history of all obese children, particularly for the morbidly obese. For many children and adolescents with mild obesity, and particularly for females, one can speculate that obesity may not be a great health risk

  1. Green tea polyphenol treatment attenuates atherosclerosis in high-fat diet-fed apolipoprotein E-knockout mice via alleviating dyslipidemia and up-regulating autophagy.

    Directory of Open Access Journals (Sweden)

    Shibin Ding

    Full Text Available Green tea polyphenol (GTP is a polyphenol source from green tea that has drawn wide attention owing to epidemiological evidence of its beneficial effects in the prevention of cardiovascular disease; the underlying molecular mechanisms of these effects are not well understood. This study aimed to investigate the effects of GTP treatment on autophagy regulation in the vessel wall and lipid metabolism of HFD-fed male ApoE-knockout mice.Adult male ApoE-knockout mice (n = 30 fed with a high-fat diet (HFD were treated with either vehicle or GTP (3.2 or 6.4 g/L administered via drinking water for 15 weeks, and C57BL/6J mice fed with standard chow diet (STD were used as the control group. Metabolic parameters, expression of key mRNAs and proteins of hepatic lipid metabolism and autophagy in the vessel wall of mice were determined after the 15-week treatment.A HFD induced atherosclerosis formation and lipid metabolism disorders as well as reduced autophagy expression in the vessel wall of ApoE-knockout mice, but GTP treatment alleviated the lipid metabolism disorders, decreased the oxLDL levels in serum, and increased the mRNA and protein expressions of hepatic PPARα and autophagy markers (LC3, Beclin1 and p62 in the vessel wall of ApoE-knockout mice.Our findings suggest that GTP supplementation showed marked suppression of atherogenesis through improved lipid metabolism as well as through a direct impact on oxLDL and autophagy flux in the vessel wall.

  2. Association of lecithin-cholesterol acyltransferase activity measured as a serum cholesterol esterification rate and low-density lipoprotein heterogeneity with cardiovascular risk: a cross-sectional study.

    Science.gov (United States)

    Tani, Shigemasa; Takahashi, Atsuhiko; Nagao, Ken; Hirayama, Atsushi

    2016-06-01

    The cholesterol-esterifying enzyme, lecithin-cholesterol acyltransferase (LCAT), is believed to play a key role in reverse cholesterol transport. However, recent investigations have demonstrated that higher LCAT activity levels increase the formation of triglyceride (TG)-rich lipoproteins (TRLs) and atherogenesis. We hypothesized that higher LCAT activity measured as a serum cholesterol esterification rate by the endogenous substrate method might increase the formation of TRLs and thereby alter low-density lipoprotein (LDL) heterogeneity. The estimated LDL particle size [relative LDL migration (LDL-Rm)] was measured by polyacrylamide gel electrophoresis with the LipoPhor system (Joko, Tokyo, Japan) in 538 consecutive patients with at least risk factor for atherosclerosis. Multivariate regression analysis after adjustments for traditional risk factors identified elevated TRL-related marker (TG, remnant-like particle cholesterol, apolipoprotein C-II, and apolipoprotein C-III) levels as independent predictors of smaller-sized LDL particle size, both in the overall subject population and in the subset of patients with serum LDL cholesterol levels of LDL-Rm value of ≥0.40, which suggests the presence of large amounts of small-dense LDL. The results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in LDL particle size. Therefore, to reduce the risk of atherosclerotic cardiovascular disease, it may be of importance to pay attention not only to a quantitative change in the serum LDL-C, but also to the LCAT activity which is possibly associated with LDL heterogeneity.

  3. Effect of vitamin supplementation on serum oxidized low-density lipoprotein levels in male subjects with cardiovascular disease risk factors.

    Science.gov (United States)

    Najafpour Boushehri, Saeid; Yusof, Rokiah Mohammad; Nasir Mohammad Taib, Mohammad; Mirzaei, Kamran; Yazdekhasti, Narges; Akbarzadeh, Samad

    2012-07-01

    Oxidized low-density lipoproteins (ox-LDLs) appear to play a significant role in atherogenesis. In fact, circulating ox-LDL concentrations have been recognized as a risk factor for cardiovascular disease (CVD). The main objectives of this study were to assess the effects of antioxidant vitamins on ox-LDL as a biomarker of CVD in male subjects with CVD risk factors. The effect of antioxidant vitamins on ox-LDL as a biomarker of CVD in male subjects with CVD in male subjects with CVD risk factors at baseline and after 12 weeks of supplementation with vitamin E (400 IU), C (500 mg), ß-carotene (15 mg), and the combined supplements (E, C, and ß-carotene) respectively defined as group E, C, B and control group was considered as group P. The mean values for ox-LDL at the baseline were 86.93 ± 26.30 U/l in group C, 94.52 ± 38.40 U/l in group E, 79.73±2.07 U/l in group B, 85.97±23.07 U/l in combined group, and 84.90± 14.66 U/l in group P. After 12 weeks of intervention the percentage of changes for group C, group E, group B, COM group, and group P were (-18.32), (-2286), (-17.31), (-19.01) and (-2.0), respectively. Using Wilcoxon method, significant differences were detected in the mean ox-LDL concentrations of baseline and after intervention, values in the C, E, B and combined groups (PLDL levels.

  4. Hydrolysis of lipoproteins by sPLA2's enhances mitogenesis and eicosanoid release from vascular smooth muscle cells: Diverse activity of sPLA2's IIA, V and X.

    Science.gov (United States)

    Pruzanski, Waldemar; Kopilov, Julia; Kuksis, Arnis

    2016-01-01

    Mitogenesis of Vascular Smooth Muscle Cells (VSMC) plays an important role in atherogenesis. Until recently, the effect of lipid subfractions has not been clarified. Secretory phospholipases A2 (sPLA2's) hydrolyse glycerophospholipids and release pro-inflammatory lyso-lipids, oxidized and non-oxidized fatty acids and isoprostanes. They localize in the vascular wall. We hypothesized that structurally similar sPLA2's may exert different impact on VSMC. The influence of sPLA2's, IIA, V, X, HDL, LDL, and hydrolysis products was tested on mitogenesis of VSMC, i.e., the early effect on the cell membrane phospholipids, and on PGE2 and LTB4 release, i.e., late effect of Cyclooxygenase and 5-lipooxygenase activity in VSMC. Mitogenesis was significantly enhanced by HDL and LDL, and by products of sPLA2 hydrolysis. Hydrolysis of HDL or LDL enhanced mitogenic activity in order V>X>IIA. The release of PGE2 was enhanced by group X sPLA2 and by HDL hydrolyzed by groups V and X. LDL and its hydrolysis products enhanced the release of PGE2 in order X>V>IIA. The release of LTB4 was markedly increased by LDL and HDL, and by hydrolytic products of group V and X, but not group IIA sPLA2. Our study demonstrates a diverse interaction of pro-inflammatory sPLA2's with HDL and LDL affecting both mitogenesis and eicosanoid release from VSMC, therefore potentially enhancing their pro-atherogenic activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Development of a liquid chromatography-mass spectrometry based enzyme activity assay for phosphatidylcholine-specific phospholipase C.

    Science.gov (United States)

    Murakami, Chiaki; Mizuno, Satoru; Kado, Sayaka; Sakane, Fumio

    2017-06-01

    Phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) hydrolyzes PC to generate the second messenger 1,2-diacylglycerol (DG) and phosphocholine. PC-PLC plays pivotal roles in inflammation, carcinogenesis, tumor progression, atherogenesis, and subarachnoid hemorrhage. Although the activity of PC-PLC in mammalian tissues was discovered approximately 40 years ago, neither the protein nor its gene has been identified. In the present study, we developed a non-radioactive enzyme activity assay for PC-PLC based on mass spectrometric detection of DG following HPLC separation. This new liquid chromatography-mass spectrometry (LC-MS) assay directly determines a specific reaction product, 1-palmitoyl-2-oleoyl-DG, that is generated from 1-palmitoyl-2-oleoyl-PC by purified Bacillus cereus PC-PLC. The LC-MS assay offers several advantages including a lower background (0.02% versus 91%), higher signal background ratio (4242 versus 1.06)/signal noise ratio (7494 versus 4.4), higher sensitivity (≥32-fold), and lower limit of quantitation (0.04 pmol versus 0.69 pmol of PC-PLC), than a conventional fluorometric assay, which indirectly detects phosphocholine produced in the reaction. In addition to Bacillus cereus PC-PLC, the LC-MS assay was applicable to the measurement of mammalian PC-PLC prepared from the mouse brain. The radioisotope-free, highly sensitive and precise LC-MS assay for PC-PLC would be useful for the purification and identification of PC-PLC protein. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Clinical and genetic correlates of soluble P-selectin in the community.

    Science.gov (United States)

    Lee, D S; Larson, M G; Lunetta, K L; Dupuis, J; Rong, J; Keaney, J F; Lipinska, I; Baldwin, C T; Vasan, R S; Benjamin, E J

    2008-01-01

    P-selectin is a cell adhesion molecule that is involved in atherogenesis, and soluble concentrations of this biomarker reflect cardiovascular risk. However, the clinical correlates and genetic characterization of soluble P-selectin have not been clearly elucidated. To describe clinical and genetic correlates of circulating P-selectin in the community. In Framingham Heart Study Offspring (European descent) and Omni (ethnic/racial minority) participants, we examined the association of cardiovascular risk factors with soluble P-selectin concentrations. In Offspring participants, we evaluated heritability, linkage and association of 29 SELP single-nucleotide polymorphisms (SNPs) with adjusted P-selectin concentrations. In multivariable analysis of 3,690 participants (54% women, mean age 60 +/- 10 years), higher log-transformed P-selectin concentrations were inversely associated with female sex and hormone replacement therapy, and positively associated with age, ethnic/racial minority status, cigarette smoking, waist circumference, systolic blood pressure, fasting glucose, and total/high-density lipoprotein cholesterol and triglyceride concentrations. Clinical factors explained 10.4% of the interindividual variability in P-selectin concentrations. In 571 extended pedigrees (n = 1,841) with >or= 2 phenotyped members per family, multivariable-adjusted heritability was 45.4 +/- 5.8%. Among the SELP SNPs examined, a non-synonymous SNP (rs6136) encoding a threonine-to-proline substitution at position 715 was highly significantly associated with decreased P-selectin concentrations (P = 5.2 x 10(-39)), explaining 9.7% of variation after adjustment for clinical factors. Multiple clinical factors and an SNP in the SELP gene were significantly associated with circulating P-selectin concentrations. One SNP in SELP explained significant variation in circulating P-selectin concentrations, even after accounting for known clinical correlates.

  7. Uric acid level and its association with carotid intima-media thickness in patients with hypertension.

    Science.gov (United States)

    Tavil, Yusuf; Kaya, Mehmet Güngör; Oktar, Suna Ozhan; Sen, Nihat; Okyay, Kaan; Yazici, Hüseyin Uğur; Cengel, Atiye

    2008-03-01

    Carotid intima-media thickness (C-IMT) measured noninvasively by ultrasonography is now widely used as a surrogate marker for atherosclerotic disease and directly associated with increased risk of cardiovascular disease. Hyperuricemia (HU) is a well recognized risk factor for cardiovascular diseases. The independence of this association from other confounding factors has remained controversial. But the possible contributory effect of HU to carotid intima-media thickness (C-IMT) produced by hypertension (HT) has not been clarified yet. The study was designed to assess the C-IMT in patients with hypertension (HT) with or without HU. The study participants consisted of 30 patients (men 60%, mean age+/-S.D.: 49+/-11 years) with HT without HU, and 25 patients with HT and HU (men 52%, mean age+/-S.D.: 52+/-12 years), and 25 age-matched healthy control subjects (men 56%, mean age+/-S.D.: 50+/-13 years). All study groups were examined by B-mode ultrasound to measure the C-IMT at the far wall of the common carotid artery. C-IMT were significantly higher in the patient groups (HT without HU and HT with HU) compared to the control cases (0.70+/-0.14, 0.83+/-0.16 versus 0.57+/-0.16, mm, respectively, p<0.001). In the patients groups, patients with HU had significantly higher carotid IMT compared to the patients without HU. In stepwise linear regression analysis, we found that serum uric acid (SUA) levels independently but modestly associated with C-IMT (beta=0.42, p=0.002). We have shown that higher SUA levels are associated with atherogenesis independent from hypertension. Prospective studies will be necessary to confirm and extend these findings including early screening for hyperuricemia and lowering of SUA level looking at potential benefits in slowing progression of C-IMT in hypertensive patients.

  8. Flavan-3-ol-enriched dark chocolate and white chocolate improve acute measures of platelet function in a gender-specific way--a randomized-controlled human intervention trial.

    Science.gov (United States)

    Ostertag, Luisa M; Kroon, Paul A; Wood, Sharon; Horgan, Graham W; Cienfuegos-Jovellanos, Elena; Saha, Shikha; Duthie, Garry G; de Roos, Baukje

    2013-02-01

    We examined whether flavan-3-ol-enriched dark chocolate, compared with standard dark and white chocolate, beneficially affects platelet function in healthy subjects, and whether this relates to flavan-3-ol bioavailability. A total of 42 healthy subjects received an acute dose of flavan-3-ol-enriched dark, standard dark or white chocolate, in random order. Blood and urine samples were obtained just before and 2 and 6 h after consumption for measurements of platelet function, and bioavailability and excretion of flavan-3-ols. Flavan-3-ol-enriched dark chocolate significantly decreased adenosine diphosphate-induced platelet aggregation and P-selectin expression in men (all p ≤ 0.020), decreased thrombin receptor-activating peptide-induced platelet aggregation and increased thrombin receptor-activating peptide-induced fibrinogen binding in women (both p ≤ 0.041), and increased collagen/epinephrine-induced ex vivo bleeding time in men and women (p ≤ 0.042). White chocolate significantly decreased adenosine diphosphate-induced platelet P-selectin expression (p = 0.002) and increased collagen/epinephrine-induced ex vivo bleeding time (p = 0.042) in men only. Differences in efficacy by which flavan-3-ols affect platelet function were only partially explained by concentrations of flavan-3-ols and their metabolites in plasma or urine. Flavan-3-ols in dark chocolate, but also compounds in white chocolate, can improve platelet function, dependent on gender, and may thus beneficially affect atherogenesis. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Population-based study of blood biomarkers in prediction of sub-acute recurrent stroke

    Science.gov (United States)

    Segal, Helen C; Burgess, Annette I; Poole, Debbie L; Mehta, Ziyah; Silver, Louise E; Rothwell, Peter M

    2017-01-01

    Background and purpose Risk of recurrent stroke is high in the first few weeks after TIA or stroke and clinic risk prediction tools have only limited accuracy, particularly after the hyper-acute phase. Previous studies of the predictive value of biomarkers have been small, been done in selected populations and have not concentrated on the acute phase or on intensively treated populations. We aimed to determine the predictive value of a panel of blood biomarkers in intensively treated patients early after TIA and stroke. Methods We studied 14 blood biomarkers related to inflammation, thrombosis, atherogenesis and cardiac or neuronal cell damage in early TIA or ischaemic stroke in a population-based study (Oxford Vascular Study). Biomarker levels were related to 90-day risk of recurrent stroke as Hazard Ratio (95%CI) per decile increase, adjusted for age and sex. Results Among 1292 eligible patients there were 53 recurrent ischaemic strokes within 90 days. There were moderate correlations (r>0.40; pstroke were weak, with significant associations limited to Interleukin-6 (HR=1.12, 1.01-1.24; p=0.035) and C-reactive protein (1.16, 1.02-1.30; p=0.019). When stratified by type of presenting event, P-selectin predicted stroke after TIA (1.31, 1.03-1.66; p=0.028) and C-reactive protein predicted stroke after stroke (1.16, 1.01-1.34; p=0.042). These associations remained after fully adjusting for other vascular risk factors. Conclusion In the largest study to date, we found very limited predictive utility for early recurrent stroke for a panel of inflammatory, thrombotic and cell damage biomarkers. PMID:25158774

  10. Prognostic value of metabolic syndrome for the development of cardiovascular disease in a cohort of premenopausal women with systemic lupus erythematosus.

    Science.gov (United States)

    García-Villegas, Elsy Aidé; Lerman-Garber, Israel; Flores-Suárez, Luis Felipe; Aguilar-Salinas, Carlos; Márquez González, Horacio; Villa-Romero, Antonio Rafael

    2015-04-08

    Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease of unknown etiology. In lupus patients there is an increased cardiovascular risk due to an accelerated atherogenesis. Furthermore, Metabolic Syndrome (MS) adds an independent risk for developing Cardiovascular Disease (CVD) in the population. Therefore, it is important to determine whether lupus patients have an increased risk of developing Cardiovascular Disease in the presence of MS. To estimate the prognostic value of MS in the incidence of cardiovascular events in a cohort of premenopausal patients with SLE. Cohort study in 238 patients was carried out. Clinical, biochemical, dietetic and anthropometric evaluations were performed. Patients were classified according to the prevalence of MS in 2001. There was a patient follow-up from 2001 to 2008. In 2008, after studying the records, we obtained the "cases" (patients with CVD) and the "no cases" (patients without CVD). The basal prevalence of MS in the cohort was of 21.8% (ATPIII). The MS component with the highest prevalence in the population studied in 2001 was low HDL-Cholesterol (<50mg/dL) with a prevalence of 55.0%. The cumulative incidence of CVD in the group with MS was 17.3% and in the group without MS it was 7.0% with a Relative Risk (RR) of 2.48 (1.12-5.46) and p<0.05. In the multivariable analysis it was noted that MS is a predictive factor of CVD. We observed the prognostic value of MS for an increased risk of cardiovascular damage in premenopausal patients with lupus. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  11. Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype.

    Science.gov (United States)

    Yamamoto, Suguru; Zhong, Jiayong; Yancey, Patricia G; Zuo, Yiqin; Linton, MacRae F; Fazio, Sergio; Yang, Haichun; Narita, Ichiei; Kon, Valentina

    2015-09-01

    Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model. Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response. UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p losartan was more effective than losartan alone in dampening lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change. Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Dual Peroxisome Proliferator-Activated Receptor-alpha/gamma Agonists : In the Treatment of Type 2 Diabetes Mellitus and the Metabolic Syndrome.

    Science.gov (United States)

    Pershadsingh, Harrihar A

    2006-01-01

    The metabolic syndrome consists of a combination of cardiovascular risk factors that include hyperglycemia with or without type 2 diabetes mellitus, visceral obesity, elevated blood pressure, and atherogenic dyslipidemia. These interrelated disorders and their associated lipotoxicity, oxidative stress, and inflammatory state predispose to a constellation of cardiovascular conditions leading to high risk of heart attack, stroke, renal failure, blindness, and lower extremity amputation. Visceral obesity, a prime risk factor for type 2 diabetes and a major component of the metabolic syndrome, potentiates atherogenesis, atherosclerosis, organ lipotoxicity, and oxidative tissue damage.Peroxisome proliferator-activated receptors (PPARs) are relatively recently discovered nuclear transcription factors that are modulated by dietary fatty acids, including the essential polyunsaturated fatty acids, arachidonic acid and its metabolites, and are essential to the control of energy metabolism. Of the three PPAR isoforms (alpha, gamma, and delta), synthetic pharmaceutical ligands that activate PPARalpha (the antidyslipidemic fibric acid derivatives ['fibrates']) and PPARgamma (the antidiabetic thiazolidinediones) have been studied extensively. Recently developed dual PPARalpha/gamma agonists may combine the therapeutic effects of these drugs, creating the expectation of greater efficacy, and perhaps other advantages in the treatment of type 2 diabetes and the metabolic syndrome. However, thiazolidinediones are hampered by adverse effects related to increased weight gain and fluid overload. It remains to be seen whether the dual PPARalpha/gamma agonists currently under development have similar limitations. Nevertheless, existing clinical data imply that the combined effects of thiazolidinediones and fibrates are likely to be emulated by dual PPARalpha/gamma agonists, providing superior efficacy to these classes for the treatment of type 2 diabetes, the metabolic syndrome, and

  13. Effect of ACAT inhibition on the progression of coronary atherosclerosis.

    Science.gov (United States)

    Nissen, Steven E; Tuzcu, E Murat; Brewer, H Bryan; Sipahi, Ilke; Nicholls, Stephen J; Ganz, Peter; Schoenhagen, Paul; Waters, David D; Pepine, Carl J; Crowe, Tim D; Davidson, Michael H; Deanfield, John E; Wisniewski, Lisa M; Hanyok, James J; Kassalow, Laurent M

    2006-03-23

    The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects. We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. The primary efficacy variable analyzing the progression of atherosclerosis--the change in percent atheroma volume--was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (-5.6 mm3, P=0.001) but not in the pactimibe group (-1.3 mm3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53). For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515.). Copyright 2006 Massachusetts Medical Society.

  14. Cellular pathology of atherosclerosis: smooth muscle cells promote adhesion of platelets to cocultured endothelial cells.

    Science.gov (United States)

    Tull, Samantha P; Anderson, Steve I; Hughan, Sascha C; Watson, Steve P; Nash, Gerard B; Rainger, G Ed

    2006-01-06

    Although platelets do not ordinarily bind to endothelial cells (EC), pathological interactions between platelets and arterial EC may contribute to the propagation of atheroma. Previously, in an in vitro model of atherogenesis, where leukocyte adhesion to EC cocultured with smooth muscle cells was greatly enhanced, we also observed attachment of platelets to the EC layer. Developing this system to specifically model platelet adhesion, we show that EC cocultured with smooth muscle cells can bind platelets in a process that is dependent on EC activation by tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1. Recapitulating the model using EC alone, we found that a combination of TGF-beta1 and TNF-alpha promoted high levels of platelet adhesion compared with either agent used in isolation. Platelet adhesion was inhibited by antibodies against GPIb-IX-V or alpha(IIb)beta3 integrin, indicating that both receptors are required for stable adhesion. Platelet activation during interaction with the EC was also essential, as treatment with prostacyclin or theophylline abolished stable adhesion. Confocal microscopy of the surface of EC activated with TNF-alpha and TGF-beta1 revealed an extensive matrix of von Willebrand factor that was able to support the adhesion of flowing platelets at wall shear rates below 400 s(-1). Thus, we have demonstrated a novel route of EC activation which is relevant to the atherosclerotic microenvironment. EC activated in this manner would therefore be capable of recruiting platelets in the low-shear environments that commonly exist at points of atheroma formation.

  15. Endothelial RIG-I activation impairs endothelial function.

    Science.gov (United States)

    Asdonk, Tobias; Motz, Inga; Werner, Nikos; Coch, Christoph; Barchet, Winfried; Hartmann, Gunther; Nickenig, Georg; Zimmer, Sebastian

    2012-03-30

    Endothelial dysfunction is a crucial part of the chronic inflammatory atherosclerotic process and is mediated by innate and acquired immune mechanisms. Recent studies suggest that pattern recognition receptors (PRR) specialized in immunorecognition of nucleic acids may play an important role in endothelial biology in a proatherogenic manner. Here, we analyzed the impact of endothelial retinoic acid inducible gene I (RIG-I) activation upon vascular endothelial biology. Wild type mice were injected intravenously with 32.5 μg of the RIG-ligand 3pRNA (RNA with triphosphate at the 5'end) or polyA control every other day for 7 days. In 3pRNA-treated mice, endothelium-depended vasodilation was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticle (EMP) numbers significantly elevated compared to controls. To gain further insight in RIG-I dependent endothelial biology, cultured human coronary endothelial cells (HCAEC) and endothelial progenitor cells (EPC) were stimulated in vitro with 3pRNA. Both cells types express RIG-I and react with receptor upregulation upon stimulation. Reactive oxygen species (ROS) formation is enhanced in both cell types, whereas apoptosis and proliferation is not significantly affected in HCAEC. Importantly, HCAEC release significant amounts of proinflammatory cytokines in response to RIG-I stimulation. This study shows that activation of the cytoplasmatic nucleic acid receptor RIG-I leads to endothelial dysfunction. RIG-I induced endothelial damage could therefore be an important pathway in atherogenesis. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. [Low-grade systemic inflammation and the development of metabolic diseases: from the molecular evidence to the clinical practice].

    Science.gov (United States)

    León-Pedroza, José Israel; González-Tapia, Luis Alonso; del Olmo-Gil, Esteban; Castellanos-Rodríguez, Diana; Escobedo, Galileo; González-Chávez, Antonio

    2015-01-01

    Systemic inflammation is characterised by high circulating levels of inflammatory cytokines and increased macrophage infiltration in peripheral tissues. Most importantly, this inflammatory state does not involve damage or loss of function of the infiltrated tissue, which is a distinctive feature of the low-grade systemic inflammation. The term "meta-inflammation" has also been used to refer to the low-grade systemic inflammation due to its strong relationship with the development of cardio-metabolic diseases in obesity. A review is presented on the recent clinical and experimental evidence concerning the role of adipose tissue inflammation as a key mediator of low-grade systemic inflammation. Furthermore, the main molecular mechanisms involved in the inflammatory polarization of macrophages with the ability to infiltrate both the adipose tissue and the vascular endothelium via activation of toll-like receptors by metabolic damage-associated molecular patterns, such as advanced glycation-end products and oxidized lipoproteins, is discussed. Finally, a review is made of the pathogenic mechanisms through which the low-grade systemic inflammation contributes to develop insulin resistance, dyslipidaemia, atherogenesis, type 2 diabetes, and hypertension in obese individuals. A better understanding of the molecular mechanisms of low-grade systemic inflammation in promoting cardio-metabolic diseases is necessary, in order to further design novel anti-inflammatory therapies that take into consideration clinical data, as well as the circulating levels of cytokines, immune cells, and metabolic damage-associated molecular patterns in each patient. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  17. Picrorhiza scrophulariiflora improves accelerated atherosclerosis through inhibition of redox-sensitive inflammation.

    Science.gov (United States)

    Guo, Zhi Jian; Hou, Fan Fan; Liu, Shang Xi; Tian, Jian Wei; Zhang, Wei Ru; Xie, Di; Zhou, Zhan Mei; Liu, Zhi Qiang; Zhang, Xun

    2009-08-21

    Accumulation of advanced glycation end products (AGEs) or advanced oxidation protein products (AOPPs) has been identified as a risk factor for accelerated atherosclerosis seen in diabetes and chronic kidney disease. However, little is known about the intervention for atherogenesis associated with these oxidized proteins. The rhizome of Picrorhiza scrophulariiflora (PS) has long been used to treat inflammatory diseases as a traditional medication. The study was performed to test the hypothesis that ethanol extraction of PS (EPS) may improve AGEs- or AOPPs-induced accelerated atherosclerosis in vivo. Hypercholesterolemic or normal rabbits were randomly assigned to 8 groups treated with intravenous injection of AGEs- or AOPPs-modified rabbit serum albumin (AGEs-RSA or AOPPs-RSA), unmodified RSA or vehicle in the presence or absence of EPS (10 mg/kg/2 days) gavage for 10 weeks. Compared with hypercholesterolemic rabbits without EPS treatment, EPS administration significantly decreased the aortic plaque volume and oxidized low density lipoprotein (Ox-LDL) deposition in hypercholesterolemic animals. This was accompanied by significant histological improvement including decrease of intimal and smooth muscle cell proliferation and macrophage influx in affected areas. EPS administration almost completely abolished the accelerated atherosclerosis induced by chronic treatment of AGEs- or AOPPs-RSA in both hypercholesterolemic and normal rabbits. EPS administration significantly restored the AGEs- or AOPPs-induced redox imbalance and inflammation, evidenced by decrease of plasma Ox-LDL, thiobarbituric acid reactive substances and TNF-alpha, and increase of glutathione peroxidase activity. These data suggested that EPS may improve atherosclerosis, particularly that induced by AGEs or AOPPs, through inhibition of redox-sensitive inflammation.

  18. Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells

    Science.gov (United States)

    Indrakusuma, Ira; Romacho, Tania; Eckel, Jürgen

    2017-01-01

    Background: Obesity is associated with impaired vascular function. In the cardiovascular system, protease-activated receptor 2 (PAR2) exerts multiple functions such as the control of the vascular tone. In pathological conditions, PAR2 is related to vascular inflammation. However, little is known about the impact of obesity on PAR2 in the vasculature. Therefore, we explored the role of PAR2 as a potential link between obesity and cardiovascular diseases. Methods: C57BL/6 mice were fed with either a chow or a 60% high fat diet for 24 weeks prior to isolation of aortas. Furthermore, human coronary artery endothelial cells (HCAEC) and human coronary smooth muscle cells (HCSMC) were treated with conditioned medium obtained from in vitro differentiated primary human adipocytes. To investigate receptor interaction vascular endothelial growth factor receptor 2 (VEGFR2) was blocked by exposure to calcium dobesilate and a VEGFR2 neutralization antibody, before treatment with PAR2 activating peptide. Student's t-test or one-way were used to determine statistical significance. Results: Both, high fat diet and exposure to conditioned medium increased PAR2 expression in aortas and human vascular cells, respectively. In HCSMC, conditioned medium elicited proliferation as well as cyclooxygenase 2 induction, which was suppressed by the PAR2 antagonist GB83. Specific activation of PAR2 by the PAR2 activating peptide induced proliferation and cyclooxygenase 2 expression which were abolished by blocking the VEGFR2. Additionally, treatment of HCSMC with the PAR2 activating peptide triggered VEGFR2 phosphorylation. Conclusion: Under obesogenic conditions, where circulating levels of pro-inflammatory adipokines are elevated, PAR2 arises as an important player linking obesity-related adipose tissue inflammation to atherogenesis. We show for the first time that the underlying mechanisms of these pro-atherogenic effects involve a potential transactivation of the VEGFR2 by PAR2. PMID

  19. Mass transport properties of the rabbit aortic wall.

    Directory of Open Access Journals (Sweden)

    Emma L Bailey

    Full Text Available Uptake of circulating macromolecules by the arterial wall may be a critical step in atherogenesis. Here we investigate the age-related changes in patterns of uptake that occur in the rabbit. In immature aortas, uptake was elevated in a triangle downstream of branch ostia, a region prone to disease in immature rabbits and children. By 16-22 months, uptake was high lateral to ostia, as is lesion prevalence in mature rabbits and young adults. In older rabbits there was a more upstream pattern, similar to the disease distribution in older people. These variations were predominantly caused by the branches themselves, rather than reflecting larger patterns within which the branches happened to be situated (as may occur with patterns of haemodynamic wall shear stress. The narrow streaks of high uptake reported in some previous studies were shown to be post mortem artefacts. Finally, heparin (which interferes with the NO pathway had no effect on the difference in uptake between regions upstream and downstream of branches in immature rabbits but reversed the difference in older rabbits, as does inhibiting NO synthesis directly. Nevertheless, examination of uptake all around the branch showed that changes occurred at both ages and that they were quite subtle, potentially explaining why inhibiting NO has only minor effects on lesion patterns in mature rabbits and contradicting the earlier conclusion that mechanotransduction pathways change with age. We suggest that recently-established changes in the patterns of haemodynamic forces themselves are more likely to account for the age-dependence of uptake patterns.

  20. Oxidation modifies the structure and function of the extracellular matrix generated by human coronary artery endothelial cells.

    Science.gov (United States)

    Chuang, Christine Y; Degendorfer, Georg; Hammer, Astrid; Whitelock, John M; Malle, Ernst; Davies, Michael J

    2014-04-15

    ECM (extracellular matrix) materials, such as laminin, perlecan, type IV collagen and fibronectin, play a key role in determining the structure of the arterial wall and the properties of cells that interact with the ECM. The aim of the present study was to investigate the effect of peroxynitrous acid, an oxidant generated by activated macrophages, on the structure and function of the ECM laid down by HCAECs (human coronary artery endothelial cells) in vitro and in vivo. We show that exposure of HCAEC-derived native matrix components to peroxynitrous acid (but not decomposed oxidant) at concentrations >1 μM results in a loss of antibody recognition of perlecan, collagen IV, and cell-binding sites on laminin and fibronectin. Loss of recognition was accompanied by decreased HCAEC adhesion. Real-time PCR showed up-regulation of inflammation-associated genes, including MMP7 (matrix metalloproteinase 7) and MMP13, as well as down-regulation of the laminin α2 chain, in HCAECs cultured on peroxynitrous acid-treated matrix compared with native matrix. Immunohistochemical studies provided evidence of co-localization of laminin with 3-nitrotyrosine, a biomarker of peroxynitrous acid damage, in type II-III/IV human atherosclerotic lesions, consistent with matrix damage occurring during disease development in vivo. The results of the present study suggest a mechanism through which peroxynitrous acid modifies endothelial cell-derived native ECM proteins of the arterial basement membrane in atherosclerotic lesions. These changes to ECM and particularly perlecan and laminin may be important in inducing cellular dysfunction and contribute to atherogenesis.

  1. Lymphatic vessels: an emerging actor in atherosclerotic plaque development.

    Science.gov (United States)

    Kutkut, Issa; Meens, Merlijn J; McKee, Thomas A; Bochaton-Piallat, Marie-Luce; Kwak, Brenda R

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease of large- to medium-sized arteries and is the main underlying cause of death worldwide. The lymphatic vasculature is critical for processes that are intimately linked to atherogenesis such as the immune response and cholesterol metabolism. However, whether lymphatic vessels truly contribute to the pathogenesis of atherosclerosis is less clear despite increasing research efforts in this field. PubMed and Ovid MEDLINE databases were searched. In addition, key review articles were screened for relevant original publications. Current knowledge about lymphatic vessels in the arterial wall came from studies that examined the presence and location of such vessels in human atherosclerotic plaque specimens, as well as in a variety of arteries in animal models for atherosclerosis (e.g. rabbits, dogs, rats and mice). Generally, three experimental approaches have been used to investigate the functional role of plaque-associated lymphatic vessels; experimental lymphostasis was used to investigate lymphatic drainage of the arterial wall, and more recently, studies with genetic interventions and/or surgical transplantation have been performed. Lymphatic vessels seem to be mostly present in the adventitial layer of the arterial walls of animals and humans. They are involved in reverse cholesterol transport from atherosclerotic lesions, and arteries with a dense lymphatic network seem naturally protected against atherosclerosis. Lymphangiogenesis is a process that is an important part of the inflammatory loop in atherosclerosis. However, how augmenting or impeding the distribution of lymphatic vessels impacts disease progression remains to be investigated in future studies. © 2014 Stichting European Society for Clinical Investigation Journal Foundation.

  2. Serum matrix metalloproteinases MMP-2 and MMP-3 levels in dialysis patients vary independently of CRP and IL-6 levels.

    Science.gov (United States)

    Preston, Gloria A; Barrett, Cheri V; Alcorta, David A; Hogan, Susan L; Dinwiddie, Lesley; Jennette, J Charles; Falk, Ronald J

    2002-12-01

    Patients on chronic hemodialysis or peritoneal dialysis often develop an inflammatory state that causes morbidity and mortality. Cross-sectional studies of dialysis patients have determined that C-reactive protein (CRP) is a predictor of morbidity. Little is known as to whether CRP, cytokines, such as IL-6 and IL-1beta that stimulate the synthesis of CRP, or matrix metalloproteinases (MMPs) are markers of inflammation in patients on dialysis. We assayed by ELISA serum levels of MMP-2, MMP-3, IL-6 and CRP in healthy individuals and in patients with pre-end-stage renal disease (pESRD, n = 10), peritoneal dialysis (PD, n = 11), hemodialysis (HD, n = 17) and renal transplant (TX, n = 10). MMP-2 was significantly elevated before dialysis, perhaps indicative of progressive chronic renal sclerosis. MMP-3 was markedly elevated in hemodialysis patients but not in pESRD or PD patients, and may be related to the hemodialysis process and/or accelerated atherogenesis in these patients. IL-6 was significantly elevated in all patient groups, including pESRD patients. There were no statistically significant differences in CRP levels among the study groups. CRP correlated with IL-6, but not with MMP-2 or MMP-3. The data indicate that there are measurable differences in the expression of MMPs within the dialysis patient population. Because dialysis can be associated with local and systemic inflammation, increased levels of MMP-3 in the hemodialysis group may be a reflection of gene stimulation induced by inflammatory cytokines and should be considered as a marker of chronic, local inflammation. Copyright 2002 S. Karger AG, Basel

  3. Asymptomatic carotid plaque and pro-inflammatory genetic profile in the elderly.

    Science.gov (United States)

    Annoni, Giorgio; Annoni, Federico; Arosio, Beatrice; Viazzoli, Chiara; Segato, Elena; Lucchi, Tiziano; Vergani, Carlo

    2009-12-01

    Several indices of subclinical atherosclerosis (ATS), including ultrasound (US) scan of carotid vessels, have received attention in clinical studies of the general population. Since inflammation takes part in the development of ATS, we studied the relationship between US imaging of carotid vessels and genetic predisposition to inflammation, in both elderly subjects without acknowledged CV risk factors and elderly subjects with acknowledged CV risk factors undergoing primary prevention. Seventy-two elderly subjects (aged between 65-84) were divided into three groups on the basis of cardiovascular (CV) risk (G0: 0-9%, G1: 10-20% and G2: >20%) according to the NCEP Adult Panel III Report. They underwent US evaluation of carotid arteries and were analyzed for single nucleotide polymorphisms in the genes of a number of cytokines: TNF-alpha, TGF-beta1, IL-10, IL-6 and IFN-gamma. Asymptomatic carotid plaque (ACP) was detected in 19 subjects, not only in those belonging to the major risk group (36.8%) but also in those at lower risk (63.2%). In these subjects, we found a different genotype distribution in the polymorphisms of IFN-gamma (+874), IL-6 (-174) and IL- 10 (-1082). The TT +874 IFN-gamma and GG -174 IL-6 high producer-genotypes and the AA IL-10 low producergenotype were indeed more frequent in the ACP group (IFN-gamma: p=0.000 and IL-6: p=0.004). We found no correlation between genotype and carotid intima-media thickening. Our data suggest that, in the elderly, inflammation-associated polymorphisms are related to atherogenesis and that the finding of ACP on US scan can be valuable in identifying subjects at risk for CV events, even if they lack traditional cardiovascular risk factors such as an increase in IMT.

  4. Dyslipidemic Diet-Induced Monocyte “Priming” and Dysfunction in Non-Human Primates Is Triggered by Elevated Plasma Cholesterol and Accompanied by Altered Histone Acetylation

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    John D. Short

    2017-08-01

    Full Text Available Monocytes and the recruitment of monocyte-derived macrophages into sites of inflammation play a key role in atherogenesis and other chronic inflammatory diseases linked to cardiometabolic syndrome and obesity. Previous studies from our group have shown that metabolic stress promotes monocyte priming, i.e., enhanced adhesion and accelerated chemotaxis of monocytes in response to chemokines, both in vitro and in dyslipidemic LDLR−/− mice. We also showed that metabolic stress-induced monocyte dysfunction is, at least to a large extent caused by the S-glutathionylation, inactivation, and subsequent degradation of mitogen-activated protein kinase phosphatase 1. Here, we analyzed the effects of a Western-style, dyslipidemic diet (DD, which was composed of high levels of saturated fat, cholesterol, and simple sugars, on monocyte (dysfunction in non-human primates (NHPs. We found that similar to mice, a DD enhances monocyte chemotaxis in NHP within 4 weeks, occurring concordantly with the onset of hypercholesterolemia but prior to changes in triglycerides, blood glucose, monocytosis, or changes in monocyte subset composition. In addition, we identified transitory decreases in the acetylation of histone H3 at the lysine residues 18 and 23 in metabolically primed monocytes, and we found that monocyte priming was correlated with the acetylation of histone H3 at lysine 27 after an 8-week DD regimen. Our data show that metabolic stress promotes monocyte priming and hyper-chemotactic responses in NHP. The histone modifications accompanying monocyte priming in primates suggest a reprogramming of the epigenetic landscape, which may lead to dysregulated responses and functionalities in macrophages derived from primed monocytes that are recruited to sites of inflammation.

  5. Uric acid as one of the important factors in multifactorial disorders – facts and controversies

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    Pasalic, Daria; Marinkovic, Natalija; Feher-Turkovic, Lana

    2012-01-01

    With considering serum concentration of the uric acid in humans we are observing hyperuricemia and possible gout development. Many epidemiological studies have shown the relationship between the uric acid and different disorders such are obesity, metabolic syndrome, hypertension and coronary artery disease. Clinicians and investigators recognized serum uric acid concentration as very important diagnostic and prognostic factor of many multifactorial disorders. This review presented few clinical conditions which are not directly related to uric acid, but the concentrations of uric acid might have a great impact in observing, monitoring, prognosis and therapy of such disorders. Uric acid is recognized as a marker of oxidative stress. Production of the uric acid includes enzyme xanthine oxidase which is involved in producing of radical-oxigen species (ROS). As by-products ROS have a significant role in the increased vascular oxidative stress and might be involved in atherogenesis. Uric acid may inhibit endothelial function by inhibition of nitric oxide-function under conditions of oxidative stress. Down regulation of nitric oxide and induction of endothelial dysfunction might also be involved in pathogenesis of hypertension. The most important and well evidenced is possible predictive role of uric acid in predicting short-term outcome (mortality) in acute myocardial infarction (AMI) patients and stroke. Nephrolithiasis of uric acid origin is significantly more common among patients with the metabolic syndrome and obesity. On contrary to this, uric acid also acts is an “antioxidant”, a free radical scavenger and a chelator of transitional metal ions which are converted to poorly reactive forms. PMID:22384520

  6. Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation.

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    Berman, Marvin D; Carey, Martin C

    2015-01-01

    Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2 plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKa values of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2 produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB. Copyright © 2015 the American Physiological Society.

  7. Anti-ApoA-1 IgG serum levels predict worse poststroke outcomes.

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    Carbone, Federico; Satta, Nathalie; Montecucco, Fabrizio; Virzi, Julien; Burger, Fabienne; Roth, Aline; Roversi, Gloria; Tamborino, Carmine; Casetta, Ilaria; Seraceni, Silva; Trentini, Alessandro; Padroni, Marina; Dallegri, Franco; Lalive, Patrice H; Mach, François; Fainardi, Enrico; Vuilleumier, Nicolas

    2016-09-01

    Autoantibodies to apolipoprotein A-1 (anti-ApoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. However, their potential relationship with clinical disability and ischaemic lesion volume after acute ischaemic stroke (AIS) remains unexplored. We included n = 76 patients admitted for AIS and we investigated whether baseline serum anti-ApoA-1 IgG levels could predict (i) AIS-induced clinical disability [assessed by the modified Rankin Scale (mRS)], and (ii) AIS-related ischaemic lesion volume [assessed by Computed Tomography (CT)]. We also evaluated the possible pro-apoptotic and pro-necrotic effects of anti-ApoA-1 IgG on human astrocytoma cell line (U251) using flow cytometry. High levels of anti-ApoA-1 IgG were retrieved in 15·8% (12/76) of patients. Increased baseline levels of anti-ApoA-1 IgG were independently correlated with worse mRS [β = 0·364; P = 0·002; adjusted odds ratio (OR): 1·05 (95% CI 1·01-1·09); P = 0·017] and CT-assessed ischaemic lesion volume [β = 0·333; P IgG. Incubating human astrocytoma cells with anti-ApoA-1 IgG dose dependently induced necrosis and apoptosis of U251 cells in vitro. Anti-ApoA-1 IgG serum levels at AIS onset are associated with poorer clinical recovery and worse brain lesion volume 3 months after AIS. These observations could be partly explained by the deleterious effect of anti-ApoA-1 IgG on human brain cell survival in vitro and may have clinical implication in the prediction of poor outcome in AIS. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

  8. Blood metabolomic fingerprint is distinct in healthy coronary and in stenosing or microvascular ischemic heart disease.

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    Deidda, Martino; Piras, Cristina; Cadeddu Dessalvi, Christian; Congia, Damiana; Locci, Emanuela; Ascedu, Federica; De Candia, Gianfranco; Cadeddu, Mauro; Lai, Giorgio; Pirisi, Raimondo; Atzori, Luigi; Mercuro, Giuseppe

    2017-05-23

    The endothelium is a key variable in the pathogenesis of atherosclerosis and its complications, particularly coronary artery disease (CAD). Current evidence suggests that the endothelial status can be regarded as an integrated index of individual atherogenic and anti-atherogenic properties, and that the interaction between circulating factors and the arterial wall might be critical for atherogenesis. In organism-level investigations, a functional view is provided by metabolomics, the study of the metabolic profile of small molecules. We sought to verify whether metabolomic analysis can reveal the presence of coronary microenvironment peculiarities associated with distinct manifestations of CAD. Thirty-two coronary blood samples were analyzed using 1H-NMR-based metabolomics. Samples collected from patients with evidence of myocardial ischemia formed the case group, and were further divided into the stenotic-disease (SD) group (N = 13) and absence of stenosis (microvascular disease; "Micro") group (N = 8); specimens of patients presenting no evidence of ischemic heart disease (dilated cardiomyopathy, valvular diseases) constituted the control group (N = 11). Application of an orthogonal partial least squares discriminant analysis (OPLS-DA) model to the entire dataset clearly separated the samples into 3 groups, indicating 3 distinct metabolic fingerprints. Relative to control-group members, Micro patients showed a higher content of 2-hydroxybutirate, alanine, leucine, isoleucine, and N-acetyl groups and lower levels of creatine/phosphocreatine, creatinine, and glucose, whereas SD patients showed higher levels of 3-hydroxybutirate and acetate and a lower content of 2-hydroxybutirate. Moreover, relative to SD patients, Micro patients showed higher levels of 2-hydroxybutirate, alanine, leucine, and N-acetyl groups and lower levels of 3-hydroxybutirate and acetate. Specific coronary microenvironments are likely associated with distinct development and pathological

  9. Perilipin1 deficiency in whole body or bone marrow-derived cells attenuates lesions in atherosclerosis-prone mice.

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    Xiaojing Zhao

    Full Text Available The objective of this study is to determine the role of perilipin 1 (Plin1 in whole body or bone marrow-derived cells on atherogenesis.Accumulated evidence have indicated the role of Plin1 in atherosclerosis, however, these findings are controversial. In this study, we showed that Plin1 was assembled and colocalized with CD68 in macrophages in atherosclerotic plaques of ApoE-/- mice. We further found 39% reduction of plaque size in the aortic roots of Plin1 and ApoE double knockout (Plin1-/-ApoE-/- females compared with ApoE-/- female littermates. In order to verify whether this reduction was macrophage-specific, the bone marrow cells from wild-type or Plin1 deficient mice (Plin1-/- were transplanted into LDL receptor deficient mice (LDLR-/-. Mice receiving Plin1-/- bone marrow cells showed also 49% reduction in aortic atherosclerotic lesions compared with LDLR-/- mice received wild-type bone marrow cells. In vitro experiments showed that Plin1-/- macrophages had decreased protein expression of CD36 translocase and an enhanced cholesterol ester hydrolysis upon aggregated-LDL loading, with unaltered expression of many other regulators of cholesterol metabolism, such as cellular lipases, and Plin2 and 3. Given the fundamental role of Plin1 in protecting LD lipids from lipase hydrolysis, it is reasonably speculated that the assembly of Plin1 in microphages might function to reduce lipolysis and hence increase lipid retention in ApoE-/- plaques, but this pro-atherosclerotic property would be abrogated on inactivation of Plin1.Plin1 deficiency in bone marrow-derived cells may be responsible for reduced atherosclerotic lesions in the mice.

  10. Prediction of calculated future cardiovascular disease by monocyte count in an asymptomatic population

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    Deirdre F Waterhouse

    2008-02-01

    Full Text Available Deirdre F Waterhouse1, Ronan A Cahill2, Frances Sheehan2, CJ McCreery11Department of Cardiovascular Medicine, St Vincent’s University Hospital, Dublin, Ireland; 2Department of Preventative Medicine, Blackrock Clinic, Dublin, IrelandIntroduction: Although atherogenesis is clearly entwined with systemic inflammation, the risk-predictive relationship between preclinical and overt cardiovascular disease (CVD and systemic white blood cell (WBC subtypes remains unclear. Implication of an association would greatly facilitate cardiac risk prediction, assessment and monitoring.Methods: 1383 asymptomatic individuals (795 men, 588 women attending for executive health screening were examined clinically as well as with phlebotomy and exercise stress testing to determine their ten-year risk of developing overt cardiovascular disease (as estimated by both Framingham and SCORE calculations. The significance of their association with overall WBC and subtypes were determined using both univariate and multiple regression modeling.Results: Of all WBC subtypes, monocyte count was found to have the strongest, independentrelationship with overall CVD risk by backwards linear regression modeling (Framingham: β = 0.057; p = 0.03; SCORE: β = 0.128; p = <0.0005. Independent associations with BMI (β = 5.214; p = <0.0005, waist circumference (β = 21.866; p = <0.0005, systolic blood pressure (β = 10.738; p = 0.003, HDL cholesterol (β = −0.639; p = <0.0005 and triglyceride concentrations (β = 0.787; p = <0.0005 were also evident. Overall WBC along with neutrophils, lymphocytes and basophil subfractions were variably (but less strongly associated with such dependents and outcome measures.Conclusions: In conclusion, monocyte count, a simple inexpensive test, may provide useful predictive cardiovascular risk information in asymptomatic individuals to inform and guide attempts at interrupting CVD development at a preclinical stage.Keywords: leukocyte, white cell count

  11. Transcript and protein analysis reveals better survival skills of monocyte-derived dendritic cells compared to monocytes during oxidative stress.

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    Ilse Van Brussel

    Full Text Available BACKGROUND: Dendritic cells (DCs, professional antigen-presenting cells with the unique ability to initiate primary T-cell responses, are present in atherosclerotic lesions where they are exposed to oxidative stress that generates cytotoxic reactive oxygen species (ROS. A large body of evidence indicates that cell death is a major modulating factor of atherogenesis. We examined antioxidant defence systems of human monocyte-derived (moDCs and monocytes in response to oxidative stress. METHODS: Oxidative stress was induced by addition of tertiary-butylhydroperoxide (tert-BHP, 30 min. Cellular responses were evaluated using flow cytometry and confocal live cell imaging (both using 5-(and-6-chloromethyl-2,7-dichlorodihydrofluorescein diacetate, CM-H(2DCFDA. Viability was assessed by the neutral red assay. Total RNA was extracted for a PCR profiler array. Five genes were selected for confirmation by Taqman gene expression assays, and by immunoblotting or immunohistochemistry for protein levels. RESULTS: Tert-BHP increased CM-H(2DCFDA fluorescence and caused cell death. Interestingly, all processes occurred more slowly in moDCs than in monocytes. The mRNA profiler array showed more than 2-fold differential expression of 32 oxidative stress-related genes in unstimulated moDCs, including peroxiredoxin-2 (PRDX2, an enzyme reducing hydrogen peroxide and lipid peroxides. PRDX2 upregulation was confirmed by Taqman assays, immunoblotting and immunohistochemistry. Silencing PRDX2 in moDCs by means of siRNA significantly increased CM-DCF fluorescence and cell death upon tert-BHP-stimulation. CONCLUSIONS: Our results indicate that moDCs exhibit higher intracellular antioxidant capacities, making them better equipped to resist oxidative stress than monocytes. Upregulation of PRDX2 is involved in the neutralization of ROS in moDCs. Taken together, this points to better survival skills of DCs in oxidative stress environments, such as atherosclerotic plaques.

  12. Endothelial RIG-I activation impairs endothelial function

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    Asdonk, Tobias, E-mail: tobias.asdonk@ukb.uni-bonn.de [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Motz, Inga; Werner, Nikos [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Coch, Christoph; Barchet, Winfried; Hartmann, Gunther [Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Nickenig, Georg; Zimmer, Sebastian [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer RIG-I activation impairs endothelial function in vivo. Black-Right-Pointing-Pointer RIG-I activation alters HCAEC biology in vitro. Black-Right-Pointing-Pointer EPC function is affected by RIG-I stimulation in vitro. -- Abstract: Background: Endothelial dysfunction is a crucial part of the chronic inflammatory atherosclerotic process and is mediated by innate and acquired immune mechanisms. Recent studies suggest that pattern recognition receptors (PRR) specialized in immunorecognition of nucleic acids may play an important role in endothelial biology in a proatherogenic manner. Here, we analyzed the impact of endothelial retinoic acid inducible gene I (RIG-I) activation upon vascular endothelial biology. Methods and results: Wild type mice were injected intravenously with 32.5 {mu}g of the RIG-ligand 3pRNA (RNA with triphosphate at the 5 Prime end) or polyA control every other day for 7 days. In 3pRNA-treated mice, endothelium-depended vasodilation was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticle (EMP) numbers significantly elevated compared to controls. To gain further insight in RIG-I dependent endothelial biology, cultured human coronary endothelial cells (HCAEC) and endothelial progenitor cells (EPC) were stimulated in vitro with 3pRNA. Both cells types express RIG-I and react with receptor upregulation upon stimulation. Reactive oxygen species (ROS) formation is enhanced in both cell types, whereas apoptosis and proliferation is not significantly affected in HCAEC. Importantly, HCAEC release significant amounts of proinflammatory cytokines in response to RIG-I stimulation. Conclusion: This study shows that activation of the cytoplasmatic nucleic acid receptor RIG-I leads to endothelial dysfunction. RIG-I induced endothelial damage could therefore be an important pathway in atherogenesis.

  13. The effect of 17β-estradiol on cholesterol content in human macrophages is influenced by the lipoprotein milieu.

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    Corcoran, Michael P; Lichtenstein, Alice H; Meydani, Mohsen; Dillard, Alice; Schaefer, Ernst J; Lamon-Fava, Stefania

    2011-08-01

    Estrogen and testosterone are thought to modulate coronary heart disease (CHD) risk. To examine how these hormones affect human macrophage cholesterol transport, a key factor in atherogenesis, we obtained monocytes from healthy male and postmenopausal female donors (age 50–70 years). Cells were allowed to differentiate in autologous serum. Human monocyte-derived macrophages (HMDMs) were exposed to estrogen, testosterone, or vehicle, during differentiation.Cells were cholesterol enriched with oxidized low-density lipoprotein (oxLDL) in the presence of treatment. Cell cholesterol mass, efflux, and the expression of proteins involved in HMDM cholesterol transport were examined.Estrogen significantly reduced cholesteryl ester (CE) content in both female and male HMDMs while having no measurable effect on cholesterol efflux. Testosterone did not affect cholesterol content or efflux. Both hormones significantly but modestly affected the gene expression of several proteins involved in HMDM transport, yet these effects did not translate into significant changes in protein expression. In THP-1 macrophages, the effect of estrogen on CE content was more potent in unloaded macrophages and was estrogen receptor dependent. A trend for a reduction in nonoxLDL uptake by estrogen was observed and was also found to be dependent upon estrogen receptor activation. Our data indicate that estrogen, but not testosterone, reduces CE accumulation in HMDMs obtained from a CHD age relevant population, independent of changes in the expression of proteins important to macrophage cholesterol transport. In THP-1 cells, this effect is reduced in the presence of oxLDL, indicating that a pro-atherogenic lipoprotein milieu is an important variable in sex hormone modulation of CHD.

  14. A Chinese Herbal Preparation Containing Radix Salviae Miltiorrhizae, Radix Notoginseng and Borneolum Syntheticum Reduces Circulating Adhesion Molecules

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    Kylie A. O’Brien

    2011-01-01

    Full Text Available Circulating adhesion molecules (CAMs, surface proteins expressed in the vascular endothelium, have emerged as risk factors for cardiovascular disease (CVD. CAMs are involved in intercellular communication that are believed to play a role in atherosclerosis. A Chinese medicine, the “Dantonic Pill” (DP (also known as the “Cardiotonic Pill”, containing three Chinese herbal material medica, Radix Salviae Miltiorrhizae, Radix Notoginseng and Borneolum Syntheticum, has been used in China for the prevention and management of CVD. Previous laboratory and animal studies have suggested that this preparation reduces both atherogenesis and adhesion molecule expression. A parallel double blind randomized placebo-controlled study was conducted to assess the effects of the DP on three species of CAM (intercellular cell adhesion molecule-1 (ICAM-1, vascular cell adhesion molecule-1 and endothelial cell selectin (E-selectin in participants with mild-moderate hypercholesterolemia. Secondary endpoints included biochemical and hematological variables and clinical effects. Forty participants were randomized to either treatment or control for 12 weeks. Treatment with DP was associated with a statistically significant decrease in ICAM-1 (9% decrease, P = .03 and E-Selectin (15% decrease, P = .004. There was no significant change in renal function tests, liver function tests, glucose, lipids or C-reactive protein levels and clinical adverse effects did not differ between the active and the control groups. There were no relevant changes in participants receiving placebo. These results suggest that this herbal medicine may contribute to the development of a novel approach to cardiovascular risk reduction.

  15. The Relationship Between Chronic Inflammation and Glucidic-Lipidic Profile Disorders in Kidney Transplant Recipients

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    Tarța I.D.

    2016-03-01

    Full Text Available Introduction: Chronic inflammation has a proven role in atherogenesis, lipid profile parameters being related to cytokine production. In kidney transplant recipients, interleukin 6 (IL-6 is significantly associated with graft-related outcomes and also alterations of cholesterol and triglyceride metabolism. The aim of this study was to investigate the relationship between chronic inflammation and glucidic-lipidic metabolism disorders in a group of patients with kidney transplantation as renal replacement therapy. Methods: A prospective observational study which enrolled thirtysix non-diabetic kidney transplant recipients was conducted in the Nephrology and Peritoneal Dialysis Department, County Clinic Hospital of Tirgu Mures. The study group was divided as following: recipients with serum IL-6 concentration higher than 3.8 pg/ml (group A and IL-6 within the normal range (group B. Results: Allograft recipients with higher serum IL-6 had significant higher erytrocyte sedimentation rate(ESR, p=0.0067. Patients with over-the-range levels of IL-6 had significant higher levels of serum cholesterol and LDL-cholesterol respectively (p=0.0242 and p=0.0081. Serum Apo-B was also significant higher in Group A than Group B. Protein excretion was significant higher in patients from group A (p=0.0013. No statistical significant relationship could be proven between elevated levels of IL-6 and hbA1c, insulin and glycosuria disturbances in the two groups. Also, we found no statistical significant association between resistivity and pulsatility indices (both hilum and intragraft or carotid intima media thickness. Conclusion: Serum interleukin 6 is related to lipid profile disorders and less to glucidic metabolism anomalies in non-diabetic kidney transplant recipients.

  16. Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells

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    Eriksson Linnéa

    2012-03-01

    Full Text Available Abstract Background The leading cause of death for patients suffering from diabetes is macrovascular disease. Endothelial dysfunction is often observed in type 2 diabetic patients and it is considered to be an important early event in the pathogenesis of atherogenesis and cardiovascular disease. Many drugs are clinically applied to treat diabetic patients. However, little is known whether these agents directly interfere with endothelial cell proliferation and apoptosis. This study therefore aimed to investigate how anti-diabetic and cardioprotective agents affect human coronary artery endothelial cells (HCAECs. Methods The effect of anti-diabetic and cardioprotective agents on HCAEC viability, proliferation and apoptosis was studied. Viability was assessed using Trypan blue exclusion; proliferation in 5 mM and 11 mM of glucose was analyzed using [3H]thymidine incorporation. Lipoapoptosis of the cells was investigated by determining caspase-3 activity and the subsequent DNA fragmentation after incubation with the free fatty acid palmitate, mimicking diabetic lipotoxicity. Results Our data show that insulin, metformin, BLX-1002, and rosuvastatin improved HCAEC viability and they could also significantly increase cell proliferation in low glucose. The proliferative effect of insulin and BLX-1002 was also evident at 11 mM of glucose. In addition, insulin, metformin, BLX-1002, pioglitazone, and candesartan significantly decreased the caspase-3 activity and the subsequent DNA fragmentation evoked by palmitate, suggesting a protective effect of the drugs against lipoapoptosis. Conclusion Our results suggest that the anti-diabetic and cardioprotective agents mentioned above have direct and beneficial effects on endothelial cell viability, regeneration and apoptosis. This may add yet another valuable property to their therapeutic effect, increasing their clinical utility in type 2 diabetic patients in whom endothelial dysfunction is a prominent feature

  17. Extracellular signal-regulated kinase-5: Novel mediator of insulin and tumor necrosis factor α-stimulated vascular cell adhesion molecule-1 expression in vascular cells.

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    Mackesy, Daniel Z; Goalstone, Marc L

    2014-11-01

    Atherosclerosis may be stimulated by the increased presence of insulin and tumor necrosis-factor-α (TNFα) with subsequent expression of vascular cell adhesion molecule-1 (VCAM-1). We hypothesized that extracellular signal-regulated kinase-5 (ERK5) plays an important role in insulin and TNFα-stimulated total and cell surface VCAM-1 expression. Rat aorta vascular endothelial cells were first transfected with either no inhibitory RNA, inactive (scrambled) inhibitory ERK5 RNA (scERK5) or active inhibitory ERK5 RNA (siERK5) and then treated with either (i) no analog; (ii) insulin (1 nM), or TNFα (1 ng/mL) alone, or (iii) insulin plus TNFα for 6 h. Thereafter either total VCAM-1 protein or surface VCAM-1 protein was determined. Genetic inhibition of ERK5 decreased TNFα-stimulated total VCAM-1 expression by 57% and surface expression by 27%. In contrast, genetic inhibition of ERK5 did not significantly decrease insulin-stimulated total or surface VCAM-1 expression. Interestingly, genetic inhibition of ERK5 did not significantly decrease insulin plus TNFα-stimulated total VCAM-1 expression, but significantly (P cell surface VCAM-1 protein expression. Taken together, these results demonstrate that not only does ERK5 have differential mediation of insulin and TNFα-stimulated VCAM-1 expression, but also has differential regulation of insulin plus TNFα-stimulated total and surface VCAM-1 expression, suggesting that other intermediates of the insulin and TNFα intracellular pathways are contributing to atherogenesis. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  18. PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, insulin-resistant mice depends on adiponectin-induced Irak3 expression.

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    Maarten Hulsmans

    Full Text Available Synthetic peroxisome proliferator-activated receptor (PPAR agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate and a PPARγ agonist (rosiglitazone on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3 and decreased monocyte chemoattractant protein-1 (Mcp1 expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM, we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3(-/- BMDM resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3(-/- BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists.

  19. Daintain/AIF-1 Plays Roles in Coronary Heart Disease via Affecting the Blood Composition and Promoting Macrophage Uptake and Foam Cell Formation

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    Junhan Wang

    2013-07-01

    Full Text Available Background: Daintain/AIF-1 is an inflammatory polypeptide factor/allograft inflammatory factor 1 derived from macrophages. It is characterized in APOE-/- mice as a novel inflammatory factor associated with atherosclerosis. The purpose of this study was to characterize its function in human atherosclerosis. Methods: Immunohistochemistry was used to identify the expression of daintain/AIF-1 in vessel segments within and far from atherosclerotic plaques; High-performance liquid chromatography (HPLC was used to display the effects of daintain/AIF-1 on C-reactive protein (CRP, oxidative capacity and superoxide dismutase (SOD in vivo; Oil Red O Staining was used to show the effects of daintain/AIF-1 on uptake of oxidized low density lipoprotein (ox-LDL into U937 cells, a macrophage line; Western Blot was used to test scavenger receptor A (SRA expression. Results: A high density of daintain/AIF-1 was observed in the tunica intima and media of coronary artery with atherosclerotic plaque, and fewer daintain/AIF-1 in the vessels without atherosclerotic plaque; Daintain/AIF-1 injected intravenously into BALB/c mice boosted oxidative capacity, significantly impaired SOD activities and augmented the CRP level in blood. According to the oil red O test, daintain/AIF-1 profoundly facilitated the uptake of ox-LDL in U937 macrophages and formation of foam cells in the endothelium. We also found that the molecular mechanisms are effective by promoting overexpression of SRA on macrophages. Conclusion: These findings implicate that the inflammatory factor daintain/AIF-1 is closely associated with atherogenesis, and could be further characterized as a novel risk factor for atherosclerosis

  20. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima.

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    Hazen, S L; Heinecke, J W

    1997-05-01

    Oxidation of LDL may be of pivotal importance in atherogenesis, but the mechanisms that promote oxidation in vivo remain poorly understood. We have explored the possibility that one pathway involves myeloperoxidase, a heme protein secreted by phagocytes. Myeloperoxidase is the only human enzyme known to generate hypochlorous acid (HOCl), a potent oxidizing agent, at physiological halide concentrations. LDL exposed to the complete myeloperoxidase-H2O2-Cl- system underwent chlorination of its protein tyrosyl residues. Treatment of LDL with reagent HOCl resulted in 3-chlorotyrosine formation, implicating HOCl as an intermediate in the enzymatic reaction pathway. In contrast, 3-chlorotyrosine was undetectable in LDL oxidized by hydroxyl radical, copper, iron, hemin, glucose, peroxynitrite, horseradish peroxidase, lactoperoxidase, or lipoxygenase. These results indicate that 3-chlorotyrosine is a specific marker for LDL oxidation by myeloperoxidase. To address the role of myeloperoxidase in promoting LDL oxidation in vivo, we used stable isotope dilution gas chromatography-mass spectrometry to quantify 3-chlorotyrosine in human aortic tissue and in LDL isolated from atherosclerotic lesions. The level of 3-chlorotyrosine in atherosclerotic tissue obtained during vascular surgery was sixfold higher than that of normal aortic intima. Moreover, the level of 3-chlorotyrosine was 30-fold higher in LDL isolated from atherosclerotic intima compared with circulating LDL. The detection of 3-chlorotyrosine in human atherosclerotic lesions indicates that halogenation reactions catalyzed by the myeloperoxidase system of phagocytes constitute one pathway for protein oxidation in vivo. These findings raise the possibility that the myeloperoxidase-H2O2-Cl- system plays a critical role in converting LDL into an atherogenic form.

  1. Cardiovascular Disease and Chronic Inflammation in End Stage Kidney Disease

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    Sofia Zyga

    2013-01-01

    Full Text Available Background: Chronic Kidney Disease (CKD is one of the most severe diseases worldwide. In patients affected by CKD, a progressive destruction of the nephrons is observed not only in structuralbut also in functional level. Atherosclerosis is a progressive disease of large and medium-sized arteries. It is characterized by the deposition of lipids and fibrous elements and is a common complication of the uremic syndrome because of the coexistence of a wide range of risk factors. High blood pressure, anaemia, insulin resistance, inflammation, high oxidative stress are some of the most common factors that cause cardiovascular disease and atherogenesis in patients suffering from End Stage Kidney Disease (ESRD. At the same time, the inflammatory process constitutes a common element in the apparition and development of CKD. A wide range of possible causes can justify the development of inflammation under uremic conditions. Such causes are oxidative stress, oxidation, coexistentpathological conditions as well as factors that are due to renal clearance techniques. Patients in ESRD and coronary disease usually show increased acute phase products. Pre-inflammatory cytokines, such as IL-6 and TNF-a, and acute phase reactants, such as CRP and fibrinogen, are closely related. The treatment of chronic inflammation in CKD is of high importance for the development ofthe disease as well as for the treatment of cardiovascular morbidity.Conclusions: The treatment factors focus on the use of renin-angiotensic system inhibitors, acetylsalicylic acid, statins and anti-oxidant treatment in order to prevent the action of inflammatorycytokines that have the ability to activate the mechanisms of inflammation.

  2. Heme oxygenase-1, oxidation, inflammation and atherosclerosis

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    Jesus A Araujo

    2012-07-01

    Full Text Available Atherosclerosis is an inflammatory process of the vascular wall characterized by the infiltration of lipids and inflammatory cells. Oxidative modifications of infiltrating low density lipoproteins and induction of oxidative stress play a major role in lipid retention in the vascular wall, uptake by macrophages and generation of foam cells, a hallmark of this disorder. The vasculature has a plethora of protective resources against oxidation and inflammation, many of them regulated by the Nrf2 transcription factor. Heme oxygenase-1 (HO-1 is a Nrf2-regulated gene that plays a critical role in the prevention of vascular inflammation. It is the inducible isoform of heme oxygenase, responsible for the oxidative cleavage of heme groups leading to the generation of biliverdin, carbon monoxide and release of ferrous iron. HO-1 has important antioxidant, antiinflammatory, antiapoptotic, antiproliferative and immunomodulatory effects in vascular cells, most of which play a significant role in the protection against atherogenesis. HO-1 may also be an important feature in macrophage differentiation and polarization to certain subtypes. The biological effects of HO-1 are largely attributable to its enzymatic activity, which can be conceived as a system with three arms of action, corresponding to its three enzymatic byproducts. HO-1 mediated vascular protection may be due to a combination of systemic and vascular local effects. It is usually expressed at low levels but can be highly upregulated in the presence of several proatherogenic stimuli. The HO-1 system is amenable for use in the development of new therapies, some of them currently under experimental and clinical trials. Interestingly, in contrast to the HO-1 antiatherogenic actions, the expression of its transcriptional regulator Nrf2 leads to proatherogenic effects instead. This article reviews the evidence that supports the antiatherogenic role of HO-1, potential pathways and mechanisms mediating

  3. Paradoxical effect of a pequi oil-rich diet on the development of atherosclerosis: balance between antioxidant and hyperlipidemic properties

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    Aguilar, E.C. [Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Jascolka, T.L. [Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Teixeira, L.G.; Lages, P.C.; Ribeiro, A.C.C.; Vieira, E.L.M. [Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Peluzio, M.C.G. [Departamento de Nutrição, Universidade Federal de Viçosa, Viçosa, MG (Brazil); Alvarez-Leite, J.I. [Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2012-05-11

    Pequi is the fruit of Caryocar brasiliense and its oil has a high concentration of monounsaturated and saturated fatty acids, which are anti- and pro-atherogenic agents, respectively, and of carotenoids, which give it antioxidant properties. Our objective was to study the effect of the intake of a cholesterol-rich diet supplemented with pequi oil, compared to the same diet containing soybean oil, on atherosclerosis development, and oxidative stress in atherosclerosis-susceptible LDL receptor-deficient mice (LDLr{sup −/−}, C57BL/6-background). Female mice were fed a cholesterol-rich diet containing 7% soybean oil (Soybean group, N = 12) or 7% pequi oil (Pequi group, N = 12) for 6 weeks. The Pequi group presented a more atherogenic lipid profile and more advanced atherosclerotic lesions in the aortic root compared to the Soybean group. However, the Pequi group presented a less advanced lesion in the aorta than the Soybean group and showed lower lipid peroxidation (Soybean group: 50.2 ± 7.1; Pequi group: 30.0 ± 4.8 µmol MDA/mg protein) and anti-oxidized LDL autoantibodies (Soybean group: 35.7 ± 9.4; Pequi group: 15.6 ± 3.7 arbitrary units). Peritoneal macrophages from the Pequi group stimulated with zymosan showed a reduction in the release of reactive oxygen species compared to the Soybean group. Our data suggest that a pequi oil-rich diet slows atherogenesis in the initial stages, possibly due to its antioxidant activity. However, the increase of serum cholesterol induces a more prominent LDL migration toward the intimae of arteries, increasing the advanced atherosclerotic plaque. In conclusion, pequi oil associated with an atherogenic diet worsens the lipid profile and accelerates the formation of advanced atherosclerotic lesions despite its antioxidant action.

  4. Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists.

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    Michael Gurven

    2009-08-01

    Full Text Available Arterial aging is well characterized in industrial populations, but scantly described in populations with little access to modern medicine. Here we characterize health and aging among the Tsimane, Amazonian forager-horticulturalists with short life expectancy, high infectious loads and inflammation, but low adiposity and robust physical fitness. Inflammation has been implicated in all stages of arterial aging, atherogenesis and hypertension, and so we test whether greater inflammation associates with atherosclerosis and CVD risk. In contrast, moderate to vigorous daily activity, minimal obesity, and low fat intake predict minimal CVD risk among older Tsimane.Peripheral arterial disease (PAD, based on the Ankle-Brachial Index (ABI, and hypertension were measured in Tsimane adults, and compared with rates from industrialized populations. No cases of PAD were found among Tsimane and hypertension was comparatively low (prevalence: 3.5%, 40+; 23%, 70+. Markers of infection and inflammation were much higher among Tsimane than among U.S. adults, whereas HDL was substantially lower. Regression models examine associations of ABI and BP with biomarkers of energy balance and metabolism and of inflammation and infection. Among Tsimane, obesity, blood lipids, and disease history were not significantly associated with ABI. Unlike the Tsimane case, higher cholesterol, C-reactive protein, leukocytes, cigarette smoking and systolic pressure among North Americans are all significantly associated with lower ABI.Inflammation may not always be a risk factor for arterial degeneration and CVD, but instead may be offset by other factors: healthy metabolism, active lifestyle, favorable body mass, lean diet, low blood lipids and cardiorespiratory health. Other possibilities, including genetic susceptibility and the role of helminth infections, are discussed. The absence of PAD and CVD among Tsimane parallels anecdotal reports from other small-scale subsistence

  5. NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet

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    Amato, Antonella; Caldara, Gaetano-Felice; Nuzzo, Domenico; Baldassano, Sara; Picone, Pasquale; Rizzo, Manfredi; Mulè, Flavia; Di Carlo, Marta

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) confers an increased risk of cardiovascular diseases. NAFDL is associated with atherogenic dyslipidemia, inflammation and renin-angiotensin system (RAS) imbalance, which in turn lead to atherosclerotic lesions. In the present study, the impact of a natural dietary supplement (NDS) containing Curcuma longa, silymarin, guggul, chlorogenic acid and inulin on NAFLD and atherosclerosis was evaluated, and the mechanism of action was examined. C57BL/6 mice were fed an HFD for 16 weeks; half of the mice were simultaneously treated with a daily oral administration (os) of the NDS. NAFLD and atherogenic lesions in aorta and carotid artery (histological analysis), hepatic expression of genes involved in the NAFLD (PCR array), hepatic angiotensinogen (AGT) and AT1R mRNA expression (real-time PCR) and plasma angiotensin (ANG)-II levels (ELISA) were evaluated. In the NDS group, steatosis, aortic lesions or carotid artery thickening was not observed. PCR array showed upregulation of some genes involved in lipid metabolism and anti-inflammatory activity (Cpt2, Ifng) and downregulation of some genes involved in pro-inflammatory response and in free fatty acid up-take (Fabp5, Socs3). Hepatic AGT, AT1R mRNA and ANG II plasma levels were significantly lower with respect to the untreated-group. Furthermore, NDS inhibited the dyslipidemia observed in the untreated animals. Altogether, these results suggest that NDS prevents NAFLD and atherogenesis by modulating the expression of different genes involved in NAFLD and avoiding RAS imbalance. PMID:28505074

  6. Activation of monocytes and cytokine production in patients with peripheral atherosclerosis obliterans

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    Lastória Sidney

    2011-08-01

    Full Text Available Abstract Background Arterial peripheral disease is a condition caused by the blocked blood flow resulting from arterial cholesterol deposits within the arms, legs and aorta. Studies have shown that macrophages in atherosclerotic plaque are highly activated, which makes these cells important antigen-presenting cells that develop a specific immune response, in which LDLox is the inducing antigen. As functional changes of cells which participate in the atherogenesis process may occur in the peripheral blood, the objectives of the present study were to evaluate plasma levels of anti-inflammatory and inflammatory cytokines including TNF-α, IFN-γ, interleukin-6 (IL-6, IL-10 and TGF-β in patients with peripheral arteriosclerosis obliterans, to assess the monocyte activation level in peripheral blood through the ability of these cells to release hydrogen peroxide (H2O2 and to develop fungicidal activity against Candida albicans (C. albicans in vitro. Methods TNF-α, IFN-γ, IL-6, IL-10 and TGF-β from plasma of patients were detected by ELISA. Monocyte cultures activated in vitro with TNF-alpha and IFN-gamma were evaluated by fungicidal activity against C. albicans by culture plating and Colony Forming Unit (CFU recovery, and by H2O2 production. Results Plasma levels of all cytokines were significantly higher in patients compared to those detected in control subjects. Control group monocytes did not release substantial levels of H2O2 in vitro, but these levels were significantly increased after activation with IFN-γ and TNF-α. Monocytes of patients, before and after activation, responded less than those of control subjects. Similar results were found when fungicidal activity was evaluated. The results seen in patients were always significantly smaller than among control subjects. Conclusions: The results revealed an unresponsiveness of patient monocytes in vitro probably due to the high activation process occurring in vivo as corroborated by high

  7. Intimal cell masses in the abdominal aortas of swine fed a low-fat, low-cholesterol diet for up to twelve years of age.

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    Kim, D N; Schmee, J; Lee, K T; Thomas, W A

    1985-05-01

    The normal subendothelial intima of large arteries in man, swine and most other species is a variegated structure from birth onwards. In some regions it contains only a few scattered cells; in others there may be a continuous single layer of cells; and in still others the cells pile up to form what we have called intimal cell masses (ICM). The cells in the normal ICM are mostly smooth muscle cells although there is also a small resident population of monocyte-like cells. We have been studying the ICM in swine with emphasis on the abdominal aorta. We have found that atherosclerotic lesions in the abdominal aorta of swine induced by high-fat high-cholesterol diets begin by a hyperplastic reaction of the smooth muscle cells in the ICM and progress to form large lesions characterized by extensive regions of lipid-rich calcific necrotic debris similar to advanced lesions in man. Because of the putative key role of the ICM in atherogenesis we think that it is important to learn as much as possible about their natural history under conditions as normal as possible. In this report we present data on ICM in the abdominal aortas of 34 male and female Hormel miniature swine maintained on a low-fat low-cholesterol diet for up to 12 years of age. The ICM grow slowly with aging and in the distal portion of the aorta account for an average of 9% in the male and 15% in the female of the total cells in the aortic wall (intima + media).(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Pomegranate phytosterol (β-sitosterol) and polyphenolic antioxidant (punicalagin) addition to statin, significantly protected against macrophage foam cells formation.

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    Rosenblat, Mira; Volkova, Nina; Aviram, Michael

    2013-01-01

    To assess the anti-atherogenic effects on macrophage cholesterol biosynthesis rate, and on cellular oxidative stress by the combination of simvastatin with a potent polyphenolic antioxidant (punicalagin), or with a phytosterol (β-sitosterol), or with pomegranate juice (POM, that contains both of them). Simvastatin (15 μg/ml) decreased J774A.1 macrophage cholesterol biosynthesis rate by 42% as compared to control cells. The addition to the statin of either punicalagin (15 or 30 μM), or β-sitosterol (50 or 100 μM), increased the inhibitory effect of the statin up to 62% or 57%, respectively. Similarly, the combination of POM and simvastatin, resulted in an inhibitory effect up to 59%. While simvastatin inhibited the rate limiting enzyme HMGCoA-reductase, punicalagin, β-sitosterol or POM inhibited macrophage cholesterol biosynthesis downstream to mevalonate. Simvastatin (15 μg/ml) also modestly decreased macrophage reactive oxygen species (ROS) formation by 11%. In the presence of punicalagin (15 or 30 μM) however, a remarkable further inhibition was noted (by 61% or 79%, respectively). Although β-sitosterol alone showed some pro-oxidant activity, the combination of simvastatin, β-sitosterol and punicalagin, clearly demonstrated a remarkable 73% reduction in ROS production. Similarly, simvastatin + POM decreased the extent of ROS formation by up to 63%. These improved antioxidant effects of the combinations could be related to various anti-oxidative properties of the different compounds, including free radicals scavenging capacity, upregulation of paraoxonase 2, and stimulation of reduced glutathione. The combination of simvastatin with potent antioxidant and phytosterol (such as present in pomegranate) could lead to attenuation of macrophage foam cell formation and atherogenesis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. Hydrogen Sulfide Up-Regulates the Expression of ATP-Binding Cassette Transporter A1 via Promoting Nuclear Translocation of PPARα

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    Dong Li

    2016-04-01

    Full Text Available ATP binding cassette transporter A1 (ABCA1 plays a key role in atherogenesis. Hydrogen sulfide (H2S, a gasotransmitter, has been reported to play an anti-atherosclerotic role. However, the underlying mechanisms are largely unknown. In this study we examined whether and how H2S regulates ABCA1 expression. The effect of H2S on ABCA1 expression and lipid metabolism were assessed in vitro by cultured human hepatoma cell line HepG2, and in vivo by ApoE−/− mice with a high-cholesterol diet. NaHS (an exogenous H2S donor treatment significantly increased the expression of ABCA1, ApoA1, and ApoA2 and ameliorated intracellular lipid accumulation in HepG2 cells. Depletion of the endogenous H2S generator cystathionine γ-lyase (CSE by small RNA interference (siRNA significantly decreased the expression of ABCA1 and resulted in the accumulation of lipids in HepG2 cells. In vivo NaHS treatment significantly reduced the serum levels of total cholesterol (TC, triglycerides (TG, and low-density lipoproteins (LDL, diminished atherosclerotic plaque size, and increased hepatic ABCA1 expression in fat-fed ApoE−/− mice. Further study revealed that NaHS upregulated ABCA1 expression by promoting peroxisome proliferator-activated receptor α (PPARα nuclear translocation. H2S up-regulates the expression of ABCA1 by promoting the nuclear translocation of PPARα, providing a fundamental mechanism for the anti-atherogenic activity of H2S. H2S may be a promising potential drug candidate for the treatment of atherosclerosis.

  10. Apocynin suppresses the progression of atherosclerosis in apoE-deficient mice by inactivation of macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Kinoshita, Hiroyuki [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556 (Japan); Matsumura, Takeshi, E-mail: takeshim@gpo.kumamoto-u.ac.jp [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556 (Japan); Ishii, Norio; Fukuda, Kazuki; Senokuchi, Takafumi; Motoshima, Hiroyuki; Kondo, Tatsuya; Taketa, Kayo; Kawasaki, Shuji; Hanatani, Satoko [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556 (Japan); Takeya, Motohiro [Department of Cell Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556 (Japan); Nishikawa, Takeshi; Araki, Eiichi [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556 (Japan)

    2013-02-08

    Highlights: ► We examined the anti-athrogenic effect of apocynin in atherosclerotic model mice. ► Apocynin prevented atherosclerotic lesion formation. ► Apocynin suppressed ROS production in aorta and in macrophages. ► Apocynin suppressed cytokine expression and cell proliferation in macrophages. ► Apocynin may be beneficial compound for the prevention of atherosclerosis. -- Abstract: Production of reactive oxygen species (ROS) and other proinflammatory substances by macrophages plays an important role in atherogenesis. Apocynin (4-hydroxy-3-methoxy-acetophenone), which is well known as a NADPH oxidase inhibitor, has anti-inflammatory effects including suppression of the generation of ROS. However, the suppressive effects of apocynin on the progression of atherosclerosis are not clearly understood. Thus, we investigated anti-atherosclerotic effects of apocynin using apolipoprotein E-deficient (apoE{sup –/–}) mice in vivo and in mouse peritoneal macrophages in vitro. In atherosclerosis-prone apoE{sup –/–} mice, apocynin suppressed the progression of atherosclerosis, decreased 4-hydroxynonenal-positive area in atherosclerotic lesions, and mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) in aorta. In mouse peritoneal macrophages, apocynin suppressed the Ox-LDL-induced ROS generation, mRNA expression of MCP-1, IL-6 and granulocyte/macrophage colony-stimulating factor, and cell proliferation. Moreover, immunohistochemical studies revealed that apocynin decreased the number of proliferating cell nuclear antigen-positive macrophages in atherosclerotic lesions of apoE{sup –/–} mice. These results suggested that apocynin suppressed the formation of atherosclerotic lesions, at least in part, by inactivation of macrophages. Therefore, apocynin may be a potential therapeutic material to prevent the progression of atherosclerosis.

  11. Coconut oil affects lipoprotein composition and structure of neonatal chicks.

    Science.gov (United States)

    Castillo, M; Hortal, J H; García-Fuentes, E; Zafra, M F; García-Peregrín, E

    1996-04-01

    Supplementation of 10 or 20% coconut oil in the diet for 1-2 weeks produced a significant hypercholesterolemia in neonatal chicks. Plasma triacylglycerol concentration significantly increased after the addition of 20% coconut oil for 2 weeks. These results show that newborn chicks are more sensitive to saturated fatty acids from coconut oil than adult animals. The effects of this saturated fat on lipoprotein composition were studied for the first 1-2 weeks of neonatal chick life. Coconut oil supplementation in the diet (20%) for 2 weeks increased cholesterol concentration in all the lipoprotein fractions, while 10% coconut oil only increased cholesterol in low-density and very-low-density lipoproteins, an increase that was significant after 1 week of treatment. Similar results were obtained for triacylglycerol concentration after 2 weeks of treatment. Changes in phospholipid and total protein levels were less profound. Coconut oil decreased low-density and very-low-density lipoprotein fluidity, measured as total cholesterol/phospholipid ratio. Changes in esterified cholesterol/phospholipid and triacylglycerol/phospholipid ratios suggest that coconut oil affects the distribution of lipid components in the core of very-low-density particles. Likewise, the esterified cholesterol/triacylglycerol ratio was clearly increased in the low-density, and especially in the very-low-density, fraction after the first week of coconut oil feeding. Our results show that neonatal chick provides a suitable model in which to study the role of very-low-density lipoproteins in atherogenesis and the rapid response to saturated fatty acids with 12-14 carbons.