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Sample records for atherogenesis

  1. Biochemical mechanisms underlying atherogenesis

    Directory of Open Access Journals (Sweden)

    Dr.P.V.L.N. Srinivasa Rao

    2012-02-01

    Full Text Available Atherosclerosis remains one of the major causes of death and premature disability in developed countries. Though atherosclerosis was formerly considered a bland lipid storage disease, substantial advances in basic and experimental sciences have illuminated the role of endothelium, inflammation and immune mechanisms in its pathogenesis. Current concept of atherosclerosis is that of a dynamic and progressive disease arising from in- jury to endothelium, also known as endothelial dysfunction and an inflammatory response to that injury. The lesions of atherosclerosis occur principally in large and medium sized arteries. Atherosclerosis affects various regions of the circulation preferentially and can lead to ischemia of heart, brain or extremities resulting in in- farction.This produces distinct clinical manifestations depending on the vessel involved. Several predisposing factors to cardiovascular diseases such as diabetes mellitus, hypertension, obesity, infections act as triggers to the devel- opment of atherosclerosis by causing endothelial dysfunction and/or promoting inflammatory response. The evolution of pathogenetic mechanisms has passed through various directions such as oxidative stress, inflam- mation and immune responses. It is now known that all these are not acting independently but are interrelated and getting unified in the current concept of atherogenesis. The following discussion aims at providing an in- sight into these developments which can help in a better comprehension of the disease and management of its clinical complications

  2. Macrophages and Dendritic Cells: Partners in Atherogenesis.

    Science.gov (United States)

    Cybulsky, Myron I; Cheong, Cheolho; Robbins, Clinton S

    2016-02-19

    Atherosclerosis is a complex chronic disease. The accumulation of myeloid cells in the arterial intima, including macrophages and dendritic cells (DCs), is a feature of early stages of disease. For decades, it has been known that monocyte recruitment to the intima contributes to the burden of lesion macrophages. Yet, this paradigm may require reevaluation in light of recent advances in understanding of tissue macrophage ontogeny, their capacity for self-renewal, as well as observations that macrophages proliferate throughout atherogenesis and that self-renewal is critical for maintenance of macrophages in advanced lesions. The rate of atherosclerotic lesion formation is profoundly influenced by innate and adaptive immunity, which can be regulated locally within atherosclerotic lesions, as well as in secondary lymphoid organs, the bone marrow and the blood. DCs are important modulators of immunity. Advances in the past decade have cemented our understanding of DC subsets, functions, hematopoietic origin, gene expression patterns, transcription factors critical for differentiation, and provided new tools for study of DC biology. The functions of macrophages and DCs overlap to some extent, thus it is important to reassess the contributions of each of these myeloid cells taking into account strict criteria of cell identification, ontogeny, and determine whether their key roles are within atherosclerotic lesions or secondary lymphoid organs. This review will highlight key aspect of macrophage and DC biology, summarize how these cells participate in different stages of atherogenesis and comment on complexities, controversies, and gaps in knowledge in the field.

  3. Pathophysiological mechanisms of angiogenesis in atherogenesis

    Directory of Open Access Journals (Sweden)

    Vučević Danijela

    2013-01-01

    Full Text Available Introduction. Atherosclerosis is a progressive, multifactorial, diffuse, multisystemic, chronic, inflammatory disease, which is manifested by disorders of vascular, immune and metabolic system. Pathogenesis of this disease is not fully understood. Accordingly, angiogenesis represents a special field of research due to its role in atherogenesis. Steps of Angiogenesis. Angiogenesis is a complex biological process, which requires the precise coordination of its four steps (vasodilatation and permeability, vessel destabilization and matrix degradation, endothelial cell proliferation and migration, and lumen formation and vessel stabilization. Mediators of Angiogenic Process. The process of forming new blood vessels is regulated by a delicate balance between proangiogenic and antiangiogenic molecules. Numerous soluble growth factors and inhibitors, cytokines, proteases, extracellular matrix proteins and adhesion molecules, as well as hypoxia, inflammatory process, shear stress, hypertension and interaction between cells and extracellular matrix strictly control the angiogenic process. Neovascularization is halted due to the downregulation of angiogenic factors or the increase of inhibitors of this process. Tumor Vascularization. In the asymptomatic phase of cancerogenesis, cancer rarely exceeds the diameter of 1-2 millimeters. However, when the metabolic demand increases, it leads to tumor vascularization. In this way, tumor switches to an angiogenic phenotype. The molecular basis of angiogenic switch refers to increased production of angiogenic factors and/or loss of angiogenic inhibitors. Conclusion. The contribution of angiogenic process has become increasingly meaningful in understanding the pathogenesis of atherosclerosis. [Projekat Ministarstva nauke Republike Srbije, br. 175015

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

    DEFF Research Database (Denmark)

    Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene;

    2010-01-01

    BACKGROUND: Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI(2)), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of C...

  5. 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.

  6. Estradiol protective role in atherogenesis through LDL structure modification

    Science.gov (United States)

    Papi, Massimiliano; Brunelli, Roberto; Ciasca, Gabriele; Maiorana, Alessandro; Maulucci, Giuseppe; Palmieri, Valentina; Parasassi, Tiziana; De Spirito, Marco

    2016-07-01

    Relevant physiological functions are exerted by circulating low density lipoprotein (LDL) as well as eventual pathological processes triggering atherogenesis. Modulation of these functions can well be founded on modifications of LDL structure. Given its large dimension, multicomponent organization and strong interactions between the protein apoB-100 and lipids, determining LDL 3D structure remains a challenge. We propose a novel quantitative physical approach to this complex biological problem. We introduce a three-component model, fitted to small angle x-ray scattering data on LDL maintained in physiological conditions, able to achieve a consistent 3D structure. Unexpected features include three distinct protein domains protruding out of a sphere, quite rough in its surface, where several core lipid areas are exposed. All LDL components are affected by 17-β-estradiol (E2) binding to apoB-100. Mostly one of the three protruding protein domains, dramatically reducing its presence on the surface and with a consequent increase of core lipids’ exposure. This result suggests a structural basis for some E2 protecting roles and LDL physiological modifications.

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

    Science.gov (United States)

    Scribano, María de la Paz; Baez, María Del Carmen; Florencia, Becerra; Tarán, Mariana Denise; Franco, Signorini; Balceda, Ariel G; Moya, Mónica

    2014-01-01

    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.

  8. 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.

  9. Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of apolipoprotein E deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Hong-Bo, E-mail: xhbzhb@yahoo.com [College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128 (China); Lu, Xiang-Yang; Sun, Zhi-Liang [Hunan Agricultural University, Changsha 410128 (China); Zhang, Heng-Bo [Furong District Red Cross Hospital, Changsha 410126 (China)

    2011-12-15

    Recent studies show that osteopontin (OPN) and its receptor cluster of differentiation 44 (CD44) are two pro-inflammatory cytokines contributing to the development of atherosclerosis. The objective of this study was to explore the inhibitory effect of kaempferol, a naturally occurring flavonoid compound, on atherogenesis and the mechanisms involved. The experiments were performed in aorta and plasma from C57BL/6J control and apolipoprotein E-deficient (ApoE{sup -/-}) mice treated or not with kaempferol (50 or 100 mg/kg, intragastrically) for 4 weeks. Kaempferol treatment decreased atherosclerotic lesion area, improved endothelium-dependent vasorelaxation, and increased the maximal relaxation value concomitantly with decrease in the half-maximum effective concentration, plasma OPN level, aortic OPN expression, and aortic CD44 expression in ApoE{sup -/-} mice. In addition, treatment with kaempferol also significantly decreased reactive oxygen species production in mice aorta. The present results suggest that kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of ApoE{sup -/-} mice. -- Graphical abstract: Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of ApoE{sup -/-} mice. Highlights: Black-Right-Pointing-Pointer OPN-CD44 pathway plays a critical role in the development of atherosclerosis. Black-Right-Pointing-Pointer We examine lesion area, OPN and CD44 changes after kaempferol treatment. Black-Right-Pointing-Pointer Kaempferol treatment decreased atherosclerotic lesion area in ApoE{sup -/-} mice. Black-Right-Pointing-Pointer Kaempferol treatment decreased aortic OPN and CD44 expressions in ApoE{sup -/-} mice. Black-Right-Pointing-Pointer Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis.

  10. Overweight: atherogenesis risk marker in children between 8 and 9 years

    OpenAIRE

    2008-01-01

    Background: Many significant health problems hold the attention of pediatricians, and even when there is an increased interest on premature atherosclerosis risk factors, it is still a field to be studied. Objectives: To determine differences in the emergence of atherogenesis risk factors in children between 8 and 9 years with normal weight and overweight. Methods: Analytic research, with case control design, developed in three primary schools belonging to the Clinic “Dr. Cecilio Ruiz de Zarat...

  11. The role of complement activation in atherogenesis: the first 40 years.

    Science.gov (United States)

    Vlaicu, Sonia I; Tatomir, Alexandru; Rus, Violeta; Mekala, Armugam P; Mircea, Petru A; Niculescu, Florin; Rus, Horea

    2016-02-01

    The pathogenesis of atherosclerotic inflammation is a multi-step process defined by the interweaving of excess modified lipid particles, monocyte-macrophages populations, and innate immune and adaptive immunity effectors. A part of innate immunity, the complement system, is an important player in the induction and progression of atherosclerosis. The accumulation of either oxidized or enzymatically modified LDL-bound to C-reactive protein or not-prompts complement activation leading to the assembly of the terminal complement C5b-9 complex in the atherosclerotic lesion. The sublytic C5b-9 assembly leads to the activation and proliferation of smooth muscle and endothelial cells, accompanied by the release of various chemotactic, pro-adhesion, and procoagulant cytokines from these cells. Response gene to complement (RGC)-32, an essential effector of the terminal complement complex C5b-9, also affects atherogenesis, propelling vascular smooth muscle cell proliferation and migration, stimulating endothelial proliferation, and promoting vascular lesion formation. A substantial amount of experimental work has suggested a role for the complement system activation during atherosclerotic plaque formation, with the proximal classical complement pathway seemingly having a protective effect and terminal complement contributing to accelerated atherogenesis. All these data suggest that complement plays an important role in atherogenesis.

  12. Oxidative stress and lectin-like ox-LDL-receptor LOX-1 in atherogenesis and tumorigenesis.

    Science.gov (United States)

    Lu, Jingjun; Mitra, Sona; Wang, Xianwei; Khaidakov, Magomed; Mehta, Jawahar L

    2011-10-15

    Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been identified as a major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, monocytes, platelets, cardiomyocytes, and vascular smooth muscle cells. Its expression is minimal under physiological conditions but can be induced under pathological conditions. The upregulation of LOX-1 by ox-LDL appears to be important for physiologic processes, such as endothelial cell proliferation, apoptosis, and endothelium remodeling. Pathophysiologic effects of ox-LDL in atherogenesis have also been firmly established, including endothelial cell dysfunction, smooth muscle cell growth and migration, monocyte transformation into macrophages, and finally platelet aggregation-seen in atherogenesis. Recent studies show a positive correlation between increased serum ox-LDL levels and an increased risk of colon, breast, and ovarian cancer. As in atherosclerosis, ox-LDL and its receptor LOX-1 activate the inflammatory pathway through nuclear factor-kappa B, leading to cell transformation. LOX-1 is important for maintaining the transformed state in developmentally diverse cancer cell lines and for tumor growth, suggesting a molecular connection between atherogenesis and tumorigenesis.

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

    OpenAIRE

    Ping Zeng; Bin Liu; Qun Wang; Qin Fan; Jian-Xin Diao; Jing Tang; Xiu-Qiong Fu; Xue-Gang Sun

    2015-01-01

    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 ...

  14. 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.

  15. Midkine, a heparin-binding growth factor, and its roles in atherogenesis and inflammatory kidney diseases.

    Science.gov (United States)

    Şalaru, Delia Lidia; Arsenescu-Georgescu, Cătălina; Chatzikyrkou, Christos; Karagiannis, Jaqueline; Fischer, Anja; Mertens, Peter R

    2016-11-01

    The heparin-binding protein midkine is a potent growth factor with emerging roles in numerous inflammatory diseases. Beyond its characterization in embryogenesis and organ development, ample insights into its function have been collected from experimental disease models using knockout animals or knockdown intervention strategies. Here a comprehensive overview on midkine and its functions in atherogenesis and kidney diseases is provided. Molecular clues to key signalling pathways (Akt, ERK, HIF1α) and key events in atherosclerotic vessels link midkine expression with vascular smooth muscle proliferation and (neo)angiogenesis. In acute and chronic kidney diseases, midkine expression is upregulated in tubular as well as endothelial cells. Experimental disease models that mimic diabetic nephropathy and/or immunologic glomerular damage indicate dichotomous midkine activities, with cytoprotective as well as injurious effects. This review also pinpoints the commonalities of the disease models. An understanding of the underlying molecular events will be required in order to design a targeted intervention into cardiovascular or renal diseases as well as inflammatory processes.

  16. 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.

  17. Overweight: atherogenesis risk marker in children between 8 and 9 years

    Directory of Open Access Journals (Sweden)

    Beatriz Sabina Roméu

    2008-12-01

    Full Text Available Background: Many significant health problems hold the attention of pediatricians, and even when there is an increased interest on premature atherosclerosis risk factors, it is still a field to be studied. Objectives: To determine differences in the emergence of atherogenesis risk factors in children between 8 and 9 years with normal weight and overweight. Methods: Analytic research, with case control design, developed in three primary schools belonging to the Clinic “Dr. Cecilio Ruiz de Zarate” in Cienfuegos. A group with overweight or obese children was formed and another control group selected by randomized simple sampling with normal weight children. Measurements of weight, height, waist circumference and blood pressure were performed. Parents were surveyed for data about children and family history. In overweight children, glucose and triglycerides were measured. To validate results, Chi-Squared test was used. To compare measurements, Mathn Whitney test was employed. Results: Overweight and obesity were associated with: male sex, with people, sedentary patients, and prenatal antecedents of overweight. 78% of overweight children had values of blood pressure higher than 90 percentile for their sex and height, contrasting with the 26% in normal weight children. Six children were diagnosed with metabolic syndrome.

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

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    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

  19. Vitamin A-Deficient Diet Accelerated Atherogenesis in Apolipoprotein E−/− Mice and Dietary β-Carotene Prevents This Consequence

    Directory of Open Access Journals (Sweden)

    Noa Zolberg Relevy

    2015-01-01

    Full Text Available Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE−/−. ApoE−/− mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified with Dunaliella powder containing βc isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with a Dunaliella powder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61% compared to the control group. Dietary βc fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietary βc, as a sole source of retinoids, can compensate for vitamin A deficiency.

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

    Directory of Open Access Journals (Sweden)

    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

  1. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  3. Combination of spices and herbal extract restores macrophage foam cell migration and abrogates the athero-inflammatory signalling cascade of atherogenesis.

    Science.gov (United States)

    Nimgulkar, Chetan; Ghosh, Sudip; Sankar, Anand B; Uday, Kumar P; Surekha, M V; Madhusudhanachary, P; Annapurna, B R; Raghu, P; Bharatraj, Dinesh Kumar

    2015-09-01

    The trapping of lipid-laden macrophages in the arterial intima is a critical but reversible step in atherogenesis. However, information about possible treatments for this condition is lacking. Here, we hypothesized that combining the polyphenol-rich fractions (PHC) of commonly consumed spices (Allium sativum L (Liliaceae), Zingiber officinale R (Zingiberaceae), Curcuma longa L (Zingiberaceae)) and herbs (Terminalia arjuna (R) W & A (Combretaceae) and Cyperus rotundus L (Cyperaceae)) prevents foam cell formation and atherogenesis. Using an in vitro foam cell formation assay, we found that PHC significantly inhibited lipid-laden macrophage foam cell formation compared to the depleted polyphenol fraction of PHC (F-PHC). We further observed that PHC attenuated the LDL and LPS induced CD36, p-FAK and PPAR-γ protein expression in macrophages and increased their migration. NK-κB-DNA interaction, TNF-α, ROS generation, and MMP9 and MMP2 protein expression were suppressed in PHC-treated macrophages. The anti-atherosclerotic activity of PHC was investigated in a high fat- and cholesterol-fed rabbit model. The inhibition of foam cell deposition within the aortic intima and atheroma formation confirmed the atheroprotective activity of PHC. Therefore, we conclude that the armoury of polyphenols in PHC attenuates the CD36 signalling cascade-mediated foam cell formation, enhances the migration of these cells and prevents atherogenesis.

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

    Science.gov (United States)

    Shan, Qiuli; Wang, Jing; Huang, Fengchen; Lv, Xiaowen; Ma, Min; Du, Yuguo

    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(-/-) 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(-/-) 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.

  5. Atorvastatin attenuates p-cresyl sulfate-induced atherogenesis and plaque instability in ApoE knockout mice

    Science.gov (United States)

    Han, Hui; Chen, Yanjia; Zhu, Jinzhou; Ni, Jingwei; Sun, Jiateng; Zhang, Ruiyan

    2016-01-01

    p-cresyl sulfate (PCS) is a protein-bound uremic toxin retained in the blood of patients with chronic kidney disease (CKD) As atherosclerosis is a primary cardiovascular complication for patients with CKD, the aim of the present study was to investigate the mechanisms underlying the aggravation of atherosclerosis by PCS. In addition, the effect of atorvastatin was assessed in reversing the effects of PCS. PCS was revealed to promote the initiation and progression of atherosclerosis. Following treatment with atorvastatin, apolipoprotein E knockout mice demonstrated a reduction in PCS-induced atherogenesis and plaque vulnerability. In addition, atorvastatin decreased the protein expression levels of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1, and the interaction between leukocytes and endothelia. The plasma lipid profiles of mice were not significantly affected by gavage of low-dose atorvastatin. The results of the present study indicate that PCS promotes plaque growth and instability by enhancing leukocyte-endothelium interaction, and that these effects may be attenuated by atorvastatin treatment. PMID:27574007

  6. 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.

  7. Oxidized low-density lipoprotein contributes to atherogenesis via co-activation of macrophages and mast cells.

    Directory of Open Access Journals (Sweden)

    Chong Chen

    Full Text Available Oxidized low-density lipoprotein (OxLDL is a risk factor for atherosclerosis, due to its role in endothelial dysfunction and foam cell formation. Tissue-resident cells such as macrophages and mast cells release inflammatory mediators upon activation that in turn cause endothelial activation and monocyte adhesion. Two of these mediators are tumor necrosis factor (TNF-α, produced by macrophages, and histamine, produced by mast cells. Static and microfluidic flow experiments were conducted to determine the number of adherent monocytes on vascular endothelium activated by supernatants of oxLDL-treated macrophages and mast cells or directly by oxLDL. The expression of adhesion molecules on activated endothelial cells and the concentration of TNF-α and histamine in the supernatants were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. A low dose of oxLDL (8 μg/ml, below the threshold for the clinical presentation of coronary artery disease, was sufficient to activate both macrophages and mast cells and synergistically increase monocyte-endothelium adhesion via released TNF-α and histamine. The direct exposure of endothelial cells to a much higher dose of oxLDL (80 μg/ml had less effect on monocyte adhesion than the indirect activation via oxLDL-treated macrophages and mast cells. The results of this work indicate that the co-activation of macrophages and mast cells by oxLDL is an important mechanism for the endothelial dysfunction and atherogenesis. The observed synergistic effect suggests that both macrophages and mast cells play a significant role in early stages of atherosclerosis. Allergic patients with a lipid-rich diet may be at high risk for cardiovascular events due to high concentration of low-density lipoprotein and histamine in arterial vessel walls.

  8. 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...

  9. Sphingosine signaling and atherogenesis

    Institute of Scientific and Technical Information of China (English)

    Cang-bao XU; Jacob HANSEN-SCHWARTZ; Lars EDVINSSON

    2004-01-01

    phingosine- 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 closely related GPCRs of EDG family (EDG1, EDG3, EDG5, EDG6, and EDG8) have recently been identified as high-affinity S1P receptors. These receptors are coupled via Gi, Gq, G12/13, and Rho. The signaling pathways are linked to vascular cell migration,proliferation, apoptosis, intracellular Ca2+ mobilization, and expression of adhesion molecules. The formation of an atherosclerotic lesion occurs through activation of cellular events that include monocyte adhesion to the endothelium and vascular smooth muscle cell (VSMC) migration and proliferation. Thus, S 1P signaling may play an important role in the pathogenesis of atherosclerotic vascular disease. This review highlights S1P signalling in vascular cells and its involvement in the formation of atherosclerotic lesions.

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

    Science.gov (United States)

    Zeng, Ping; Liu, Bin; Wang, Qun; Fan, Qin; Diao, Jian-Xin; Tang, Jing; Fu, Xiu-Qiong; Sun, Xue-Gang

    2015-01-01

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. The opposite associations of lycopene and body fat mass with humoral immunity in type 2 diabetes mellitus: a possible role in atherogenesis.

    Science.gov (United States)

    Neyestani, Tirang R; Shariat-Zadeh, Nastaran; Gharavi, A'azam; Kalayi, Ali; Khalaji, Niloufar

    2007-06-01

    This study examined the possible effects of lycopene at physiological dosage and body fat mass on the humoral immune response in patients with type 2 diabetes mellitus (T2DM). A total of 35 patients with Typ2 diabetes mellitus from both sexes aged 54+/-9 yrs from the Iranian Diabetes Society were introduced into a double blind placebo controlled clinical trial conducted for 2 months. After a 2-week lycopene free diet washout period, patients were allocated to either lycopene supplementation group (10mg/d) (n=16) or placebo age- and sex matched group (n=19) for 8 weeks. Patients were instructed to keep their diets and physical activities as unchanged as possible. Lycopene supplements increased serum lycopene levels (pdiabetic complications, notably atherogenesis.

  14. 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

  15. 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.

  16. The Opposite Associations of Lycopene and Body Fat Mass with HumoralImmunity in Type 2 Diabetes Mellitus: A Possible Role in Atherogenesis

    Directory of Open Access Journals (Sweden)

    Tirang R. Neyestani

    2007-06-01

    Full Text Available This study examined the possible effects of lycopene at physiological dosage and body fat mass on the humoral immune response in patients with type 2 diabetes mellitus (T2DM.A total of 35 patients with Typ2 diabetes mellitus from both sexes aged 54±9 yrs from the Iranian Diabetes Society were introduced into a double blind placebo controlled clinical trial conducted for 2 months. After a 2-week lycopene free diet washout period, patients were allocated to either lycopene supplementation group (10mg/d (n=16 or placebo age- and sex matched group (n=19 for 8 weeks.Patients were instructed to keep their diets and physical activities as unchanged as possible.Lycopene supplements increased serum lycopene levels (pand nutrients did not change in either groups, the ratio of total antioxidant capacity tomalondialdehyde increased significantly in the lycopene group (p=0.007. There was an inversecorrelation between serum levels of lycopene and those of IgG (r= -0.338, p=0.008. On the contrary, changes of serum levels of lycopene directly correlated with those of IgM (r=0.466, p=0.005. Interestingly, changes of the amount of fat mass correlated directly with those of serum IgG (r=0.415, p=0.044 but inversely with of serum IgM (r= -0.469, p=0.021.While truncal fat might promote adaptive humoral immunity, lycopene probably by inhibitingMDA-LDL formation might attenuate T cell dependent adaptive (pro-atherogenic humoral immune response. These findings may have preventive implications in long term diabetic complications, notably atherogenesis.

  17. Transcription and translation of human F11R gene are required for an initial step of atherogenesis induced by inflammatory cytokines

    Directory of Open Access Journals (Sweden)

    Kornecki Elizabeth

    2011-06-01

    of F11R in ECs is required for the adhesion of platelets to inflamed ECs. Because platelet adhesion to an inflamed endothelium is crucial for plaque formation in non-denuded blood vessels, we conclude that the de-novo translation of F11R is a crucial early step in the initiation of atherogenesis, leading to atherosclerosis, heart attacks and stroke.

  18. 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)

  19. Magnesium deficiency upregulates sphingomyelinases in cardiovascular tissues and cells: cross-talk among proto-oncogenes, Mg(2+), NF-κB and ceramide and their potential relationships to resistant hypertension, atherogenesis and cardiac failure.

    Science.gov (United States)

    Altura, Burton M; Shah, Nilank C; Shah, Gatha J; Li, Wenyan; Zhang, Aimin; Zheng, Tao; Li, Zhiqiang; Jiang, Xian-Cheng; Perez-Albela, Jose Luis; Altura, Bella T

    2013-01-01

    drug-resistant hypertension, atherogenesis, and difficult-to-treat forms of cardiac failure.

  20. The Dynamics of Oxidized LDL during Atherogenesis

    Directory of Open Access Journals (Sweden)

    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.

  1. 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

    Directory of Open Access Journals (Sweden)

    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.

  2. 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...

  3. [Lipoprotein (a)--a mysterious factor in atherogenesis].

    Science.gov (United States)

    Jelaković, Bojan; Laganović, Mario; Kuzmanić, Dusko

    2002-01-01

    Etiopathogenesis of arterial hypertension and coronary disease involves interaction of numerous exogenous factors which determine the clinical course and therapeutic response in genetically predisposed individuals. The role of numerous cardiovascular risk factors has been reevaluated during the past few years, yet some unresolved issues and gaps still remain. One of the still insufficiently studied factors is lipoprotein (a) [Lp (a)] which belongs to a subclass of LDL lipoproteins. Its important component is apolipoprotein (a) which is structurally similar to plasminogen. This characteristic can be followed through evolution and is probably crucial for its physiologic but also pathophysiologic role. Actually, through its competition with plasminogen, Lp (a) interferes with the process of fibrinolysis and may contribute to tissue healing and restoration but also support and accelerate atherothrombotic process. Lp (a) concentration is stable and genetically determined in an individual and the indication that persons with elevated levels are permanently exposed to increased risk is supported by the data on twofold incidence of myocardial infarction in mothers of children with highest Lp (a) concentrations. Apart from competing with plasminogen via apolipoprotein (a), Lp (a) increases the activity of inhibitors of plasminogen-I activator and reduces the activity of transforming growth factor-beta. This results both in the absence of fibrinolysis and promotion of migration and proliferation of media smooth muscle cells, which are important in the onset of atherosclerotic process. Lp (a) binds to elastin via apolipoprotein B, resulting in oxidation and facilitated entry into macrophages and their transition into the so-called foam cells, also an important sign of early atherosclerosis. Although many pathophysiologic processes by which Lp (a) contributes to atherosclerosis have also been confirmed by animal experiments as well as by the presence of histologic evidence, clinical significance of elevated Lp (a) concentration is still questionable. However, results of prospective studies and metaanalyses were published few months ago and identified decisively Lp (a) as a factor that increases cardiovascular risk primarily in patients in whom other risk factors were also present. According to currently prevailing attitude, routine determination of Lp (a) is not justified and, according to most authors, its determination is useful in patients who had a cardiovascular incident at the age under 55 years, in those with recurrent coronary stenosis, or those with positive family history of such incidents. As Lp (a) is genetically determined, its detection in the early stages of essential hypertension might be a useful prognostic marker but a period of observation is still necessary for correct selection of hypertensive patients. Apart from the observation that hormone replacement therapy significantly decreases the Lp (a) level, there is currently no information on the effectiveness of either dietary or drug therapy. Due to Lp (a) antifibrotic effects, small aspirin doses may be beneficial to these patients, as well as B complex vitamins since hyperhomocysteinemia enhances atherogenicity of Lp (a). Therapeutic approach to patient with increased Lp (a) levels is currently based on as strict regulation of arterial pressure, glycemia and other dislipidemias as possible. In the present clinical practice, the elevated level of this lipoprotein indicates a patients with elevated cardiovascular risk, regardless of the fact whether Lp (a) is only a marker or an active factor of pathophysiologic process. Increased Lp (a) concentration may refer to the need for therapy, frequent monitoring and determination of even stricter aims for these individuals by selecting metabolically neutral and best tolerated drugs.

  4. Effects of valsartan on oxidative stress and the atherogenesis

    Institute of Scientific and Technical Information of China (English)

    陈钧; 王琳; 陈欣; 卜军; 刘念; 阮燕菲

    2003-01-01

    Objective:To investigate the therapy effect of valsartan on oxidative stress and the formation of atherosclerosis of rabbit.Methods:An atherosclerotic rabbit model was established by feeding high cholesterol diet supplemented by bovine serum albumin injection bolus.The rabbits were randomly divided into the control,model,and valsartan treated group,six rabbits in each group.Blood samples were collected at the end of 8 weeks for examination of serum lipid levels and MDA levels; the aortas were harvested for histological morphometry analysis,vascular cell adhesion molecule-1(VCAM-1)immunohistochemical analysis and in situ superoxide detection to reflect the activity of NAD(P)H oxidase.Results:Rabbits fed with high cholesterol diet showed higher serum lipids levels than those fed with normal diet(P<0.01).Treatment with valsartan(10 mg/kg per day)did not alter serum lipids levels.But the serum MDA level and ratio of lesion to intima area reduced significantly compared with model group(P < 0.05).The expression of VCAM-1 decreased significantly in the valsartan treated group than in the model group(P < 0.05).In addition,in situ superoxide detection also show the markedly reduction of superoxide as a result of valsartan treatment.Conclusion:These results indicate that the valsartan treatment can reducethe atherosclerotic progression,the mechanisms of which may include the inhibiting the NAD(P)H oxidase activity to produce superoxide and the downregulating the expression of redox sensitive genes in the downstream,such as VCAM-1.

  5. Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

    DEFF Research Database (Denmark)

    Poulsen, Christian Bo; Mortensen, Martin Bødtker; Koechling, Wolfgang;

    2016-01-01

    BACKGROUND: Treatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin-releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested...... allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe-deficient mice, all types...... associated with GnRH agonist-based ADT....

  6. Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin

    Directory of Open Access Journals (Sweden)

    László Potor

    2013-01-01

    Full Text Available Oxidized cell-free hemoglobin (Hb, including covalently cross-linked Hb multimers, is present in advanced atherosclerotic lesions. Oxidation of Hb produces methemoglobin (Fe3+ and ferryl hemoglobin (Fe4+=O2−. Ferryl iron is unstable and can return to the Fe3+ state by reacting with specific amino acids of the globin chains. In these reactions globin radicals are produced followed by termination reactions yielding covalently cross-linked Hb multimers. Despite the evanescent nature of the ferryl state, herein we refer to this oxidized Hb as “ferryl Hb.” Our aim in this work was to study formation and biological effects of ferrylHb. We demonstrate that ferrylHb, like metHb, can release its heme group, leading to sensitization of endothelial cells (ECs to oxidant-mediated killing and to oxidation of low-density lipoprotein (LDL. Furthermore, we observed that both oxidized LDL and lipids derived from human atherosclerotic lesions trigger Hb oxidation and subsequent production of covalently cross-linked ferrylHb multimers. Previously we showed that ferrylHb disrupts EC monolayer integrity and induces expression of inflammatory cell adhesion molecules. Here we show that when exposed to ferrylHb, EC monolayers exhibit increased permeability and enhanced monocyte adhesion. Taken together, interactions between cell-free Hb and atheroma lipids engage in a vicious cycle, amplifying oxidation of plaque lipids and Hb. These processes trigger EC activation and cytotoxicity.

  7. Spirulina platensis and phycocyanobilin activate atheroprotective heme oxygenase-1: a possible implication for atherogenesis.

    Science.gov (United States)

    Strasky, Zbynek; Zemankova, Lenka; Nemeckova, Ivana; Rathouska, Jana; Wong, Ronald J; Muchova, Lucie; Subhanova, Iva; Vanikova, Jana; Vanova, Katerina; Vitek, Libor; Nachtigal, Petr

    2013-11-01

    Spirulina platensis, a water blue-green alga, has been associated with potent biological effects, which might have important relevance in atheroprotection. We investigated whether S. platensis or phycocyanobilin (PCB), its tetrapyrrolic chromophore, can activate atheroprotective heme oxygenase-1 (Hmox1), a key enzyme in the heme catabolic pathway responsible for generation of a potent antioxidant bilirubin, in endothelial cells and in a mouse model of atherosclerosis. In vitro experiments were performed on EA.hy926 endothelial cells exposed to extracts of S. platensis or PCB. In vivo studies were performed on ApoE-deficient mice fed a cholesterol diet and S. platensis. The effect of these treatments on Hmox1, as well as other markers of oxidative stress and endothelial dysfunction, was then investigated. Both S. platensis and PCB markedly upregulated Hmox1 in vitro, and a substantial overexpression of Hmox1 was found in aortic atherosclerotic lesions of ApoE-deficient mice fed S. platensis. In addition, S. platensis treatment led to a significant increase in Hmox1 promoter activity in the spleens of Hmox-luc transgenic mice. Furthermore, both S. platensis and PCB were able to modulate important markers of oxidative stress and endothelial dysfunction, such as eNOS, p22 NADPH oxidase subunit, and/or VCAM-1. Both S. platensis and PCB activate atheroprotective HMOX1 in endothelial cells and S. platensis increased the expression of Hmox1 in aortic atherosclerotic lesions in ApoE-deficient mice, and also in Hmox-luc transgenic mice beyond the lipid lowering effect. Therefore, activation of HMOX1 and the heme catabolic pathway may represent an important mechanism of this food supplement for the reduction of atherosclerotic disease.

  8. On the advantage of screening kindergarten children for atherogenesis-related risk indicators.

    Science.gov (United States)

    Kupke, I R

    1985-01-01

    On the basis of our practical experience we can recommend screening of young children outside the clinic. Our methodology has proven to be appropriate for this purpose. Among young children, three groups are easily accessible: Newborns - since delivery occurs mostly in a clinic; infants up to one year - since these children are provided with basic medical care, and kindergarten children. According to our experience, kindergartens are favorable places for screening children because many children are together in one place. Children of this age can be easily motivated to cooperate during the examination, and since they stay in the kindergartens for a considerable period of the day, they only can be guided by nurses who can provide positive motivation for educational programs. As an additional advantage, the cooperation between nurses and parents, as well as positive influence on the parents, by the nurses might be taken into account. In this context, nurses must be regarded as key persons for strategies when considering life-style changes. Identifying children at risk at this early age could shorten the pathogenetic period and increase the chance for regression of the atherosclerotic disease process. Furthermore, children of this age are willing to learn and to change their habits. There is also a possibility that children may implant in their families experiences and information obtained in the kindergartens. Such parents might be more open to advice from kindergarten personnel, and thus also profit for themselves. An additional and valuable advantage of screening kindergarten children is the possibility of detecting first-degree relatives at risk before clinical manifestation of the disease, thereby having a good chance for successful intervention.

  9. Humoral response towards high density lipoprotein : a new mechanism for atherogenesis

    OpenAIRE

    Batuca, Joana Rita

    2014-01-01

    RESUMO:Aterosclerose é uma das principais causas de morbilidade e mortalidade no mundo ocidental. É responsável, direta ou indiretamente, pela maior percentagem de gastos com a saúde na maioria dos países europeus. A “teoria lipídica” da aterosclerose, que se baseia na dislipidemia como causa primária para a doença vascular tem algumas implicações práticas importantes: permite a definição de linhas de orientação e protocolos simples e ainda estabelece alvos terapêuticos que podem ser atin...

  10. 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.

  11. Chronic alcohol feeding inhibits atherogenesis in C57BL/6 hyperlipidemic mice.

    Science.gov (United States)

    Emeson, E E; Manaves, V; Singer, T; Tabesh, M

    1995-12-01

    Although there is abundant clinical evidence that the consumption of alcohol (ethanol) in moderate amounts has a protective effect on coronary artery disease, the mechanism of this effect is not understood. The prevailing theory supported by a limited number of clinical and experimental animal studies indicates that the ability of alcohol to elevate serum high-density lipoprotein cholesterol levels is an important mechanism. Although there have been a large number of studies on the effects of alcohol on serum lipoprotein and apolipoproteins on coronary artery disease, there have been very few that have, at the same time, looked directly and systematically at its effects on the histopathological development of atherosclerotic lesions. In the following studies we employed the hyperlipidemic C57BL/6 female mouse model and formulated an all liquid high fat atherogenic diet to provide the mice with the 3% or 6% alcohol. After 22 weeks on this diet, alcohol markedly inhibited the development of fatty streak atherosclerotic lesions in a dose-dependent fashion. Surprisingly, there was a dose-dependent decrease in plasma high-density lipoprotein cholesterol values, which suggests that high-density lipoprotein alterations play little or no role in the amelioration of atherosclerosis in this model.

  12. Serum lipids in the young : an epidemiological view of early atherogenesis

    NARCIS (Netherlands)

    W.A.H.J. van Stiphout (Willy-Anne)

    1986-01-01

    textabstractCardiovascular diseases are the leading cause of mortality in the industrialized world. together accounting for about one-half of the total number of annual deaths. Coronary heart disease comprises about one·half of the cardiovascular mortality and cerebrovascular disease about one-quart

  13. Augmented atherogenesis in LDL receptor deficient mice lacking both macrophage ABCA1 and ApoE.

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    Bart Lammers

    Full Text Available AIM: ABCA1 protects against atherosclerosis by facilitating cholesterol efflux from macrophage foam cells in the arterial wall to extracellular apolipoprotein (apo A-I. In contrast to apoA-I, apoE is secreted by macrophages and can, like apoA-I, induce ABCA1-mediated cholesterol efflux. Yet, the combined effect of macrophage ABCA1 and apoE on lesion development is unexplored. METHODS AND RESULTS: LDL receptor knockout (KO mice were transplanted with bone marrow from ABCA1/apoE double KO (dKO mice, their respective single KO's, and wild-type (WT controls and were challenged with a high-fat/high-cholesterol diet for 9 weeks. In vitro cholesterol efflux experiments showed no differences between ABCA1 KO and dKO macrophages. The serum non-HDL/HDL ratio in dKO transplanted mice was 1.7-fold and 2.4-fold (p<0.01 increased compared to WT and ABCA1 KO transplanted mice, respectively. The atherosclerotic lesion area in dKO transplanted animals (650±94×10(3 µm(2, however, was 1.9-fold (p<0.01 and 1.6-fold (p<0.01 increased compared to single knockouts (ABCA1 KO: 341±20×10(3 µm(2; apoE KO: 402±78×10(3 µm(2, respectively and 3.1-fold increased (p<0.001 compared to WT (211±20×10(3 µm(2. When normalized for serum cholesterol exposure, macrophage ABCA1 and apoE independently protected against atherosclerotic lesion development (p<0.001. Moreover, hepatic expression levels of TNFα and IL-6 were highly induced in dKO transplanted animals (3.0-fold; p<0.05, and 4.3-fold; p<0.001, respectively. In agreement, serum IL-6 levels were also enhanced in ABCA1 KO transplanted mice (p<0.05 and even further enhanced in dKO transplanted animals (3.1-fold as compared to ABCA1 KO transplanted animals; p<0.05. CONCLUSIONS: Combined deletion of macrophage ABCA1 and apoE results in a defect in cholesterol efflux and, compared to ABCA1 KO transplanted mice, elevated serum total cholesterol levels. Importantly, these mice also suffer from enhanced systemic and hepatic inflammation, together resulting in the observed augmented atherosclerotic lesion development.

  14. Do the Apoe-/- and Ldlr-/- Mice Yield the Same Insight on Atherogenesis?

    Science.gov (United States)

    Getz, Godfrey S; Reardon, Catherine A

    2016-09-01

    Murine models of atherosclerosis are useful for investigating the environmental and genetic influences on lesion formation and composition. Apoe(-/-) and Ldlr(-/-) mice are the 2 most extensively used models. The models differ in important ways with respect to the precise mechanism by which their absence enhances atherosclerosis, including differences in plasma lipoproteins. The majority of the gene function studies have utilized only 1 model, with the results being generalized to atherogenic mechanisms. In only a relatively few cases have studies been conducted in both atherogenic murine models. This review will discuss important differences between the 2 atherogenic models and will point out studies that have been performed in the 2 models where results are comparable and those where different results were obtained.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Dietary corn fractions reduce atherogenesis in low-density lipoprotein receptor knockout mice.

    Science.gov (United States)

    Masisi, Kabo; Le, Khuong; Ghazzawi, Nora; Moghadasian, Mohammed H; Beta, Trust

    2017-01-01

    Accumulating evidence has suggested that intake of whole grains is a protective factor against pathogenesis of coronary artery disease. The exact mechanisms, however, are still not clearly understood. In this study, we hypothesized that adequate intake of corn fractions (aleurone, endosperm and germ) can modify lipid profiles in relation to atherosclerotic lesion development in low-density lipoprotein receptor knockout (LDLr-KO) mice. The purpose of the present study was to investigate the potential cardiovascular benefits of corn fractions in LDLr-KO mice through a number of biomarkers including lipid profile, and morphologic and morphometrical analysis of atherosclerotic lesions in aortic root. Four groups of male LDLr-KO mice were fed with the experimental diets supplemented with (3 treated) or without (control) 5% (wt/wt) of each of corn fractions for 10 weeks. All diets were supplemented with 0.06% (wt/wt) cholesterol. Compared with mice in the control group, atherosclerotic lesions in the aortic roots were significantly reduced (P=.003) in the mice that were fed diet supplemented with aleurone and germ fractions. This effect was associated with significant reductions in plasma total (P=.02) and LDL (P=.03) cholesterol levels, and an increase in fecal cholesterol excretion (P=.04). Furthermore, abdominal fat mass was significantly reduced by consumption of aleurone (P=.03). In summary, the consumption of aleurone and germ may help attenuate atherosclerosis by reducing plasma total and LDL cholesterol levels.

  17. Thalidomide influences atherogenesis in aortas of ApoE(-/-)/LDLR (-/-) double knockout mice: a nano-CT study.

    Science.gov (United States)

    Kampschulte, Marian; Gunkel, Irina; Stieger, Philipp; Sedding, Daniel G; Brinkmann, Anne; Ritman, Erik L; Krombach, Gabriele A; Langheinrich, Alexander C

    2014-04-01

    Plaque progression in atherosclerosis is closely connected to angiogenesis due to vasa vasorum (VV) growth. Objective of this study was to determine the unknown long-term effect of thalidomide on adventitial VV neovascularization and plaque progression using nano-focussed computed tomography (nano-CT). Proliferation and migration assays in human coronary artery endothelial cells (HCAEC) measured number of viable cells after incubation with thalidomide. Male ApoE(-/-)/LDLR(-/-) (AL) mice (n = 5) received a thalidomide containing western diet (WD) over 29 weeks. Another five male AL mice (WD without thalidomide) served as control group. Descending aortas were scanned with nano-CT at (1.5 μm)(3) isotropic voxel size. Number and area of adventitial VV as well as plaque cross sectional area were measured. Results were complemented by histology. Thalidomide inhibited proliferation and migration of HCAEC dose-dependently. VV neovascularization decreased in number per cross section (7.66 ± 0.301 vs. 8.62 ± 0.164, p thalidomide (0.57 ± 0.0187 vs. 0.803 ± 0.0148 mm(2), p thalidomide. Therefore, nano-CT can be considered as a new method to detect therapeutic effects in experimental models of atherosclerosis.

  18. A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy.

    Science.gov (United States)

    Bot, Ilze; Ortiz Zacarías, Natalia V; de Witte, Wilhelmus E A; de Vries, Henk; van Santbrink, Peter J; van der Velden, Daniël; Kröner, Mara J; van der Berg, Dirk-Jan; Stamos, Dean; de Lange, Elizabeth C M; Kuiper, Johan; IJzerman, Adriaan P; Heitman, Laura H

    2017-12-01

    CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE(-/-) mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2(+) monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors.

  19. ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis.

    Science.gov (United States)

    Getz, Godfrey S; Reardon, Catherine A

    2016-05-01

    ApoE is a multifunctional protein that is expressed by many cell types that influences many aspects of cardiovascular physiology. In humans, there are three major allelic variants that differentially influence lipoprotein metabolism and risk for the development of atherosclerosis. Apoe-deficient mice and human apoE isoform knockin mice, as well as hypomorphic Apoe mice, have significantly contributed to our understanding of the role of apoE in lipoprotein metabolism, monocyte/macrophage biology, and atherosclerosis. This brief history of these mouse models will highlight their contribution to the understanding of the role of apoE in these processes. These Apoe(-/-) mice have also been extensively utilized as an atherosensitive platform upon which to assess the impact of modulator genes on the development and regression of atherosclerosis.

  20. Dietary cladode powder from wild type and domesticated Opuntia species reduces atherogenesis in apoE knock-out mice.

    Science.gov (United States)

    Garoby-Salom, Sandra; Guéraud, Françoise; Camaré, Caroline; de la Rosa, Ana-Paulina Barba; Rossignol, Michel; Santos Díaz, María del Socorro; Salvayre, Robert; Negre-Salvayre, Anne

    2016-03-01

    Dietary intake of Opuntia species may prevent the development of cardiovascular diseases. The present study was designed to characterize the biological antioxidant and anti-inflammatory properties of Opuntia species and to investigate whether Opuntia cladodes prevent the development of atherosclerosis in vivo, in apoE(-)KO mice. The effects of the two Opuntia species, the wild Opuntia streptacantha and the domesticated Opuntia ficus-indica, were tested on the generation of intra- and extracellular reactive oxygen species (ROS) production and kinetics of the LDL oxidation by murine CRL2181 endothelial cells and on the subsequent inflammatory signaling leading to the adhesion of monocytes on the activated endothelium and the formation of foam cells. Opuntia species blocked the extracellular ROS (superoxide anion) generation and LDL oxidation by CRL2181, as well as the intracellular ROS rise and signaling evoked by the oxidized LDL, including the nuclear translocation of the transcription factor NFκB, the expression of ICAM-1 and VCAM-1 adhesion molecules, and the adhesion of monocytes to CRL2181. In vivo, Opuntia significantly reduced the formation of atherosclerotic lesions and the accumulation of 4-hydroxynonenal adducts in the vascular wall of apoE-KO mice, indicating that Opuntia cladodes prevent lipid oxidation in the vascular wall. In conclusion, wild and domesticated Opuntia species exhibit antioxidant, anti-inflammatory, and antiatherogenic properties which emphasize their nutritional benefit for preventing cardiovascular diseases.

  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. Molecular Etiology of Atherogenesis – In Vitro Induction of Lipidosis in Macrophages with a New LDL Model

    Science.gov (United States)

    Estronca, Luis M. B. B.; Silva, Joao C. P.; Sampaio, Julio L.; Shevchenko, Andrej; Verkade, Paul; Vaz, Alfin D. N.; Vaz, Winchil L. C.; Vieira, Otilia V.

    2012-01-01

    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. PMID:22514671

  3. Chlamydial virulence determinants in atherogenesis: the role of chlamydial lipopolysaccharide and heat shock protein 60 in macrophage-lipoprotein interactions.

    Science.gov (United States)

    Kalayoglu, M V; Indrawati; Morrison, R P; Morrison, S G; Yuan, Y; Byrne, G I

    2000-06-01

    Data from a spectrum of epidemiologic, pathologic, and animal model studies show that Chlamydia pneumoniae infection is associated with coronary artery disease, but it is not clear how the organism may initiate or promote atherosclerosis. It is postulated that C. pneumoniae triggers key atherogenic events through specific virulence determinants. C. pneumoniae induces mononuclear phagocyte foam cell formation by chlamydial lipopolysaccharide (cLPS) and low-density lipoprotein oxidation by chlamydial hsp60 (chsp60). Thus, different chlamydial components may promote distinct events implicated in the development of atherosclerosis. Data implicating cLPS and chsp60 in the pathogenesis of atherosclerosis are discussed and novel approaches are presented for attempting to elucidate how these putative virulence determinants signal mononuclear phagocytes to modulate lipoprotein influx and modification.

  4. Lactobacillus acidophilus K301 Inhibits Atherogenesis via Induction of 24 (S), 25-Epoxycholesterol-Mediated ABCA1 and ABCG1 Production and Cholesterol Efflux in Macrophages.

    Science.gov (United States)

    Hong, Yi-Fan; Kim, Hangeun; Kim, Hye Sun; Park, Woo Jung; Kim, Joo-Yun; Chung, Dae Kyun

    2016-01-01

    Lactobacillus acidophilus species are well-known probiotics with the beneficial activity of regulating cholesterol levels. In this study, we showed that L. acidophilus K301 reduced the level of cholesterol through reverse transport in macrophages. L. acidophilus K301 upregulated the mRNA and protein levels of genes such as ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) under the control of liver X receptor (LXR), resulting in increased apoA-I-dependent cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. L. acidophilus K301 induced both ABCA1 and ABCG1 through the endogenous LXR agonist 24(S), 25-epoxcycholesterol, which is synthesized by intracellular cholesterol synthetic pathways. In vivo studies using L. acidophilus K301-treated ApoE-/- mice showed reduced accumulation of lipoproteins in the arterial lumen. The inhibitory effects of L. acidophilus K301 on accumulation of lipoprotein in atherosclerotic plaques were mediated by the induction of squalene reductase (SQLE) and oxidosqualene cyclase (OSC) and resulted in ABCA1-mediated cholesterol efflux. Taken together, our findings revealed that Lactobacillus acidophilus K301 regulates the expression of genes related to cholesterol reverse transport via the induction of endogenous LXR agonist, suggesting the therapeutic potential of Lactobacillus acidophilus K301 as an anti-atherosclerotic agent.

  5. 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.

  6. The action of peroxyl radicals, powerful deleterious reagents, explains why neither cholesterol nor saturated fatty acids cause atherogenesis and age-related diseases.

    Science.gov (United States)

    Spiteller, Gerhard; Afzal, Mohammad

    2014-11-10

    Cells respond to alterations in their membrane structure by activating hydrolytic enzymes. Thus, polyunsaturated fatty acids (PUFAs) are liberated. Free PUFAs react with molecular oxygen to give lipid hydroperoxide molecules (LOOHs). In case of severe cell injury, this physiological reaction switches to the generation of lipid peroxide radicals (LOO(·)). These radicals can attack nearly all biomolecules such as lipids, carbohydrates, proteins, nucleic acids and enzymes, impairing their biological functions. Identical cell responses are triggered by manipulation of food, for example, heating/grilling and particularly homogenization, representing cell injury. Cholesterol as well as diets rich in saturated fat have been postulated to accelerate the risk of atherosclerosis while food rich in unsaturated fatty acids has been claimed to lower this risk. However, the fact is that LOO(·) radicals generated from PUFAs can oxidize cholesterol to toxic cholesterol oxides, simulating a reduction in cholesterol level. In this review it is shown how active LOO(·) radicals interact with biomolecules at a speed transcending usual molecule-molecule reactions by several orders of magnitude. Here, it is explained how functional groups are fundamentally transformed by an attack of LOO(·) with an obliteration of essential biomolecules leading to pathological conditions. A serious reconsideration of the health and diet guidelines is required.

  7. 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.

  8. Chronic over-expression of heat shock protein 27 attenuates atherogenesis and enhances plaque remodeling: a combined histological and mechanical assessment of aortic lesions.

    Directory of Open Access Journals (Sweden)

    Charles M Cuerrier

    Full Text Available AIMS: Expression of Heat Shock Protein-27 (HSP27 is reduced in human coronary atherosclerosis. Over-expression of HSP27 is protective against the early formation of lesions in atherosclerosis-prone apoE(-/- mice (apoE(-/-HSP27(o/e - however, only in females. We now seek to determine if chronic HSP27 over-expression is protective in a model of advanced atherosclerosis in both male and female apoE(-/- mice. METHODS AND RESULTS: After 12 weeks on a high fat diet, serum HSP27 levels rose more than 16-fold in male and female apoE(-/-HSP27(o/e mice, although females had higher levels than males. Relative to apoE(-/- mice, female apoE(-/-HSP27(o/e mice showed reductions in aortic lesion area of 35% for en face and 30% for cross-sectional sinus tissue sections - with the same parameters reduced by 21% and 24% in male cohorts; respectively. Aortic plaques from apoE(-/-HSP27(o/e mice showed almost 50% reductions in the area occupied by cholesterol clefts and free cholesterol, with fewer macrophages and reduced apoptosis but greater intimal smooth muscle cell and collagen content. The analysis of the aortic mechanical properties showed increased vessel stiffness in apoE(-/-HSP27(o/e mice (41% in female, 34% in male compare to apoE(-/- counterparts. CONCLUSIONS: Chronic over-expression of HSP27 is atheroprotective in both sexes and coincides with reductions in lesion cholesterol accumulation as well as favorable plaque remodeling. These data provide new clues as to how HSP27 may improve not only the composition of atherosclerotic lesions but potentially their stability and resilience to plaque rupture.

  9. Interaction of OX-LDL and monocytes-macrophages promote atherogenesis%OX-LDL与单核巨噬细胞相互作用促进动脉粥样硬化形成

    Institute of Scientific and Technical Information of China (English)

    张良; 韩丹; 赵诗萌; 吴红敏

    2013-01-01

    目的 单核-巨噬细胞在动脉粥样硬化(AS)发病过程中的作用日益受到关注,但泡沫化过程中细胞内脂质变化情况的研究报道尚不多见.方法 一次性密度梯度超速离心分离LDL制成ox-LDL,动态观察小鼠巨噬细胞内脂质成分和细胞形态的变化.结果 纯化的LDL纯度可达92.39%.细胞形态学观察细胞内红色脂质颗粒增多,电镜显示细胞核周围包含染色质,胞浆稀少含有大量的核糖体,线粒体丰富.随浓度的增加LDL组及OX-LDL组细胞内TC、FC、CE均明显增加.结论 OX-LDL同单核巨噬细胞相互作用可使动脉壁局部形成AS病变的特征病理性细胞.OX-LDL较LDL更易使单核巨噬细胞形成泡沫细胞.高浓度的OX-LDL可以导致细胞膜结构的损伤.%Objective There is growing concern about the role of monocytes-macrophages in the progression of atherosclerosis (AS). However, the mechanism of lipid changes in those cells in the foaming process is not fully clear. Methods LDL was isolated by density-gradient centrifugation and to make Ox-LDL. The changes of lipid composition and cellular morphology of the rat macrophages were dynamically observed. Results The purity of separated LDL reached 92. 39% . Increased amount of red lipid droplets in the macrophages were observed. Electron microscopy showed the presence of perinuclear chromatin, numerous mitochondria and ribosomes in the sparse cytoplasm. In the LDL group, TC, FC, and CE were all increased along with the increasing LDL concentration. Similar results were observed in the Ox-LDL group. Conclusions Interaction of Ox-LDL and monocytes-macrophages may promote the formation of characteristic pathologic cells of AS nature in the arterial wall. OX-LDL is more easy than LDL to promote the changes of monocytes/ macrophages into foam cells. High concentration of OX-LDL can lead to cell membrane damages.

  10. 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

    Directory of Open Access Journals (Sweden)

    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.

  11. 烟酸对p38丝裂原活化蛋白激酶信号通路介导的内皮细胞功能障碍的早期干预研究%Effects of niacin on cell adhesion and early atherogenesis:involvement of the p38 mitogen-activated protein kinases pathway

    Institute of Scientific and Technical Information of China (English)

    牛娜; 韩波; 孙书珍; 于永慧; 汪翼; 王立俊

    2013-01-01

    目的 探讨烟酸对p38MAPK通路介导的内皮细胞功能障碍的早期干预作用及可能机制.方法 人脐静脉内皮细胞株(HUVECs),用Medium200培养基培养,实验分组:①阴性对照组:培养基;②溶血磷脂酰胆碱(LPC)不同作用时间组:培养基中加入终浓度为20 μmol/L的LPC,分别培养10 min、8h、24 h;③LPC+ p38MAPK的抑制剂(SB203580)组:培养基中加入SB203580 10 μmol/L培养1h,再分别加入LPC培养10 min、8h、24 h;④LPC+不同剂量烟酸组:培养基中分别加入终浓度为0.25、0.5、1 mmol/L烟酸培养18h,再加入LPC培养10 min、8h及24 h.应用Western blot定量分析检测内皮细胞磷酸化的p38 MAPK(pp38 MAPK)、细胞间黏附分子(ICAM-1)蛋白含量,实时定量PCR方法检测内皮细胞ICAM-1 mRNA表达,细胞免疫荧光方法检测LPC诱导的ICAM-1蛋白表达.结果 ICAM-1的蛋白表达LPC 24 h组为0.786±0.021,LPC+烟酸(1 mmol/L)组培养24 h为0.487±0.015,LPC+ SB203580组培养24 h为0.461±0.011,LPC+烟酸组和LPC+ SB203580组均低于LPC 24 h组,差异有统计学意义(F=6.3,P<0.01),但均未达到阴性对照组水平(0.134±0.012).pp38MAPK蛋白在LPC 10 min组最高,为0.47±0.02,烟酸能降低pp38MAPK,LPC+烟酸(1 mmol/L)组为0.07±0.02,LPC+ SB203580为0.11±0.02,均低于LPC 10 min组(F=91.91,P<0.01).加入LPC培养8h后,ICAM-1 mRNA的表达(8.16±0.15),高于阴性对照组(1.00±0.02),差异有统计学意义(t=24.34,P<0.01);与LPC培养8h比较,烟酸降低LPC诱导的ICAM-1 mRNA的表达,LPC+烟酸(1 mmol/L)组为3.85±0.14(F =8.06,P<0.01),而SB203580则不能有效的降低ICAM-1的mRNA的表达(8.09±0.11).结论 在LPC诱导的HUVECs中,ICAM-1的蛋白与mRNA的表达均明显增强,pp38MAPK蛋白明显增强,烟酸干预可降低ICAM-1的蛋白与mRNA的表达,同时亦可降低pp38 MAPK的蛋白表达,p38MAPK的抑制剂SB203580仅能降低ICAM-1的蛋白的表达,而不能影响其mRNA表达,其作用机制有待进一步研究.%Objective To examine the effects of niacin on lysophosphatidylcholine (LPC)-induced intercellular adhesion molecule-1 (ICAM-1),and gained insight to the mechanisms.Method Human umbilical vein endothelial cell line was cultured using Medium 200 medium in incubator at 37 ℃ and 5% CO2 condition.Experimental groups:(1) the negative control group:medium; (2) LPC different time groups:the medium added with 20 μmol/L final concentration of LPC,were cultured for 10 min and 8 h,24 h; (3) LPC + p38-mitogen-activated protein kinase (p38MAPK) inhibitor (SB203580) group:the medium added with 10 μmol/L p38MAPK inhibitor (SB203580) was cultured for 1 h,then human umbilical vein endothelial cells (HUVECs) added with the LPC were cultured for 10 min,8 h and 24 h.(4) LPC + different niacin dose group:after separately adding with 0.25,0.5,1 mmol/L niacin,the cells were cultured for 18 h,then HUVECs added with the LPC were cultured for 10 min,8 h and 24 h.Cell concentration in each group was 5 × 105/ml,inoculated in 6-well plates,each well 1 ml.Detected by Western blot analysis of pp38MAPK,ICAM-1 protein content,real-time quantitative PCR to detect endothelial cell ICAM-1 mRNA expression,cell immunofluorescence to detect LPC-induced ICAM-1 protein expression.Result In LPC 24 h group,the expression of ICAM-1 protein was significantly increased 0.786 ± 0.02,the LPC + niacin group,ICAM-1 protein levels (0.487 ±0.015) was significantly lower than the LPC 24 h group (P <0.01),in LPC + SB203580 intervention group,ICAM-1 protein levels (0.461 ± 0.011) was significantly lower than that of the LPC 24 h group (P < 0.01),but did not reach the level of the control group.Adding LPC to culture for 10 min,phosphorylation of p38MAPK (pp38MAPK) reached its peak (0.47 ± 0.02),niacin could reduce the pp38MAPK (0.07 ± 0.02),SB203580 could also reduce its activity (0.11 ± 0.02).Adding LPC to culture for 8 h,ICAM-1 mRNA expression (8.16 ± 0.15) compared with the control group (1.00 ± 0.02) had a significant increase (t =24.34,P < 0.01).Compared with the LPC 8 h,niacin reduced LPC-induced ICAM-1 mRNA expression (3.85 ± 0.14),and showed a dose-de pendent manner (F =8.06,P < 0.01),while SB203580 could not effectively reduce the ICAM-1 mRNA (8.09 ± 0.11).Conclusion Niacin prevented LPC-induced endothelial dysfunction by reducing expression of ICAM-1.These mechanisms appeared to be at least partly mediated by suppression of the pp38MAPK in endothelial cells.These pleiotropic effects of niacin may potentially contribute to the beneficial effects of risk reduction for atherosclerotic disease.

  12. 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 r

  13. Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice

    Science.gov (United States)

    Consuming curcumin may benefit health by modulating lipid metabolism and suppressing atherogenesis. Fatty acid binding proteins (FABP-4/aP2) and CD36 expression are key factors in lipid accumulation in macrophages and foam cell formation in atherogenesis. Our earlier observations suggest that curcum...

  14. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice.

    OpenAIRE

    1997-01-01

    Previous in vitro and in vivo studies have suggested that macrophage colony-stimulating factor (M-CSF) plays a role in atherogenesis. To examine this hypothesis, we have studied atherogenesis in osteopetrotic (op/op) mice, which lack M-CSF due to a structural gene mutation. Atherogenesis was induced either by feeding the mice a high fat, high cholesterol diet or by crossing op mice with apolipoprotein E (apo E) knockout mice to generate mice lacking both M-CSF and apo E. In both the dietary a...

  15. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis

    NARCIS (Netherlands)

    Zhang, B.; Ye, S.; Herrmann, S.M.; Eriksson, P.; Maat, M. de; Evans, A.; Arveiler, D.; Luc, G.; Cambien, F.; Hamsten, A.; Watkins, H.; Henney, A.M.

    1999-01-01

    Background - Gelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence va

  16. The relationship between cholesteryl ester transfer protein levels and risk factor profile in patients with familial hypercholesterolemia

    NARCIS (Netherlands)

    de Grooth, Greetje J; Smilde, Tineke J; Van Wissen, Sanne; Klerkx, Anke H E M; Zwinderman, Aeilko H; Fruchart, Jean-Charles; Kastelein, John J P; Stalenhoef, Anton F H; Kuivenhoven, Jan Albert

    2004-01-01

    BACKGROUND: Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. The role of CETP in atherogenesis is controversial. To better understand the relationships between plasma CETP levels, lipoproteins and atherosclerosis, we assessed these parameters in

  17. 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.

  18. Factor VIII deficiency does not protect against atherosclerosis

    NARCIS (Netherlands)

    Biere-Rafi, S.; Tuinenburg, A.; Haak, B.W.; Peters, M.; Huijgen, R.; de Groot, E.; Verhamme, P.; Peerlinck, K.; Visseren, F.L.J.; Kruip, M.J.H.A.; Laros-van Gorkom, B.A.P.; Gerdes, V.E.A.; Buller, H.R.; Schutgens, R.E.G.; Kamphuisen, P.W.

    2012-01-01

    Summary. Background: Hemophilia A patients have a lower cardiovascular mortality rate than the general population. Whether this protection is caused by hypocoagulability or decreased atherogenesis is unclear. Objectives: To evaluate atherosclerosis and endothelial function in hemophilia A patients w

  19. (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.......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....

  20. Enhancing reverse cholesterol transport/raising HDL cholesterol : new options for prevention and treatment of cardiovascular disease

    NARCIS (Netherlands)

    Jukema, J W; Lenselink, M; de Grooth, G J; Boekholdt, S M; Liem, A H; Kuivenhoven, J-A; Kastelein, J J P

    2004-01-01

    High-density lipoprotein cholesterol (HDL-c) plays a crucial role in the concept of reverse cholesterol transport and has many other beneficial properties which may interfere with atherogenesis and plaque rupture. Low HDL-c levels are currently considered to be an important risk factor for the devel

  1. Experimental atherosclerosis in rabbits on diets with milk fat and different proteins

    NARCIS (Netherlands)

    Hermus, R.J.J.

    1975-01-01

    In this thesis the literature about the pathogenesis of atherosclerosis has been reviewed. The various risk indicators for atherosclerosis are discussed and related to the theory about atherogenesis. A review of the influence of milk fat constituents and dietary proteins on serum lipids and atherosc

  2. 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 as a...

  3. 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 developin

  4. C242T Polymorphism in CYBA Gene (p22phox and Risk of Coronary Artery Disease in a Population of Caucasian Italians

    Directory of Open Access Journals (Sweden)

    Sabina Nasti

    2006-01-01

    Full Text Available Background: specific polymorphisms of genes regulating intracellular redox balance and oxidative stress are related to atherogenesis. Some studies have identified a relationship between progression of atherosclerosis and C242T mutation in CYBA gene coding for p22phox, a subunit of the NADH/NADPH oxidase system.

  5. Localizing role of hemodynamics in atherosclerosis in several human vertebrobasilar junction geometries

    NARCIS (Netherlands)

    Ravensbergen, J; Ravensbergen, JW; Krijger, JKB; Hillen, B; Hoogstraten, HW

    1998-01-01

    Atherosclerosis is a common finding in the vertebrobasilar junction and in the basilar artery. Several theories try to link the process of atherogenesis with the forces exerted by the flowing blood. An attractive relation has been found between the locations in vessels at which atherosclerotic plaqu

  6. Accumulation of myeloperoxidase-positive neutrophils in atherosclerotic lesions in LDLR-/- mice

    NARCIS (Netherlands)

    van Leeuwen, Marcella; Gijbels, Marion J. J.; Duijvestijn, Adriaan; Smook, Marjan; van de Gaar, Marie Jose; Heeringa, Peter; de Winther, Menno P. J.; Tervaert, Jan Willem Cohen

    2008-01-01

    Objective-Atherosclerosis is a chronic inflammatory disease in which the immune system plays an important role. Neutrophils have not been thoroughly studied in the context of atherogenesis. Here, we investigated neutrophils in the development of murine atherosclerotic lesions. Methods and Results-LD

  7. 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.

  8. 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, placebo-control

  9. High-density lipoprotein loses its anti-inflammatory capacity by accumulation of pro-inflammatory-serum amyloid A

    NARCIS (Netherlands)

    Toelle, Markus; Huang, Tao; Schuchardt, Mirjam; Jankowski, Vera; Pruefer, Nicole; Jankowski, Joachim; Tietge, Uwe J. F.; Zidek, Walter; van der Giet, Markus

    2012-01-01

    Aims High-density lipoprotein (HDL) is known to have potent anti-inflammatory properties. Monocyte chemoattractant protein-1 is an important pro-inflammatory cytokine in early atherogenesis. There is evidence that HDL can lose its protective function during inflammatory disease. In patients with end

  10. Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes

    NARCIS (Netherlands)

    Stoger, J. Lauran; Boshuizen, Marieke C. S.; Brufau, Gemma; Gijbels, Marion J. J.; Wolfe, Ine M. J.; van der Velden, Saskia; Pottgens, Chantal C. H.; Vergouwe, Monique N.; Wijnands, Erwin; Beckers, Linda; Goossens, Pieter; Kerksiek, Anja; Havinga, Rick; Muller, Werner; Luetjohann, Dieter; Groen, Albert K.; de Winther, Menno P. J.

    2016-01-01

    Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be d

  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 plasm...

  12. 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...

  13. Different effects of anthocyanins and phenolic acids from wild blueberry (Vaccinium angustifolium) on monocytes adhesion to endothelial cells in a TNF-α stimulated proinflammatory environment

    DEFF Research Database (Denmark)

    Del Bo', Cristian; Roursgaard, Martin; Porrini, Marisa;

    2016-01-01

    Scope: Monocyte adhesion to the vascular endothelium is a crucial step in the early stagesof atherogenesis. This study aims to investigate the capacity of an anthocyanin (ACN) andphenolic acid (PA) rich fraction (RF) of a wild blueberry, single ACNs (cyanidin, malvidin,delphinidin) and related...

  14. 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 bot

  15. Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development

    NARCIS (Netherlands)

    Luchtefeld, Maren; Grothusen, Christina; Gagalick, Andreas; Jagavelu, Kumaravelu; Schuett, Harald; Tietge, Uwe J. F.; Pabst, Oliver; Grote, Karsten; Drexler, Helmut; Foerster, Reinhold; Schieffer, Bernhard

    2010-01-01

    Background-Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the

  16. 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)

    2007-11-02

    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

  17. Inflammation and its echo in atherosclerosis

    NARCIS (Netherlands)

    van Leuven, S.I.

    2009-01-01

    Inflammation plays a major role during all phases of atherogenesis from plaque initiation up to plaque rupture. In this thesis the role of inflammation in the pathophysiology of atherosclerosis is examined from different angles. In part I the effect of various pro-inflammatory mediators is examined

  18. In silico analyses of metagenomes from human atherosclerotic plaque samples

    DEFF Research Database (Denmark)

    Mitra, Suparna; Drautz-Moses, Daniela I; Alhede, Morten;

    2015-01-01

    BACKGROUND: Through several observational and mechanistic studies, microbial infection is known to promote cardiovascular disease. Direct infection of the vessel wall, along with the cardiovascular risk factors, is hypothesized to play a key role in the atherogenesis by promoting an inflammatory ...

  19. 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....

  20. 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.

  1. 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

    Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both cl...... 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....... 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...

  2. [CHARACTERISTIC OF ALTERATIONS OF ARTERIES IN PATIENTS WITH ISCHEMIC HEART DISEASE AND CHRONIC HEPATITIS C].

    Science.gov (United States)

    Guliaev, N I; Kuznetsov, V V; Poltareĭko, D S; Qleksiuk, I B; Gordienko, A V; Barsukov, A V

    2015-01-01

    The article presents an assessment of degree and type of atherosclerosis of coronary and non-coronary vessels in old patients with ischemic heart disease associated with chronic viral hepatitis C (VHC), the incidence of myocardial infarction and the possibility of participation chronic VHC in atherogenesis. Patients with ischemic heart disease have correlation of atherosclerosis of arteries with age, hypercholesterinemia. Patients without chronic VHC more often give a higher risk of myocardial infarction, especially in early period (1-1,5 years) of onset of ischemic heart disease clinical implications. Patients with ischemic heart disease associated with chronic viral hepatitis C more often have generalized alterations in vessels, multifocal type of alteration. So, participation of VHC in atherogenesis is most probably connected with maintenance of chronic immune inflammation in vascular endothelium.

  3. Treating dyslipidemias: is inflammation the missing link?

    Science.gov (United States)

    Papoutsidakis, Nikolaos; Deftereos, Spyridon; Giannopoulos, Georgios; Panagopoulou, Vasiliki; Manolis, Antonis S; Bouras, Georgios

    2014-01-01

    Low-grade chronic inflammation is now being held as an important process in the development of atherosclerosis, with new links between dyslipidemia and inflammation being constantly found. While most studies aim to discover inflammatory pathways leading from dyslipidemia to atherogenesis, there is evidence that inflammation can also act in reverse, altering lipid metabolism in unfavorable ways, possibly creating a vicious cycle of inflammationdyslipidemia- inflammation. This is highly relevant for the search of novel therapeutic targets. In this review, after a brief account of the inflammatory mechanisms leading from dyslipidemia to atherogenesis, we focus on what is currently known about the ways inflammation can impair lipid metabolism and whether anti-inflammatory therapies could have a role in dyslipidemia management.

  4. Mycophenolate mofetil (MMF): firing at the atherosclerotic plaque from different angles?

    Science.gov (United States)

    van Leuven, Sander I; Kastelein, John J P; Allison, Anthony C; Hayden, Michael R; Stroes, Erik S G

    2006-02-01

    Atherosclerosis is characterized by a persistent, low-grade inflammatory state in which immune cell activation is inseparably linked to plaque formation and destabilization. The T-lymphocyte in particular has emerged as a pivotal player throughout the course of atherogenesis. As a consequence, the concept that immune modulation is a suitable target for cardiovascular prevention is currently an important focus of research. Mycophenolate mofetil (MMF) has emerged as a non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) that exerts cytostatic effects, particularly on proliferating T-lymphocytes. In addition, MMF has other immune-modulating effects, such as downregulation of the expression of adhesion molecules and attenuation of monocyte and macrophage responses. Given the added benefit that MMF is well tolerated, this immunosuppressive agent constitutes an attractive candidate for the modulation of inflammatory activation in atherogenesis. The present review provides an overview of the potential anti-atherogenic properties of MMF.

  5. 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.

  6. 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

  7. 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.

  8. Oxidized LDL Triggers Pro-Oncogenic Signaling in Human Breast Mammary Epithelial Cells Partly via Stimulation of MiR-21

    OpenAIRE

    2012-01-01

    Dyslipidemia and obesity are primary risk factors for the development of atherosclerosis and are also epidemiologically linked to increased susceptibility to a variety of cancers including breast cancer. One of the prominent features of dyslipidemia is enhanced production of oxidized LDL (ox-LDL), which has been shown to be implicated in key steps of atherogenesis including inflammatory signaling and proliferation of vascular cells. In this study we analyzed the effects of ox-LDL in human mam...

  9. Molecular mechanisms regulating expression and function of transcription regulator "inhibitor of differentiation 3"

    Institute of Scientific and Technical Information of China (English)

    Robert Wai-sui LIM; Jin-mei WU

    2005-01-01

    The transcription factor antagonist inhibitor of differentiation 3 (Id3) has been implicated in many diverse developmental, physiological and pathophysiological processes. Its expression and function is subjected to many levels of complex regulation. This review summarizes the current understanding of these mechanisms and describes how they might be related to the diverse functions that have been attributed to the Id3 protein. Detailed understanding of these mechanisms should provide insights towards the development of therapeutic approaches to various diseases, including cancer and atherogenesis.

  10. Increased platelet aggregability following an atherogenic diet in rabbits

    OpenAIRE

    Velkovski Saško D.; Mazić Sanja; Nešić Dejan M.; Igrački Iva; Milošević Verica L.; Starčević Vesna P.

    2002-01-01

    In atherosclerosis researches different animal models are used but the most common is the rabbit, because of the easy development of atherosclerotic lesions. Atherosclerosis is a multicellular process and platelets play an important role in atherogenesis. Excessive plasma lipids stimulate platelet aggregability and thus atherosclerosis development. The effects of an atherogenic diet on lipid status, abdominal aorta wall structure, and platelet aggregability were studied in rabbits. Adult male...

  11. 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...

  12. Influence of glycated low density lipoprotein on the proliferation,expression of intercellular adhesion molecule-1,von Willebrand factor of human umbilical endothelial cells

    Institute of Scientific and Technical Information of China (English)

    LU Jun; LIU Hui-ying; ZHANG Xiu-zhen; LEI Tao

    2009-01-01

    @@ Diabetes mellitus known as its macro-and microangiopathy has caused thousands of mortality per year.Recent researches showed that hyperglycemia,advanced glycation end products(AGEs)and some other factors acted on the process of atherogenesis.AGEs can combine with receptors of AGEs(RAGEs),which exist on the vascular endothelium,smooth muscle cells,macrophage,lymphocyte and so on.

  13. 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...... antibodies other than the ability to inhibit uptake of OxLDL by macrophages, to inhibit atherosclerosis....

  14. Ivabradine Reduces Chemokine-Induced CD4-Positive Lymphocyte Migration

    OpenAIRE

    Thomas Walcher; Peter Bernhardt; Dusica Vasic; Helga Bach; Renate Durst; Wolfgang Rottbauer; Daniel Walcher

    2010-01-01

    Aims. Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that ivabradine, a selective I(f)-channel blocker, reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice, hitherto nothing is known about the mechanism by which ivabradine modulates plaque formation. Therefore, the present study investigated whether ivabradine regulates chemokine-induced migration of lymphocytes. Methods and results. Stimulation of CD...

  15. Protective effects of trilinolein extracted from Panax notoginseng against cardiovascular disease

    Institute of Scientific and Technical Information of China (English)

    Paul CHAN; G Neil THOMAS; Brian TOMLINSON

    2002-01-01

    Trilinolein is a triacylglycerol purified from a commonly used traditional Chinese medicine Panax notoginseng.Trilinolein has been reported to provide a number of beneficial effects including reducing thrombogenicity and arrhythmias and increasing erythrocyte deformability. Additionally, trilinolein has been reported to be an antioxidant,which can counteract free radical damage associated with atherogenesis, and myocardial damage seen with ischaemia and reperfusion. These pharmacologic effects may explain the perceived benefits derived from treating circulatory disorders with the herb over the centuries.

  16. 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.

  17. Angiogenesis is a link between atherosclerosis and tumorigenesis: role of LOX-1.

    Science.gov (United States)

    Jiang, Junlin; Yan, Meiling; Mehta, Jawahar L; Hu, Changping

    2011-10-01

    Angiogenesis is defined as the formation of new blood vessels sprouting from pre-existing vessels. It plays an important role not only in physiological situations such as embryonic vascular development and wound healing, but also in pathological conditions including atherogenesis and evolution and spread of certain tumors. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor for oxidized low density lipoprotein (ox-LDL), is mainly expressed in endothelial cells. It has diverse physiological functions and it could be a link between atherogenesis and tumorigenesis. The risk factors for atherosclerosis like hypertension, diabetes mellitus and hyperlipidemia are associated with LOX-1. Dyslipidemia and obesity are also being recognized as risk factor for certain tumors. LOX-1 is also found to be important for maintaining the transformed state in developmentally diverse cancer cell lines and for tumor growth. There is emerging evidence that LOX-1 plays an important role in the angiogenesis process. In this review, we outline the roles of angiogenesis in atherogenesis and tumorigenesis, and describe the role of LOX-1 as a potential molecular target for blocking angiogenesis.

  18. 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

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

    Science.gov (United States)

    Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M; Brown, Robert J

    2014-09-05

    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.

  20. Sex Steroids Block the Initiation of Atherosclerosis.

    Science.gov (United States)

    Naftolin, Frederick; Mehr, Holly; Fadiel, Ahmed

    2016-12-01

    Atherosclerosis is the main cause of death in men and women. This so-called "hardening of the arteries" results from advanced atherogenesis, the accumulation and death of subendothelial fat-laden macrophages (vascular plaque). The macrophages are attracted as the result of signals from injured vessels recruiting and activating cells to quell the injury by inflammation. Among the recruited cells are circulating monocytes that may be captured by the formation of neural cell adhesion molecule (nCAM) tethers between the monocytes and vascular endothelium; the tethers are dependent on electrostatic binding between distal segments of apposed nCAM molecules. The capture of monocytes is followed by their entry into the subendothelial area as macrophages, many of which will remain and become the fat-laden foam cells in vascular plaque. Neural cell adhesion molecules are subject to sialylation that blocks their electrostatic binding. We showed that estradiol-induced nCAM sialylases are present in vascular endothelial cells and tested whether sex steroid pretreatment of human vascular endothelium could inhibit the capture of monocytes. Using in vitro techniques, pretreatment of human arterial endothelial cells with estradiol, testosterone, dehydroepiandrosterone and dihydrotestosterone all induced sialylation of endothelial cells and, in a dose-response manner, reduced the capture of monocytes. Steroid hormones are protective against atherogenesis and its sequellae. Sex steroid depletion is associated with atherosclerosis. Based on this knowledge plus our results using sex steroid pretreatment of endothelial cells, we propose that the blockade of the initial step in atherogenesis by sex steroid-induced nCAM sialylation may be crucial to hormonal prevention of atherosclerosis.

  1. 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.

  2. Interaction of vascular smooth muscle cells and monocytes by soluble factors synergistically enhances IL-6 and MCP-1 production.

    Science.gov (United States)

    Chen, Li; Frister, Adrian; Wang, Song; Ludwig, Andreas; Behr, Hagen; Pippig, Susanna; Li, Beibei; Simm, Andreas; Hofmann, Britt; Pilowski, Claudia; Koch, Susanne; Buerke, Michael; Rose-John, Stefan; Werdan, Karl; Loppnow, Harald

    2009-04-01

    Inflammatory mechanisms contribute to atherogenesis. Monocyte chemoattractant protein (MCP)-1 and IL-6 are potent mediators of inflammation. Both contribute to early atherogenesis by luring monocytes and regulating cell functions in the vessel wall. MCP-1 and IL-6 production resulting from the interaction of invading monocytes with local vessel wall cells may accelerate atherosclerosis. We investigated the influence of the interaction of human vascular smooth muscle cells (SMCs) with human mononuclear cells (MNCs) or monocytes on IL-6 and MCP-1 production in a coculture model. Interaction synergistically enhanced IL-6 and MCP-1 production (up to 30- and 10-fold, respectively) compared with separately cultured cells. This enhancement was mediated by CD14-positive monocytes. It was dependent on the SMC-to-MNC/monocyte ratio, and as few as 0.2 monocytes/SMC induced the synergism. Synergistic IL-6 production was observed at the protein, mRNA, and functional level. It was mediated by soluble factors, and simultaneous inhibition of IL-1, TNF-alpha, and IL-6 completely blocked the synergism. IL-1, TNF-alpha, and IL-6 were present in the cultures. Blockade of the synergism by soluble glycoprotein 130Fc/soluble IL-6 receptor, as well as the induction of synergistic IL-6 production by costimulation of SMCs with IL-1, TNF-alpha, and hyper-IL-6, suggested the involvement of IL-6 trans-signaling. The contribution of IL-6 was consistent with enhanced STAT3 phosphorylation. The present data suggest that SMC/monocyte interactions may augment the proinflammatory status in the tissue, contributing to the acceleration of early atherogenesis.

  3. Paraoxonase 1 polymorphism Q192R affects the pro-inflammatory cytokine TNF-alpha in healthy males

    Directory of Open Access Journals (Sweden)

    Rimbach Gerald

    2011-05-01

    Full Text Available Abstract Background Human paraoxonase 1 (PON1 is an HDL-associated enzyme with anti-oxidant/anti-inflammatory properties that has been suggested to play an important protective role against coronary heart diseases and underlying atherogenesis. The common PON1 Q192R polymorphism (rs662, A>G, a glutamine to arginine substitution at amino acid residue 192, has been analyzed in numerous association studies as a genetic marker for coronary heart diseases, however, with controversial results. Findings To get a better understanding about the pathophysiological function of PON1, we analyzed the relationships between the Q192R polymorphism, serum paraoxonase activity and serum biomarkers important for atherogenesis. Genotyping a cohort of 49 healthy German males for the Q192R polymorphism revealed an allele distribution of 0.74 and 0.26 for the Q and R allele, respectively, typical for Caucasian populations. Presence of the R192 allele was found to be associated with a significantly increased paraoxonase enzyme activity of 187.8 ± 11.4 U/l in comparison to the QQ192 genotype with 60.5 ± 4.9 U/l. No significant differences among the genotypes were found for blood pressure, asymmetric dimethylarginine, LDL, HDL, triglycerides, and cholesterol. As expected, MIP-2 alpha a cytokine rather not related to atherosclerosis is not affected by the PON1 polymorphism. In contrast to that, the pro-inflammatory cytokine TNF-alpha is enhanced in R192 carriers (163.8 ± 24.7 pg/ml vs 94.7 ± 3.2 pg/ml in QQ192 carriers. Conclusions Our findings support the hypothesis that the common PON1 R192 allele may be a genetic risk factor for atherogenesis by inducing chronic low-grade inflammation.

  4. Characterization of ASC-2 as an antiatherogenic transcriptional coactivator of liver X receptors in macrophages.

    Science.gov (United States)

    Kim, Geun Hyang; Park, Keunhee; Yeom, Seon-Yong; Lee, Kyung Jin; Kim, Gukhan; Ko, Jesang; Rhee, Dong-Kwon; Kim, Young Hoon; Lee, Hye Kyung; Kim, Hae Won; Oh, Goo Taeg; Lee, Ki-Up; Lee, Jae W; Kim, Seung-Whan

    2009-07-01

    Activating signal cointegrator-2 (ASC-2) functions as a transcriptional coactivator of many nuclear receptors and also plays important roles in the physiology of the liver and pancreas by interacting with liver X receptors (LXRs), which antagonize the development of atherosclerosis. This study was undertaken to establish the specific function of ASC-2 in macrophages and atherogenesis. Intriguingly, ASC-2 was more highly expressed in macrophages than in the liver and pancreas. To inhibit LXR-specific activity of ASC-2, we used DN2, which contains the C-terminal LXXLL motif of ASC-2 and thereby acts as an LXR-specific, dominant-negative mutant of ASC-2. In DN2-overexpressing transgenic macrophages, cellular cholesterol content was higher and cholesterol efflux lower than in control macrophages. DN2 reduced LXR ligand-dependent increases in the levels of ABCA1, ABCG1, and apolipoprotein E (apoE) transcripts as well as the activity of luciferase reporters driven by the LXR response elements (LXREs) of ABCA1, ABCG1, and apoE genes. These inhibitory effects of DN2 were reversed by overexpression of ASC-2. Chromatin immunoprecipitation analysis demonstrated that ASC-2 was recruited to the LXREs of the ABCA1, ABCG1, and apoE genes in a ligand-dependent manner and that DN2 interfered with the recruitment of ASC-2 to these LXREs. Furthermore, low-density lipoprotein receptor (LDLR)-null mice receiving bone marrow transplantation from DN2-transgenic mice showed accelerated atherogenesis when administered a high-fat diet. Taken together, these results indicate that suppression of the LXR-specific activity of ASC-2 results in both defective cholesterol metabolism in macrophages and accelerated atherogenesis, suggesting that ASC-2 is an antiatherogenic coactivator of LXRs in macrophages.

  5. 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...

  6. Reduced glomerular size- and charge-selectivity in clinically healthy individuals with microalbuminuria

    DEFF Research Database (Denmark)

    Jensen, J S; Borch-Johnsen, K; Deckert, T

    1995-01-01

    The pathophysiologic mechanism behind microalbuminuria, a potential atherosclerotic risk factor, was explored by measuring fractional clearances of four endogenous plasma proteins of different size and electric charge (albumin, beta 2-microglobulin, immunoglobulin G, and immunoglobulin G4). Twenty......-microglobulin clearance was similar in the two groups. Since total IgG and the IgG4 subclass are of similar size and configuration but electrically neutral and negative, respectively; these findings indicate that microalbuminuria is associated with decreased size- and charge-selectivity of the glomerular vessel...... wall. Hypothetically, such alterations may reflect generalized vascular abnormalities linking microalbuminuria to atherogenesis....

  7. 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 measured...... phenotypes. 74% of hemodialysis patients showed PON phenotype 1, 21% PON phenotype 2, and 5% PON phenotype 3. Compared to hemodialysis patients with PON 1, patients with PON 2 or 3 showed higher conversion rates for 4-nitrophenylacetate. We observed a significant reduction of PON ratio with increasing...

  8. 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.

  9. [Myocardial infarction and anabolic steroid use. A case report].

    Science.gov (United States)

    Godon, P; Bonnefoy, E; Guérard, S; Munet, M; Velon, S; Brion, R; Touboul, P

    2000-07-01

    The potential cardiotoxicity of anabolic steroids is not well known. The authors report the case of a young man who was a top class body builder and who developed severe ischaemic cardiomyopathy presenting with an inferior wall myocardial infarction. The clinical history revealed prolonged and intensive usage of two types of anabolic steroids to be the only risk factor. This cardiotoxicity may be related to several physiopathological mechanisms: accelerated atherogenesis by lipid changes, increased platelet aggregation, coronary spasm or a direct toxic effect on the myocytes. The apparent scarcity of the reported clinical details in the literature is probably an underestimation of the consequences of this usage.

  10. Nonfasting hyperlipidemia and cardiovascular disease

    DEFF Research Database (Denmark)

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

    2009-01-01

    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......, total cholesterol/HDL cholesterol, and apolipoprotein B/apolipoprotein A1 all associate with increased risk of cardiovascular disease. These new data open the possibility that nonfasting rather than fasting lipid profiles can be used for cardiovascular risk prediction. If implemented, this would...

  11. Interaction of reactive oxygen species in atherogenetic properties of advanced glycation end products in diabetes%活性氧与糖基化终产物致动脉粥样硬化作用的关系

    Institute of Scientific and Technical Information of China (English)

    冯契; 刘乃丰

    2003-01-01

    There is overwhelming evidence for an involvement of reactive oxygen species(ROS) in the pathogenesis of atherosclerosis (AS) in diabetes mellitus (DM). For many years, knowledge on the contribution to diabetic complications and vascular disease induced by advanced glycation end-products (AGEs) has been rising. During the development of atherosclerosis, AGEs and ROS might have interaction. In this article, weprovided four angles of view to discuss the role of ROS in the pathogenesis of atherosclerosis: the chemistry of ROS, the effect of vascular targets of ROS on activity of AGEs, the role of ROS in the pathogenesis of atherogenesis by AGEs, the same effect of ROS and AGEs-transcriptional regulation.

  12. Using recombinant CD74 protein to inhibit the activity of macrophage migration inhibitory factor (MIF) in vitro

    Institute of Scientific and Technical Information of China (English)

    Zhi-xinSHAN; Xi-yongYU; Qiu-xiongLIN; Yong-hengFU

    2005-01-01

    AIM Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in the pathogenesis of a variety of autoimmune and inflammatory diseases, including arthritis, glomerulonephritis, Gram-positive and Gram-negative sepsis, and atherogenesis. Recent studies showed that CD74(antigen-associated invariant chain Ⅱ) is a high-affinity membrane-binding protein for MIF. The purpose of the present study was to express the recombinant human CD74 in E. coli and inhibit the activity of MIF by using recombinant CD74 in vitro.

  13. 18F-FDG PET Imaging of Murine Atherosclerosis: Association with Gene Expression of Key Molecular Markers

    OpenAIRE

    2012-01-01

    AIM: 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. METHODS: Nine groups of apoE(-/-) mice were given normal chow or high-fat diet. At different time-points, (18)F-FDG PET/contrast-enhanced CT scans were performed on dedicated animal scanners. After scans, animals were euthanized, aortas removed, gamma counted, RNA extracted from...

  14. Imaging coronary artery disease and the myocardial ischemic cascade: clinical principles and scope.

    Science.gov (United States)

    Renker, Matthias; Baumann, Stefan; Rier, Jeremy; Ebersberger, Ullrich; Fuller, Stephen R; Batalis, Nicholas I; Schoepf, U Joseph; Chiaramida, Salvatore A

    2015-03-01

    On a subcellular level, atherogenesis is characterized by the translocation of proatherogenic lipoproteins into the arterial wall. An inflammatory response involving complex repair mechanisms subsequently causes maladaptive vascular changes resulting in coronary stenosis or occlusion. The chronology of the underlying processes occurring from atherosclerosis to myocardial ischemia affect the selection and interpretation of diagnostic testing. An understanding of the ischemic cascade, atherosclerosis, coronary remodeling, plaque morphology, and their relationship to clinical syndromes is essential in determining which diagnostic modalities are useful in clinical practice.

  15. Primary and Secondary Prevention of Acute Coronary Syndromes: The Role of the Statins.

    Science.gov (United States)

    Diamantis, Evangelos; Troupis, Theodoros; Mazarakis, Antonios; Kyriakos, Giorgos; Troupis, Georgios; Skandalakis, Panagiotis

    2014-01-01

    Poor prognosis is strongly associated with Acute Coronary Syndrome (ACS) and, even though a number of treatment strategies are available, the incidence of subsequent serious complications after an acute event is still high. Statins are hypolipidemic factors and recent studies have demonstrated that they have a protective role during the process of atherogenesis and that they reduce mortality caused by cardiovascular diseases. This review tries to reveal the function of the statins as a component of the primary and secondary action of acute coronary syndrome and to describe the lifestyle changes that have the same effect as the use of statins.

  16. Wnt signaling in cardiovascular physiology.

    Science.gov (United States)

    Marinou, K; Christodoulides, C; Antoniades, C; Koutsilieris, M

    2012-12-01

    Wnt signaling pathways play a key role in cardiac development, angiogenesis, and cardiac hypertrophy; emerging evidence suggests that they are also involved in the pathophysiology of atherosclerosis. Specifically, an important role for Wnts has been described in the regulation of endothelial inflammation, vascular calcification, and mesenchymal stem cell differentiation. Wnt signaling also induces monocyte adhesion to endothelial cells and is crucial for the regulation of vascular smooth-muscle cell (VSMC) behavior. We discuss how the Wnt pathways are implicated in vascular biology and outline the role of Wnt signaling in atherosclerosis. Dissecting Wnt pathways involved in atherogenesis and cardiovascular disease may provide crucial insights into novel mechanisms with therapeutic potential for atherosclerosis.

  17. A novel approach to the assessment of vascular endothelial function

    Energy Technology Data Exchange (ETDEWEB)

    Sathasivam, S; Siddiqui, Z; Greenwald, S [Pathology Group, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (United Kingdom); Phababpha, S; Sengmeuan, P; Detchaporn, P; Kukongviriyapan, U, E-mail: s.e.greenwald@qmul.ac.uk [Department of Physiology, Khon Kaen University, Khon Kaen (Thailand)

    2011-08-17

    Impaired endothelial function (EF) is associated with atherogenesis, and its quantitative assessment has prognostic value. Currently, methods based on assessing flow-mediated dilation (FMD) are technically difficult and expensive. We tested a novel way of assessing EF by measuring the time difference between pulses arriving at the middle fingers of each hand (f-f{Delta}T), whilst FMD is induced in one arm. We compared f-f{Delta}T with standard methods in healthy and diseased subjects. Our findings suggest that the proposed simple and inexpensive technique gives comparable results and has the potential to qualitatively assess EF in the clinical setting, although further work is required.

  18. Inflammation, lipid metabolism dysfunction, and hypertension: Active research fields in atherosclerosis-related cardiovascular disease in China

    Institute of Scientific and Technical Information of China (English)

    YIN Kai; TANG ChaoKe

    2011-01-01

    Atherosclerosis-related cardiovascular disease is one of the leading causes of death in China [1].With advances in our understanding of the molecular mechanisms of atherosclerosis vascular inflammation,lipid metabolism dysfunction,and hypertension are regarded as the main pathogenetic pathways of both early atherogenesis and advanced plaque rupture [2,3].Currently,much attention is being paid to the control of these pathways,which offers the potential for development of novel therapeutic approaches in the treatment of cardiovascular disease in China.

  19. 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....

  20. OxLDL induced p53-dependent apoptosis by activating p38MAPK and PKCδ signaling pathways in J774A.1 macrophage cells

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Dear Editor,The sub-endothelial retention of lipoproteins is one of the key events that trigger the atherosclerosis process.Low-density lipoprotein (LDL) particles trapped within the arterial wall are prone to progressive oxidation by monocytes/macrophages.Oxidized LDL (oxLDL) is present in atherosclerotic lesions,and has been suggested to play a significant role in atherogenesis (Nishi et al.,2002).The pathophysiology of atherosclerosis involves both apoptosis and proliferation at different stages of the vessel lesion.In advanced atherosclerotic plaques,up to 50% of the apoptotic cells are macrophages,which may promote core expansion and plaque instability (Tabas et al.,2009).

  1. [Hyperhomocysteinaemia: physiopathology and medical implications].

    Science.gov (United States)

    Torre Delgadillo, A; Téllez Zenteno, J F; Morales Buenrrostro, L E

    2000-01-01

    Homocysteine is an intermediate aminoacid result of the conversion of methionine to cysteine. Homocystinuria or the hyperhomocysteinaemia are the most frequently related disorders of this aminoacid, being the former an autosomic recessive alteration, whereas the latter is conditioned by multiple factors, being the most important the genetic and nutritional factors. In the last years this alteration has regained special interest because of its increasing role in the thrombotic pathologies and the identification that hyperhomocysteinaemia represents an independent risk factor for the accelerated atherogenesis of multiple diseases. In this review physiopathological aspects and clinical implications of hyperhomocysteinaemia are mentioned as well as its diagnoses and treatment.

  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

    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. 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......]) at 868 sites in 36 countries. INTERVENTIONS: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES...

  4. Focal adhesion kinase modulates activation of NF-κB by flow in endothelial cells

    OpenAIRE

    Petzold, Tobias; Orr, A. Wayne; Hahn, Cornelia; Jhaveri, Krishna A.; Parsons, J Thomas; Schwartz, Martin Alexander

    2009-01-01

    Atherogenesis involves activation of NF-κB in endothelial cells by fluid shear stress. Because this pathway involves integrins, we investigated the involvement of focal adhesion kinase (FAK). We found that FAK was not required for flow-stimulated translocation of the p65 NF-κB subunit to the nucleus but was essential for phosphorylation of p65 on serine 536 and induction of ICAM-1, an NF-κB-dependent gene. NF-κB activation by TNF-α or hydrogen peroxide was FAK independent. Events upstream of ...

  5. Metabolic syndrome, inflammation and atherosclerosis - the role of adipokines in health and in systemic inflammatory rheumatic diseases.

    Science.gov (United States)

    Santos, Maria José; Fonseca, João Eurico

    2009-01-01

    Cardiovascular (CV) events are among the leading causes of morbidity and mortality in patients with inflammatory rheumatic diseases. It has been hypothesized that, in addition to the traditional CV risk factors, inflammation is a major contributor to atherogenesis. Metabolic syndrome (MetS) stands for a cluster of risk factors associated with insulin resistance and increased abdominal fat. Inflammation and MetS are intimately linked. Inflammatory biomarkers are frequently elevated in people with MetS and, conversely, the prevalence of MetS is higher in patients with chronic inflammatory rheumatic diseases, such as Rheumatoid Arthritis and Systemic Lupus Erythematosus. Inflammatory cytokines impair insulin sensitivity and can induce an adverse lipoprotein profile as seen in MetS. Furthermore, the presence of MetS correlates with increased subclinical atherosclerosis, major adverse CV events and death, making an important contribution to the CV burden in inflammatory diseases. Adipose tissue has recently emerged as an active organ that produces and secretes numerous mediators - adipokines - particularly relevant in energy homeostasis, inflammation, immune regulation and angiogenesis. These mediators arise as a potential link between MetS, inflammation and atherogenesis. Understanding the complex regulation and function of adipokines in health and disease is a priority since it may lead to new preventive and therapeutic interventions aiming to decrease CV risk.

  6. Adipose tissue deficiency results in severe hyperlipidemia and atherosclerosis in the low-density lipoprotein receptor knockout mice.

    Science.gov (United States)

    Wang, Mengyu; Gao, Mingming; Liao, Jiawei; Qi, Yanfei; Du, Ximing; Wang, Yuhui; Li, Ling; Liu, George; Yang, Hongyuan

    2016-05-01

    Adipose tissue can store over 50% of whole-body cholesterol; however, the physiological role of adipose tissue in cholesterol metabolism and atherogenesis has not been directly assessed. Here, we examined lipoprotein metabolism and atherogenesis in a unique mouse model of severe lipodystrophy: the Seipin(-/-) mice, and also in mice deficient in both low-density lipoprotein receptor (Ldlr) and Seipin: the Ldlr(-/-)Seipin(-/-) mice. Plasma cholesterol was moderately increased in the Seipin(-/-) mice when fed an atherogenic diet. Strikingly, plasma cholesterol reached ~6000 mg/dl in the Seipin(-/-)Ldlr(-/-) mice on an atherogenic diet, as compared to ~1000 mg/dl in the Ldlr(-/-) mice on the same diet. The Seipin(-/-)Ldlr(-/-) mice also developed spontaneous atherosclerosis on chow diet and severe atherosclerosis on an atherogenic diet. Rosiglitazone treatment significantly reduced the hypercholesterolemia of the Seipin(-/-)Ldlr(-/-) mice, and also alleviated the severity of atherosclerosis. Our results provide direct evidence, for the first time, that the adipose tissue plays a critical role in the clearance of plasma cholesterol. Our results also reveal a previously unappreciated strong link between adipose tissue and LDLR in plasma cholesterol metabolism.

  7. Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

    Science.gov (United States)

    Lindau, Alexandra; Härdtner, Carmen; Hergeth, Sonja P; Blanz, Kelly Daryll; Dufner, Bianca; Hoppe, Natalie; Anto-Michel, Nathaly; Kornemann, Jan; Zou, Jiadai; Gerhardt, Louisa M S; Heidt, Timo; Willecke, Florian; Geis, Serjosha; Stachon, Peter; Wolf, Dennis; Libby, Peter; Swirski, Filip K; Robbins, Clinton S; McPheat, William; Hawley, Shaun; Braddock, Martin; Gilsbach, Ralf; Hein, Lutz; von zur Mühlen, Constantin; Bode, Christoph; Zirlik, Andreas; Hilgendorf, Ingo

    2016-03-01

    Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.

  8. Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing

    Science.gov (United States)

    Tonami, Kazuo; Hata, Shoji; Aiuchi, Toshihiro; Lei, Xiao-Feng; Kim-Kaneyama, Joo-ri; Takeya, Motohiro; Itabe, Hiroyuki; Kurihara, Hiroki; Miyazaki, Akira

    2016-01-01

    Macrophages contribute to the development of atherosclerosis through pinocytotic deposition of native LDL–derived cholesterol in macrophages in the vascular wall. Inhibiting macrophage-mediated lipid deposition may have protective effects in atheroprone vasculature, and identifying mechanisms that potentiate this process may inform potential therapeutic interventions for atherosclerosis. Here, we report that dysregulation of exon junction complex–driven (EJC-driven) mRNA splicing confers hyperpinocytosis to macrophages during atherogenesis. Mechanistically, we determined that inflammatory cytokines induce an unconventional nonproteolytic calpain, calpain-6 (CAPN6), which associates with the essential EJC-loading factor CWC22 in the cytoplasm. This association disturbs the nuclear localization of CWC22, thereby suppressing the splicing of target genes, including those related to Rac1 signaling. CAPN6 deficiency in LDL receptor–deficient mice restored CWC22/EJC/Rac1 signaling, reduced pinocytotic deposition of native LDL in macrophages, and attenuated macrophage recruitment into the lesions, generating an atheroprotective phenotype in the aorta. In macrophages, the induction of CAPN6 in the atheroma interior limited macrophage movements, resulting in a decline in cell clearance from the lesions. Consistent with this finding, we observed that myeloid CAPN6 contributed to atherogenesis in a murine model of bone marrow transplantation. Furthermore, macrophages from advanced human atheromas exhibited increased CAPN6 induction and impaired CWC22 nuclear localization. Together, these results indicate that CAPN6 promotes atherogenicity in inflamed macrophages by disturbing CWC22/EJC systems. PMID:27525442

  9. 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.

  10. 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.

  11. Inhibition of autophagy ameliorates atherogenic inflammation by augmenting apigenin-induced macrophage apoptosis.

    Science.gov (United States)

    Wang, Qun; Zeng, Ping; Liu, Yuanliang; Wen, Ge; Fu, Xiuqiong; Sun, Xuegang

    2015-07-01

    Increasing evidences showed that the survival of macrophages promotes atherogenesis. Macrophage apoptosis in the early phase of atherosclerotic process negatively regulates the progression of atherosclerotic lesions. We demonstrated that a natural anti-oxidant apigenin could ameliorate atherogenesis in ApoE(-/-) mice. It reduced the number of foam cells and decreased the serum levels of tumor necrosis factor α, interleukin 1β (IL-1β) and IL-6. Our results showed that oxidized low-density lipoprotein (oxLDL) led to the secretion of pro-inflammatory cytokines. Apigenin-induced apoptosis and downregulated the secretion of TNF-α, IL-6 and IL-1β. It is further supported by the use of zVAD, a pan-caspase inhibitor, demonstrating that apigenin lowered cytokine profile through induction of macrophage apoptosis. Moreover, apigenin-induced Atg5/Atg7-dependent autophagy in macrophages pretreated with oxLDL. Results illustrated that autophagy inhibition increased apigenin-induced apoptosis through activation of Bax. The present findings suggest that oxLDL maintained the survival of macrophages and activated the secretion of pro-inflammatory cytokines to initiate atherosclerosis. Apigenin-induced apoptosis of lipid-laden macrophages and resolved inflammation to ameliorate atherosclerosis. In conclusion, combination of apigenin with autophagy inhibition may be a promising strategy to induce foam cell apoptosis and subdue atherogenic cytokines.

  12. Neutrophils, lymphocytes, and monocytes exhibit diverse behaviors in transendothelial and subendothelial migrations under coculture with smooth muscle cells in disturbed flow.

    Science.gov (United States)

    Chen, Cheng-Nan; Chang, Shun-Fu; Lee, Pei-Ling; Chang, Kyle; Chen, Li-Jing; Usami, Shunichi; Chien, Shu; Chiu, Jeng-Jiann

    2006-03-01

    Atherosclerosis develops at regions of the arterial tree exposed to disturbed flow. The early stage of atherogenesis involves the adhesion of leukocytes (white blood cells [WBCs]) to and their transmigration across endothelial cells (ECs), which are located in close proximity to smooth muscle cells (SMCs). We investigated the effects of EC/SMC coculture and disturbed flow on the adhesion and transmigration of 3 types of WBCs (neutrophils, peripheral blood lymphocytes [PBLs], and monocytes) using our vertical-step flow (VSF) chamber, in which ECs were cocultured with SMCs in collagen gels. Such coculture significantly increased the adhesion and transmigration of neutrophils, PBLs, and monocytes under VSF, particularly in the reattachment area, where the rolling velocity of WBCs and their transmigration time were decreased, as compared with the other areas. Neutrophils, PBLs, and monocytes showed different subendothelial migration patterns under VSF. Their movements were more random and shorter in distance in the reattachment area. Coculture of ECs and SMCs induced their expressions of adhesion molecules and chemokines, which contributed to the increased WBC adhesion and transmigration. Our findings provide insights into the mechanisms of WBC interaction with the vessel wall (composed of ECs and SMCs) under the complex flow environments found in regions of prevalence for atherogenesis.

  13. In vitro model of atherosclerosis using coculture of arterial wall cells and macrophage.

    Science.gov (United States)

    Wada, Y; Sugiyama, A; Kohro, T; Kobayashi, M; Takeya, M; Naito, M; Kodama, T

    2000-12-01

    In order to determine the precise mechanism of the interactions between different types of cells, which are common phenomena in tissues and organs, the importance of coculture techniques are becoming increasingly important. In the area of cardiology, artificial arteries have been developed, based on the understanding of physiological communication of the arterial smooth muscle cells (SMC), endothelial cells (EC), and the extracellular matrix (ECM). In the study of atherosclerosis, the modification of low-density lipoprotein (LDL), which result in the recruitment and accumulation of white blood cells, especially, monocytes/macrophages, and foam cell formation, are hypothesized. Although there are well known animal models, an in vitro model of atherogenesis with a precisely known atherogenesis mechanism has not yet been developed. In this paper, an arterial wall reconstruction model using rabbit primary cultivated aortic SMCs and ECs, was shown. In addition, human peripheral monocytes were used and the transmigration of monocytes was observed by scanning electron and laser confocal microscopy. Monocyte differentiation into macrophages was shown by immunohistochemistry and comprehensive gene expression analysis. With the modified form of LDL, the macrophages were observed to accumulate lipids with a foamy appearance and differentiate into the foam cells in the ECM between the ECs and SMCs in the area of our coculture model.

  14. Effect of zinc and nitric oxide on monocyte adhesion to endothelial cells under shear stress.

    Science.gov (United States)

    Lee, Sungmun; Eskin, Suzanne G; Shah, Ankit K; Schildmeyer, Lisa A; McIntire, Larry V

    2012-03-01

    This study describes the effect of zinc on monocyte adhesion to endothelial cells under different shear stress regimens, which may trigger atherogenesis. Human umbilical vein endothelial cells were exposed to steady shear stress (15 dynes/cm(2) or 1 dyne/cm(2)) or reversing shear stress (time average 1 dyne/cm(2)) for 24 h. In all shear stress regimes, zinc deficiency enhanced THP-1 cell adhesion, while heparinase III reduced monocyte adhesion following reversing shear stress exposure. Unlike other shear stress regimes, reversing shear stress alone enhanced monocyte adhesion, which may be associated with increased H(2)O(2) and superoxide together with relatively low levels of nitric oxide (NO) production. L-N(G)-Nitroarginine methyl ester (L-NAME) treatment increased monocyte adhesion under 15 dynes/cm(2) and under reversing shear stress. After reversing shear stress, monocyte adhesion dramatically increased with heparinase III treatment followed by a zinc scavenger. Static culture experiments supported the reduction of monocyte adhesion by zinc following endothelial cell cytokine activation. These results suggest that endothelial cell zinc levels are important for the inhibition of monocyte adhesion to endothelial cells, and may be one of the key factors in the early stages of atherogenesis.

  15. Optical monitoring of the concentration profile of submicron latex particles in flow through a translucent water-permeable tube: demonstration of flow-dependent concentration polarization of plasma proteins at a blood/endothelium boundary

    Science.gov (United States)

    Wada, Shigeo; Iwai, Toshiaki; Karino, Takeshi

    1999-05-01

    It is well accepted that hemodynamics plays an important role in atherogenesis in man. However, the precise mechanisms have not been elucidated yet. Recently, Karino and his coworkers hypothesized that flow-dependent concentration polarization of low-density lipoproteins (LDL: a carrier of cholesterol) may occur at a blood/endothelium boundary, leading to a high risk of atherogenesis in regions of slow flow and low wall shear rate where the concentration of LDL builds up. In this study, we attempted to confirm experimentally their predictions by measuring optically the concentration profile of polystyrene microspheres (used as a model of LDL) flowing in steady flow through a dialyses tube (used as a model of an artery) by transversing a laser beam across the tube and detecting the intensity of the transmitted light. It was found that surface concentration of the microsphere certainly increases with decreasing the flow rate (hence wall shear rate) and it occurs even under the conditions of a very low water filtration velocity encountered in normal arteries in vivo, thus giving a strong support to the hypothesis proposed by Karino et al.

  16. Inflammation in coronary artery diseases

    Institute of Scientific and Technical Information of China (English)

    LI Jian-jun

    2011-01-01

    The concept that atherosclerosis is an inflammation has been increasingly recognized,and subsequently resulted in great interest in revealing the inflammatory nature of the atherosclerotic process.More recently,a large body of evidence has supported the idea that inflammatory mechanisms play a pivotal role throughout all phases of atherogenesis,from endothelial dysfunction and the formation of fatty streaks to plaque destabilization and the acute coronary events due to vulnerable plaque rupture.Indeed,although triggers and pathways of inflammation are probably multiple and vary in different clinical entities of atherosclerotic disorders,an imbalance between anti-inflammatory mechanisms and pro-inflammatory factors will result in an atherosclerotic progression.Vascular endothelial dysfunction and lipoprotein retention into the arterial intima have been reported as the earliest events in atherogenesis with which inflammation is linked.Inflammatory has also been extended to the disorders of coronary microvasculature,and associated with special subsets of coronary artery disease such as silent myocardial ischemia,myocardial ischemia-reperfusion,cardiac syndrome X,variant angina,coronary artery ectasia,coronary calcification and in-stent restenosis.Inflammatory biomarkers,originally studied to better understand the pathophysiology of atherosclerosis,have generated increasing interest among researches and clinicians.The identification of inflammatory biomarkers and cellular/molecular pathways in atherosclerotic disease represent important goals in cardiovascular disease research,in particular with respect of the development of therapeutic strategies to prevent or reverse atherosclerotic diseases.

  17. 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.

  18. Phenotypic and functional heterogeneity of macrophages and dendritic cell subsets in the healthy and atherosclerosis-prone aorta.

    Directory of Open Access Journals (Sweden)

    Elena V Galkina

    2012-03-01

    Full Text Available Atherosclerosis continues to be the leading cause of cardiovascular disease. Development of atherosclerosis depends on chronic inflammation in the aorta and multiple immune cells are involved in this process. Importantly, resident macrophages and dendritic cells are present within the healthy aorta, but the functions of these cells remain poorly characterized. Local inflammation within the aortic wall promotes the recruitment of monocytes and dendritic cell precursors to the aorta and micro-environmental factors direct the differentiation of these emigrated cells into multiple subsets of macrophages and dendritic cells. Recent data suggest that several populations of macrophages and dendritic cells can co-exist within the aorta. Although the functions of M1, M2, Mox and M4 macrophages are well characterized in vitro, there is a limited set of data on the role of these populations in atherogenesis in vivo. Recent studies on the origin and the potential role of aortic dendritic cells provide novel insights into the biology of aortic dendritic cell subsets and prospective mechanisms of the immune response in atherosclerosis. This review integrates the results of experiments analyzing heterogeneity of dendritic cells and macrophage subsets in healthy and diseased vessels and briefly discusses the known and potential functions of these cells in atherogenesis.

  19. Effects of cyclodextrins on the structure of LDL and its susceptibility to copper-induced oxidation.

    Science.gov (United States)

    Ao, Meiying; Gan, Chaoye; Shao, Wenxiang; Zhou, Xing; Chen, Yong

    2016-08-25

    Cyclodextrins (CDs) have long been widely used as drug/food carriers and were recently developed as drugs for the treatment of diseases (e.g. Niemann-Pick C1 and cancers). It is unknown whether cyclodextrins may influence the structure of low-density lipoprotein (LDL), its susceptibility to oxidation, and atherogenesis. In this study, four widely used cyclodextrins including α-CD, γ-CD, and two derivatives of β-CD (HPβCD and MβCD) were recruited. Interestingly, agarose gel electrophoresis (staining lipid and protein components of LDL with Sudan Black B and Coomassie brilliant blue, respectively but simultaneously) shows that cyclodextrins at relatively high concentrations caused disappearance of the LDL band and/or appearance of an additional protein-free lipid band, implying that cyclodextrins at relatively high concentrations can induce significant electrophoresis-detectable lipid depletion of LDL. Atomic force microscopy (AFM) detected that MβCD (as a representative of cyclodextrins) induced size decrease of LDL particles in a dose-dependent manner, further confirming the lipid depletion effects of cyclodextrins. Moreover, the data from agarose gel electrophoresis, conjugated diene formation, MDA production, and amino group blockage of copper-oxidized LDL show that cyclodextrins can impair LDL susceptibility to oxidation. It implies that cyclodextrins probably help to inhibit atherogenesis by lowering LDL oxidation.

  20. Effect of LDL concentration polarization on the uptake of LDL by human endothelial cells and smooth muscle cells co-cultured

    Institute of Scientific and Technical Information of China (English)

    Zufeng Ding; Yubo Fan; Xiaoyan Deng

    2009-01-01

    To substantiate our hypothesis that concentration polarization of low-density lipoprotein (LDL) plays an important role in the localization of atherogenesis, we investigated the effects of wall shear stress and water fdtration rate (or perfusion pressure) on the luminal surface LDL concentration (cw) and the LDL uptake by human vascular endothelial cells and smooth muscle cells co-cultured on a permeable membrane using a parallel-plate flow chamber technique and a flow cyto-metry method. The results indicated that the uptake of fluorescent labeled LDL (DiI-LDL) by the co-cultured cells was positively correlated with cw in a non-linear fashion. When cw was low, the uptake increased very sharply with increasing cw. Then the increase became gradual and the uptake was seemingly leveled out when cw reached beyond 160 μg/ml. The present study therefore has provided further experimental evidence that concentration polarization may occur in the arterial system and have a positive correlation with the uptake of LDLs by the arterial wall, which gives support to our hypothesis regarding the localization of atherogenesis.

  1. Cryptotanshinone inhibits TNF-α-induced early atherogenic events in vitro.

    Science.gov (United States)

    Ahmad, Zuraini; Ng, Chin Theng; Fong, Lai Yen; Bakar, Nurul Ain Abu; Hussain, Nor Hayuti Mohd; Ang, Kok Pian; Ee, Gwendoline Cheng Lian; Hakim, Muhammad Nazrul

    2016-05-01

    Endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis. Salvia miltiorrhiza (danshen) is a traditional Chinese medicine that has been effectively used to treat cardiovascular disease. Cryptotanshinone (CTS), a major lipophilic compound isolated from S. miltiorrhiza, has been reported to possess cardioprotective effects. However, the anti-atherogenic effects of CTS, particularly on tumor necrosis factor-α (TNF-α)-induced endothelial cell activation, are still unclear. This study aimed to determine the effect of CTS on TNF-α-induced increased endothelial permeability, monocyte adhesion, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), monocyte chemoattractant protein 1 (MCP-1) and impaired nitric oxide production in human umbilical vein endothelial cells (HUVECs), all of which are early events occurring in atherogenesis. We showed that CTS significantly suppressed TNF-α-induced increased endothelial permeability, monocyte adhesion, sICAM-1, sVCAM-1 and MCP-1, and restored nitric oxide production. These observations suggest that CTS possesses anti-inflammatory properties and could be a promising treatment for the prevention of cytokine-induced early atherogenesis.

  2. Low-density lipoprotein accumulation within a carotid artery with multilayer elastic porous wall: fluid-structure interaction and non-Newtonian considerations.

    Science.gov (United States)

    Deyranlou, Amin; Niazmand, Hamid; Sadeghi, Mahmood-Reza

    2015-09-18

    Low-density lipoprotein (LDL), which is recognized as bad cholesterol, typically has been regarded as a main cause of atherosclerosis. LDL infiltration across arterial wall and subsequent formation of Ox-LDL could lead to atherogenesis. In the present study, combined effects of non-Newtonian fluid behavior and fluid-structure interaction (FSI) on LDL mass transfer inside an artery and through its multilayer arterial wall are examined numerically. Navier-Stokes equations for the blood flow inside the lumen and modified Darcy's model for the power-law fluid through the porous arterial wall are coupled with the equations of mass transfer to describe LDL distributions in various segments of the artery. In addition, the arterial wall is considered as a heterogeneous permeable elastic medium. Thus, elastodynamics equation is invoked to examine effects of different wall elasticity on LDL distribution in the artery. Findings suggest that non-Newtonian behavior of filtrated plasma within the wall enhances LDL accumulation meaningfully. Moreover, results demonstrate that at high blood pressure and due to the wall elasticity, endothelium pores expand, which cause significant variations on endothelium physiological properties in a way that lead to higher LDL accumulation. Additionally, results describe that under hypertension, by increasing angular strain, endothelial junctions especially at leaky sites expand more dramatic for the high elastic model, which in turn causes higher LDL accumulation across the intima layer and elevates atherogenesis risk.

  3. Chlamydophila pneumoniae infection and cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Rajnish Joshi

    2013-01-01

    Full Text Available Atherosclerosis is a multifactorial vascular inflammatory process; however, the inciting cause for inflammation remains unclear. Two decades ago, Chlamydophila pneumoniae (formerly Chlamydia pneumoniae infection was proposed as a putative etiologic agent. We performed a PubMed search using the keywords Chlamydia and atherosclerosis in a Boolean query to identify published studies on C. pneumoniae and its role in atherogenesis, and to understand research interest in this topic. We found 1,652 published articles on this topic between 1991 and 2011. We analyzed relevant published studies and found various serological, molecular, and animal modeling studies in the early period. Encouraged by positive results from these studies, more than a dozen antibiotic clinical-trials were subsequently conducted, which did not find clinical benefits of anti-Chlamydophila drug therapy. While many researchers believe that the organism is still important, negative clinical trials had a similar impact on overall research interest. With many novel mechanisms identified for atherogenesis, there is a need for newer paradigms in Chlamydophila-atherosclerosis research.

  4. Cilostazol inhibits accumulation of triglyceride in aorta and platelet aggregation in cholesterol-fed rabbits.

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    Hideki Ito

    Full Text Available Cilostazol is clinically used for the treatment of ischemic symptoms in patients with chronic peripheral arterial obstruction and for the secondary prevention of brain infarction. Recently, it has been reported that cilostazol has preventive effects on atherogenesis and decreased serum triglyceride in rodent models. There are, however, few reports on the evaluation of cilostazol using atherosclerotic rabbits, which have similar lipid metabolism to humans, and are used for investigating the lipid content in aorta and platelet aggregation under conditions of hyperlipidemia. Therefore, we evaluated the effect of cilostazol on the atherosclerosis and platelet aggregation in rabbits fed a normal diet or a cholesterol-containing diet supplemented with or without cilostazol. We evaluated the effects of cilostazol on the atherogenesis by measuring serum and aortic lipid content, and the lesion area after a 10-week treatment and the effect on platelet aggregation after 1- and 10-week treatment. From the lipid analyses, cilostazol significantly reduced the total cholesterol, triglyceride and phospholipids in serum, and moreover, the triglyceride content in the atherosclerotic aorta. Cilostazol significantly reduced the intimal atherosclerotic area. Platelet aggregation was enhanced in cholesterol-fed rabbits. Cilostazol significantly inhibited the platelet aggregation in rabbits fed both a normal diet and a high cholesterol diet. Cilostazol showed anti-atherosclerotic and anti-platelet effects in cholesterol-fed rabbits possibly due to the improvement of lipid metabolism and the attenuation of platelet activation. The results suggest that cilostazol is useful for prevention and treatment of atherothrombotic diseases with the lipid abnormalities.

  5. Phenotypic and functional heterogeneity of macrophages and dendritic cell subsets in the healthy and atherosclerosis-prone aorta.

    Science.gov (United States)

    Butcher, Matthew J; Galkina, Elena V

    2012-01-01

    Atherosclerosis continues to be the leading cause of cardiovascular disease. Development of atherosclerosis depends on chronic inflammation in the aorta and multiple immune cells are involved in this process. Importantly, resident macrophages and dendritic cells (DCs) are present within the healthy aorta, but the functions of these cells remain poorly characterized. Local inflammation within the aortic wall promotes the recruitment of monocytes and DC precursors to the aorta and micro-environmental factors direct the differentiation of these emigrated cells into multiple subsets of macrophages and DCs. Recent data suggest that several populations of macrophages and DCs can co-exist within the aorta. Although the functions of M1, M2, Mox, and M4 macrophages are well characterized in vitro, there is a limited set of data on the role of these populations in atherogenesis in vivo. Recent studies on the origin and the potential role of aortic DCs provide novel insights into the biology of aortic DC subsets and prospective mechanisms of the immune response in atherosclerosis. This review integrates the results of experiments analyzing heterogeneity of DCs and macrophage subsets in healthy and diseased vessels and briefly discusses the known and potential functions of these cells in atherogenesis.

  6. 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.

  7. Ivabradine Reduces Chemokine-Induced CD4-Positive Lymphocyte Migration

    Directory of Open Access Journals (Sweden)

    Thomas Walcher

    2010-01-01

    Full Text Available Aims. Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that ivabradine, a selective I(f-channel blocker, reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice, hitherto nothing is known about the mechanism by which ivabradine modulates plaque formation. Therefore, the present study investigated whether ivabradine regulates chemokine-induced migration of lymphocytes. Methods and results. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.0±0.1 fold increase in cell migration (P<.01; n=7. Pretreatment of cells with ivabradine reduces this effect to a maximal 1.2±0.1 fold induction at 0.1 µmol/L ivabradine (P<.01 compared to SDF-1-treated cells, n=7. The effect of ivabradine on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, ivabradine inhibits activation of the small GTPase Rac and phosphorylation of the Myosin Light Chain (MLC. Moreover, ivabradine treatment reduces f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration. Conclusion. Ivabradine inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T-cell migration in early atherogenesis, ivabradine may be a promising tool to modulate this effect.

  8. Study of Interleukin-1ß in Essential Hypertension

    Directory of Open Access Journals (Sweden)

    Hoda A. Hassan ,Amal Ahmed Mokhar,Adila M.Gad, Amal Abdel Aleem

    2002-09-01

    Full Text Available The observation of increased blood interleukin 1ß levels in subjects with hypertension is a finding that raises the hypothesis that the immune mechanisms may be involved in the atherogenic cascade . Our aim in this study was to investigate the possible interrelations between blood pressure, lipid profile and IL-1ß to clarify the possible participation of this cytokine in the cascade phenomena presented during the process of essential hypertension (EH such as atherogenesis. 28 hypertensive patients and 10 healthy volunteers served as control matched for age and sex were included. IL-1ß (enzyme immunoassay, total cholesterol , triglycerides, high and low density lipoprotein cholesterol were estimated. Significant elevation of IL- 1ß in hypertensive patients in comparison to the control was found with positive correlation between IL- 1ß and diastolic. Systolic and the mean Blood pressure r=0.16, 0.046 and 0.28 respectively . Also the study showed positive correlation between IL-1ß and body mass index (r=0.42, serum cholesterol and LDL cholesterol and negative one with TG while no correlation was found with HDL cholesterol TG. Elevated IL-1ß levels in subjects with EH may be related causally to the role of immunologic mechanisms in the development of EH and even to the atherogenic cascade.Thus we can suggest that the presence of high levels of IL-1ß may be an additional risk factor for atherogenesis in patients with EH

  9. Enhanced External Counterpulsation Inducing Arterial Hemodynamic Variations and Its Chronic Effect on Endothelial Function

    Institute of Scientific and Technical Information of China (English)

    DU Jian-hang; WU Gui-fu; ZHENG Zhen-sheng; DAI Gang; FENG Ming-zhe

    2014-01-01

    To make clear the precise hemodynamic mechanism underlying the anti-atherogenesis benefit of enhanced external couterpulsation(EECP) treatment, and to investigate the proper role of some important hemodynamic factors during the atherosclerotic progress, a comprehensive study combining long-term animal experiment and numerical solving was conducted in this paper. An experimentally induced hypercholesterolemic porcine model was developed and the chronic EECP intervention was subjected. Basic hemodynamic measurement was performed in vivo, as well as the arterial endothelial samples were extracted for physiological examination. Meanwhile, a numerical model was introduced to solve the complex hemodynamic factors such as WSS and OSI. The results show that EECP treatment resulted in significant increase of the instant levels of arterial WSS, blood pressure, and OSI. During EECP treatment, the instant OSI level of the common carotid arteries over cardiac cycles raised to a mean value of 8.58 ×10-2 ±2.13 ×10-2. Meanwhile, the chronic intervention of EECP treatment significantly reduced the atherosclerotic lesions in abdominal aortas and the endothelial cellular adherence. The present study suggests that the unique blood flow pattern induced by EECP treatment and the augmentation of WSS level in cardiac cycles may be the most important hemodynamic mechanism that contribute to its anti-atherogenesis effect. And as one of the indices that cause great concern in current hemodynamic study, OSI may not play a key role during the initiation of atherosclerosis.

  10. [Atherosclerosis--progression by nonspecific activation of the immune system].

    Science.gov (United States)

    Lehr, Hans-Anton; Sagban, Tolga Atilla; Kirkpatrick, C James

    2002-04-15

    Atherogenesis is a disease of middle-sized and large-caliber blood vessels that can be divided into three major phases. The initial lesions of early atherosclerosis are characterized by the adhesion and subendothelial emigration of blood-borne monocytes, which differentiate into macrophages and provide the morphologic basis for the formation of foam cells and fatty streak lesions. These lesions are found in most children and teenagers in industrialized nations. The next key event in atherogenesis is the proliferation of smooth muscle cells within the intima and media, resulting in the gradual compromise of the vessel lumen. Myofibroblastic cells also contribute to lesion growth through the production of excessive amounts of extracellular matrix. Such lesions are clinically silent unless progression to the next phase continues: the lesions degenerate, forming a mostly necrotic "lipid core" consisting of extracellular lipid, cholesterol crystals, inflammatory cells and necrotic debris. A fibrous cap is formed which prevents the interaction of blood cells, particularly of platelets with the highly proaggregatory material found in the lipid core. However, continuous inflammatory activity and/or heightened mechanical stress (i.e., in hypertension) tends to weaken the fibrous caps. Eventually, plaque rupture ensues, platelets aggregate, and the lesions become clinically manifest in such dramatic events as myocardial infarction, stroke, or mesenteric ischemia. Research into lesion formation and progression is limited by the fact that lesions develop in silence over many decades and that animal models only incompletely model the situation in humans. Most currently debated concepts accept the "response to injury" hypothesis formulated by the late Russell Ross and the multi-factorial nature of atherogenesis. The discussion today circles around the relative contributions of low density lipoproteins (oxidized or enzymatically modified LDL?), the immune response (adaptive or

  11. HDL functionality in reverse cholesterol transport--Challenges in translating data emerging from mouse models to human disease.

    Science.gov (United States)

    Lee-Rueckert, Miriam; Escola-Gil, Joan Carles; Kovanen, Petri T

    2016-07-01

    Whereas LDL-derived cholesterol accumulates in atherosclerotic lesions, HDL particles are thought to facilitate removal of cholesterol from the lesions back to the liver thereby promoting its fecal excretion from the body. Because generation of cholesterol-loaded macrophages is inherent to atherogenesis, studies on the mechanisms stimulating the release of cholesterol from these cells and its ultimate excretion into feces are crucial to learn how to prevent lesion development or even induce lesion regression. Modulation of this key anti-atherogenic pathway, known as the macrophage-specific reverse cholesterol transport, has been extensively studied in several mouse models with the ultimate aim of applying the emerging knowledge to humans. The present review provides a detailed comparison and critical analysis of the various steps of reverse cholesterol transport in mouse and man. We attempt to translate this in vivo complex scenario into practical concepts, which could serve as valuable tools when developing novel HDL-targeted therapies.

  12. Steady flow in a model of the human carotid bifurcation. Part II--laser-Doppler anemometer measurements.

    Science.gov (United States)

    Bharadvaj, B K; Mabon, R F; Giddens, D P

    1982-01-01

    The evidence for hypothesizing a relationship between hemodynamics and atherogenesis as well as the motivation for selecting the carotid bifurcation for extensive fluid dynamic studies has been discussed in Part I of this two-paper sequence. Part II deals with velocity measurements within the bifurcation model described by Fig. 1 and Table 1 of the previous paper. A plexiglass model conforming to the dimensions of the average carotid bifurcation was machined and employed for velocity measurements with a laser-Doppler anemometer (LDA). The objective of this phase of the study was to obtain quantitative information on the velocity field and to estimate levels and directions of wall shear stress in the region of the bifurcation.

  13. DEGENERATIVE AORTIC STENOSIS: PATHOGENESIS AND NEW PRINCIPLES OF TREATMENT

    Directory of Open Access Journals (Sweden)

    O. V. Andropova

    2006-01-01

    Full Text Available Aim. To reveal of markers of inflammation and progression of calcification in patients with degenerative aortic stenosis (DAS. Material and methods. A single-stage study was done in 85 patients with degenerative calcification of aortic valve (42 patients with DAS and 43 patients without DAS. The techniques for assessing the severity of aortic valve calcification included ultrasonic diagnostics and multislice spiral computed tomography. Markers of inflammation and lipid profile were investigated.    Results. Higher blood levels of total holesterol and holesterol of low density lipoprotein were revealed in patients with DAS in comparison with patients without DAS. They also had higher levels of inflammation markers: C-reactive protein and interleukin-6. There were significant correlations between DAS severity, lipid metabolism disturbances and inflammation markers. Conclusion. Atherogenesis and inflammation may have pathogenic influence on progression of aortic valve calcification and DAS development by lipid infiltration and endothelium cells damage.

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

    Science.gov (United States)

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

    2010-12-01

    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 measured PON activity in 377 hemodialysis patients photometrically using the substrates 4-nitrophenylacetate and phenylacetate. The PON ratio was calculated from 4-nitrophenylacetate-derived activity divided by phenylacetate-derived activity. Frequency distribution of the PON ratio showed three different PON phenotypes. 74% of hemodialysis patients showed PON phenotype 1, 21% PON phenotype 2, and 5% PON phenotype 3. Compared to hemodialysis patients with PON 1, patients with PON 2 or 3 showed higher conversion rates for 4-nitrophenylacetate. We observed a significant reduction of PON ratio with increasing dialysis vintage (Pvintage. In conclusion, plasma PON ratio significantly declines with increasing dialysis vintage.

  15. 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...

  16. Alcohol and atherosclerosis

    Directory of Open Access Journals (Sweden)

    Murilo Foppa

    2001-02-01

    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.

  17. 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

  18. Cathepsins and cystatin C in atherosclerosis and obesity.

    Science.gov (United States)

    Lafarge, Jean-Charles; Naour, Nadia; Clément, Karine; Guerre-Millo, Michèle

    2010-11-01

    Given the increasing prevalence of human obesity worldwide, there is an urgent need for a better understanding of the molecular mechanisms linking obesity to metabolic and cardiovascular diseases. Our knowledge is nevertheless limited regarding molecules linking adipose tissue to downstream complications. The importance of cathepsins was brought to light in this context. Through a large scale transcriptomic analysis, our group recently identified the gene encoding cathepsin S as one of the most deregulated gene in the adipose tissue of obese subjects and positively correlated with body mass index. Other members of the cathepsin family are expressed in the adipose tissue, including cathepsin K and cathepsin L. Given their implication in atherogenesis, these proteases could participate into the well established deleterious relationship between enlarged adipose tissue and increased cardiovascular risk. Here, we review the clinical and experimental evidence relevant to the role of cathepsins K, L and S and their most abundant endogenous inhibitor, cystatin C, in atherosclerosis and in obesity.

  19. Physiology and pathophysiology of selectins, integrins, and IgSF cell adhesion molecules focusing on inflammation. A paradigm model on infectious endocarditis.

    Science.gov (United States)

    Golias, Christos; Batistatou, Anna; Bablekos, Georgios; Charalabopoulos, Alexandros; Peschos, Dimitrios; Mitsopoulos, Panagiotis; Charalabopoulos, Konstantinos

    2011-06-01

    The development of adhesion bonds, either among cells or among cells and components of the extracellular matrix, is a crucial process. These interactions are mediated by some molecules collectively known as adhesion molecules (CAMs). CAMs are ubiquitously expressed proteins playing a central role in controlling cell migration, proliferation, survival, and apoptosis. Besides their key function in physiological maintenance of tissue integrity, CAMs play an eminent role in various pathological processes such as cardiovascular disorders, atherogenesis, atherosclerotic plaque progression and regulation of the inflammatory response. CAMs such as selectins, integrins, and immunoglobulin superfamily take part in interactions between leukocyte and vascular endothelium (leukocyte rolling, arrest, firm adhesion, migration). Experimental data and pathologic observations support the assumption that pathogenic microorganisms attach to vascular endothelial cells or sites of vascular injury initiating intravascular infections. In this review a paradigm focusing on cell adhesion molecules pathophysiology and infective endocarditis development is given.

  20. 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.

  1. 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

    1997-01-01

    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. PMID:9108101

  2. [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.

  3. [Vitamin K2 as a protector of bone health and beyond].

    Science.gov (United States)

    Kaneki, Masao

    2005-04-01

    Several lives of evidence indicate a protective effect of vitamin K against osteoporosis. Epidemiological studies showed that low vitamin K intake is associated with the increased risk of osteoporosis. Vitamin K2 (menatetrenone, MK-4) has been clinically used in the treatment of patients with osteoporosis in Japan, Korea and Thailand. Previous studies demonstrated the efficacy of vitamin K2 (45 mg/day) to prevent bone loss and reduce the rate of vertebral fractures, although a large, randomized intervention study is anticipated to provide more detailed evidence. Recently, vitamin K2 has been shown to reduce the progression of hepatocarcinoma. Moreover, it has been proposed that vitamin K may also have beneficial effects to prevent atherogenesis. The clarification of molecular mechanisms by which vitamin K2 exerts these salutary effects deserve further investigations.

  4. Economics of health and mortality special feature: race, infection, and arteriosclerosis in the past.

    Science.gov (United States)

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

    2007-08-14

    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.

  5. Mechanisms of endothelial dysfunction in obstructive sleep apnea

    Directory of Open Access Journals (Sweden)

    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

  6. 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....... to develop an animal model with combined atherosclerosis and psoriasis-like skin inflammation. METHODS: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to the ears twice per week for 8 weeks in atherosclerosis-prone apolipoprotein E deficient (ApoE(-/-)) mice. RESULTS: TPA led to localized...

  7. In silico analyses of metagenomes from human atherosclerotic plaque samples

    DEFF Research Database (Denmark)

    Mitra, Suparna; Drautz-Moses, Daniela I; Alhede, Morten

    2015-01-01

    BACKGROUND: Through several observational and mechanistic studies, microbial infection is known to promote cardiovascular disease. Direct infection of the vessel wall, along with the cardiovascular risk factors, is hypothesized to play a key role in the atherogenesis by promoting an inflammatory...... response leading to endothelial dysfunction and generating a proatherogenic and prothrombotic environment ultimately leading to clinical manifestations of cardiovascular disease, e.g., acute myocardial infarction or stroke. There are many reports of microbial DNA isolation and even a few studies of viable...... a challenge. RESULTS: To investigate microbiome diversity within human atherosclerotic tissue samples, we employed high-throughput metagenomic analysis on: (1) atherosclerotic plaques obtained from a group of patients who underwent endarterectomy due to recent transient cerebral ischemia or stroke. (2...

  8. Syndrom-Pathogen Effect of Ozone Therapy and Nauheim Baths on Patients with Cardiovascular Disease

    Directory of Open Access Journals (Sweden)

    Elena I. Sycheva

    2014-03-01

    Full Text Available Despite different theories of atherogenesis, pathogenesis of this disease is, foremost, associated with the lipid storage disease, blood rheological properties, lipid peroxidation. Microcirculation disorders have significant role for pathogenesis of many illnesses, primarily, cardiovascular. Among possible reasons of increased risk of their pathway are the increase in the activity of sympathetic neurovegetative system, psychoemotional tension emergion. Application of ‘gas’ therapy methods, such as ozone therapy and carbon dioxide in the form of Nauheim baths is one of the prospect trends in preventive treatment. The obtained results of these methods application in the course of resort treatment showed positive dynamics for homeostasis indicants. They can serve as an indication for the use of carbon dioxide and, especially, ozone therapy for multifactor preventive treatment of patients with cardiovascular diseases.

  9. Macrophage cholesterol homeostasis and metabolic diseases: critical role of cholesteryl ester mobilization.

    Science.gov (United States)

    Ghosh, Shobha

    2011-03-01

    Atherogenic dyslipidemia, including low HDL levels, is the major contributor of residual risk of cardiovascular disease that remains even after aggressive statin therapy to reduce LDL-cholesterol. Currently, distinction is not made between HDL-cholesterol and HDL, which is a lipoprotein consisting of several proteins and a core containing cholesteryl esters (CEs). The importance of assessing HDL functionality, specifically its role in facilitating cholesterol efflux from foam cells, is relevant to atherogenesis. Since HDLs can only remove unesterified cholesterol from macrophages while cholesterol is stored as CEs within foam cells, intracellular CE hydrolysis by CE hydrolase is vital. Reduction in macrophage lipid burden not only attenuates atherosclerosis but also reduces inflammation and linked pathologies such as Type 2 diabetes and chronic kidney disease. Targeting reduction in macrophage CE levels and focusing on enhancing cholesterol flux from peripheral tissues to liver for final elimination is proposed.

  10. 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.

  11. Fish oil may be an antidote for the cardiovascular risk of smoking.

    Science.gov (United States)

    McCarty, M F

    1996-04-01

    The fact that the cardiovascular risk of ex-smokers approximates that of non-smokers after two years of abstinence, implies that accelerated atherogenesis is not the chief mechanism of smoking-related heart disease. Indeed, smoking or nicotine have adverse effects on blood rheology, thrombotic risk, coronary blood flow, and risk for arrhythmias. Omega-3-rich fish oils can be expected to correct or compensate for a remarkable number of the adverse impacts of smoking/nicotine: increased plasma fibrinogen, decreased erythrocyte distensibility, increased plasma and blood viscosity, increased platelet aggregability, increased plasminogen activator inhibitor levels, vasoconstriction of the coronary bed, reduced fibrillation threshold, increased triglycerides, reduced high-density lipoprotein cholesterol, and increased production of superoxide by phagocytes. Smokers who cannot overcome their addiction should be encouraged to substitute nicotine aerosols/gum for tobacco and advised to use supplementary fish oil and other cardioprotective nutrients.

  12. Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression

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    Petrović Isidora

    2011-01-01

    Full Text Available The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene.

  13. Myeloperoxidase-Dependent LDL Modifications in Bloodstream Are Mainly Predicted by Angiotensin II, Adiponectin, and Myeloperoxidase Activity: A Cross-Sectional Study in Men

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    Karim Zouaoui Boudjeltia

    2013-01-01

    Full Text Available The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO, an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels.

  14. 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.

  15. 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.

  16. Oxygen transfer in human carotid artery bifurcation

    Institute of Scientific and Technical Information of China (English)

    Z.G.Zhang; Y.B.Fan; X.Y.Deng

    2007-01-01

    Arterial bifurcations are places where blood flow may be disturbed and slow recirculation flow may occur.To reveal the correlation between local oxygen transfer and atherogenesis, a finite element method was employed to simulate the blood flow and the oxygen transfer in the human carotid artery bifurcation. Under steady-state flow conditions, the numerical simulation demonstrated a variation in local oxygen transfer at the bifurcation, showing that the convective condition in the disturbed flow region may produce uneven local oxygen transfer at the blood/wall interface.The disturbed blood flow with formation of slow eddies in the carotid sinus resulted in a depression in oxygen supply to the arterial wall at the entry of the sinus, which in turn may lead to an atherogenic response of the arterial wall, and contribute to the development of atherosclerotic stenosis there.

  17. Testing the Role of Myeloid Cell Glucose Flux in Inflammation and Atherosclerosis

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    Tomohiro Nishizawa

    2014-04-01

    Full Text Available Inflammatory activation of myeloid cells is accompanied by increased glycolysis, which is required for the surge in cytokine production. Although in vitro studies suggest that increased macrophage glucose metabolism is sufficient for cytokine induction, the proinflammatory effects of increased myeloid cell glucose flux in vivo and the impact on atherosclerosis, a major complication of diabetes, are unknown. We therefore tested the hypothesis that increased glucose uptake in myeloid cells stimulates cytokine production and atherosclerosis. Overexpression of the glucose transporter GLUT1 in myeloid cells caused increased glycolysis and flux through the pentose phosphate pathway but did not induce cytokines. Moreover, myeloid-cell-specific overexpression of GLUT1 in LDL receptor-deficient mice was ineffective in promoting atherosclerosis. Thus, increased glucose flux is insufficient for inflammatory myeloid cell activation and atherogenesis. If glucose promotes atherosclerosis by increasing cellular glucose flux, myeloid cells do not appear to be the key targets.

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

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    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.

  19. [Secondary dyslipidemias].

    Science.gov (United States)

    Vargová, V; Pytliak, M; Mechírová, V

    2012-03-01

    Dyslipidemias rank among the most important preventabile factors of atherogenesis and its progression. This topic is increasingly being discussed as e.g. more than 50% of Slovak population die on atherosclerotic complications. According to etiology we distinguish primary dyslipidemias with strictly genetic background and secondary ones with origin in other disease or pathological state. Secondary dyslipidemias accompany various diseases, from common (endocrinopathies, renal diseases etc) to rare ones (thesaurismosis etc.) and represents one of symptoms of these diseases. Apart from particular clinical follow up of diagnosed dysipidemias, basic screening and secondary causes as well as treatment due to updated guidelines is recuired. In this review we present the most frequent dyslipidemias of clinical practice.

  20. Macrophages, Dendritic Cells, and Regression of Atherosclerosis

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    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.

  1. Atherogenic Factors and Their Epigenetic Relationships

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    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.

  2. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

    DEFF Research Database (Denmark)

    Koenen, RR; Hundelshausen, P; Nesmelova, IV

    2009-01-01

    Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4...... and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely...... monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects...

  3. ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression

    Science.gov (United States)

    Aryal, Binod; Rotllan, Noemi; Araldi, Elisa; Ramírez, Cristina M.; He, Shun; Chousterman, Benjamin G.; Fenn, Ashley M.; Wanschel, Amarylis; Madrigal-Matute, Julio; Warrier, Nikhil; Martín-Ventura, Jose L.; Swirski, Filip K.; Suárez, Yajaira; Fernández-Hernando, Carlos

    2016-07-01

    Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.

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

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    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.

  5. 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.

  6. 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.

  7. Update in atherothrombotic disease.

    Science.gov (United States)

    Viles-Gonzalez, Juan F; Anand, Sunil X; Valdiviezo, Carolina; Zafar, M Urooj; Hutter, Randolf; Sanz, Javier; Rius, Teresa; Poon, Michael; Fuster, Valentin; Badimon, Juan J

    2004-05-01

    Crucial advances in our understanding of the pathogenesis of atherothrombosis, defined as atherosclerosis and its thrombotic complications, have been achieved during the past two decades. The historical hypothesis of pathogenesis ("lipid accumulation") has evolved to integrate several factors contributing to the initiation and evolution of this complex disease. Endothelial dysfunction is considered to be the earliest event in atherogenesis. Inflammation and apoptosis play critical roles in its progression and onset. Tissue factor is postulated to be a central actor in determining plaque thrombogenicity. A hyperreactive state of the blood ("vulnerable blood") may be responsible for one-third of all the acute coronary syndromes. This review will discuss emerging concepts in the pathogenesis of and therapeutic approaches to atherothrombotic disease.

  8. Glycation of high-density lipoprotein in type 2 diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    SUN Jia-teng; SHEN Ying; L(U) An-kang; LU Lin; SHEN Wei-feng

    2013-01-01

    Objective To evaluate whether glycation of high-density lipoprotein (HDL) increases cardiovascular risk in patients with type 2 diabetes mellitus by altering its anti-atherogenic property.Data sources Data cited in this review were obtained mainly from Pubmed and Medline in English from 2000 to 2013,with keywords "glycation","HDL",and "atherosclerosis".Study selection Articles regarding glycation of HDL and its role in atherogenesis in both humans and experimental animal models were identified,retrieved and reviewed.Results Glycation alters the structure of HDL and its associated enzymes,resulting in an impairment of atheroprotective functionality and increased risks for cardiovascular events in type 2 diabetic patients.Conclusion Glycation of HDL exerts a deleterious effect on the development of cardiovascular complications in diabetes.

  9. Adventitial inflammation and its interaction with intimal atherosclerotic lesions

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    Mohammadreza eAkhavanpoor

    2014-08-01

    Full Text Available The presence of adventitial inflammation in correlation with atherosclerotic lesions has been recognized for decades. In the last years, several studies have investigated the relevance and impact of adventitial inflammation on atherogenesis. In the abdominal aorta of elderly Apoe-/- mice, adventitial inflammatory structures were characterized as organized ectopic lymphoid tissue, and therefore termed adventitial tertiary lymphoid organs (ATLOs. These ATLOs possess similarities in development, structure and function to secondary lymphoid organs. A crosstalk between intimal atherosclerotic lesions and ATLOs has been suggested, and several studies could demonstrate a potential role for medial vascular smooth muscle cells in this process. We here review the development, phenotypic characteristics, and function of ATLOs in atherosclerosis. Furthermore, we discuss the possible role of medial vascular smooth muscle cells and their interaction between plaque and ATLOs.

  10. Toll-Like Receptors, Their Ligands, and Atherosclerosis

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    Conrad P. Hodgkinson

    2011-01-01

    Full Text Available Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs and the expression of inflammatory proteins. TLRs, which recognize various pathogen-associated molecular patterns, are expressed in various cell types within the atherosclerotic plaque. Microbial agents are associated with an increased risk of atherosclerosis and this is, in part, due to activation of TLRs. Recently considerable evidence has been provided suggesting that endogenous proteins promote atherosclerosis by binding to TLRs. In this review, we describe the role of TLRs in atherosclerosis with particular emphasis on those atherogenic endogenous proteins that have been implicated as TLR ligands.

  11. Serum paraoxonase activity and protein thiols in patients with hyperlipidemia

    Institute of Scientific and Technical Information of China (English)

    Mungli Prakash; Jeevan K Shetty; Sudeshna Tripathy; Pannuri Vikram; Manish Verma

    2009-01-01

    Objective: In the present study we evaluated the paraoxonase activity and protein thiols level in south Indian population with newly diagnosed hyperlipidemia. Methods: The study was conducted on 55 newly diagnosed hyperlipidemic pa-tients and 57 healthy controls. Serum paraoxonase activity and protein thiols were estimated by spectrophotometeric method and lipid profile by enzymatic kinetic assay method. Results: Serum paraoxonase activity, protein thiols and high density lipoprotein levels were low and total cholesterol, triglycerides and low density lipoprutein levels were high in patients with hyperlipidemia compared to healthy controls ( P < 0.01 ). Serum paranxonase activity correlated positively with protein thiols and high density lipoprotein (P<0.01). Conclusion: Decreased paraoxonase activity and protein thiols were found in patients with hyperlipi-demia. This may indicate the susceptibility of this population to accelerated atherogenesis and protein oxidation.

  12. 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.

  13. Cytokines and Immune Responses in Murine Atherosclerosis.

    Science.gov (United States)

    Kusters, Pascal J H; Lutgens, Esther

    2015-01-01

    Atherosclerosis is an inflammatory disease of the vessel wall characterized by activation of the innate immune system, with macrophages as the main players, as well as the adaptive immune system, characterized by a Th1-dominant immune response. Cytokines play a major role in the initiation and regulation of inflammation. In recent years, many studies have investigated the role of these molecules in experimental models of atherosclerosis. While some cytokines such as TNF or IFNγ clearly had atherogenic effects, others such as IL-10 were found to be atheroprotective. However, studies investigating the different cytokines in experimental atherosclerosis revealed that the cytokine system is complex with both disease stage-dependent and site-specific effects. In this review, we strive to provide an overview of the main cytokines involved in atherosclerosis and to shed light on their individual role during atherogenesis.

  14. Beneficial or harmful influence of phytosterols on human cells?

    Science.gov (United States)

    Rubis, Blazej; Paszel, Anna; Kaczmarek, Mariusz; Rudzinska, Magdalena; Jelen, Henryk; Rybczynska, Maria

    2008-12-01

    So far, a protective influence of phytosterols on the human organism and atherogenesis has been suggested. Most studies have concentrated on the cytotoxic efficacy of phytosterols on cancer cells. However, there are only a few reports showing their influence on normal cells. The aim of the present study was to determine whether dietary plant sterols and their thermal processing products could influence the viability of normal, abdominal endothelial cells that play a crucial role in atherogenesis. Thus, we studied the effect of rapeseed oil-extract components, beta-sitosterol, cholesterol and their epoxy-derivatives, 5 alpha,6 alpha-epoxy-beta-sitosterol and 5 alpha,6 alpha-epoxycholesterol, on the proliferation and viability of human abdominal aorta endothelial cells HAAE-2 in vitro. We showed strong cytotoxic properties of beta-sitosterol in HAAE-2 cells (half maximal inhibitory concentration (IC50) = 1.99 (SEM 0.56) microm) and, interestingly, a weaker cytotoxic effect of 5 alpha,6 alpha-epoxy-beta-sitosterol (IC50>200 microm). Moreover, we observed a significantly stronger cytotoxic activity of beta-sitosterol than cholesterol (IC50 = 8.99 (SEM 2.74) microm). We also revealed that beta-sitosterol as well as cholesterol caused apoptosis, inducing caspase-3 activity in the cells (60 % increase compared with control cells) that corresponded to the DNA fragmentation analysis in a terminal uridine deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) study. Although absorption of plant sterols is low compared with cholesterol, they can still influence other physiological functions. Since they effectively reduce serum LDL-cholesterol and atherosclerotic risk but also decrease the viability of cancer cells as well as normal cells in a time- and dose-dependent manner in vitro, their influence on other metabolic processes remains to be elucidated.

  15. Oxidized Cholesteryl Esters and Phospholipids in Zebrafish Larvae Fed a High Cholesterol Diet

    Science.gov (United States)

    Fang, Longhou; Harkewicz, Richard; Hartvigsen, Karsten; Wiesner, Philipp; Choi, Soo-Ho; Almazan, Felicidad; Pattison, Jennifer; Deer, Elena; Sayaphupha, Tiffany; Dennis, Edward A.; Witztum, Joseph L.; Tsimikas, Sotirios; Miller, Yury I.

    2010-01-01

    A novel hypercholesterolemic zebrafish model has been developed to study early events of atherogenesis. This model utilizes optically transparent zebrafish larvae, fed a high cholesterol diet (HCD), to monitor processes of vascular inflammation in live animals. Because lipoprotein oxidation is an important factor in the development of atherosclerosis, in this study, we characterized the oxidized lipid milieu in HCD-fed zebrafish larvae. Using liquid chromatography-mass spectrometry, we show that feeding an HCD for only 2 weeks resulted in up to 70-fold increases in specific oxidized cholesteryl esters, identical to those present in human minimally oxidized LDL and in murine atherosclerotic lesions. The levels of oxidized phospholipids, such as 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine, and of various lysophosphatidylcholines were also significantly elevated. Moreover, lipoproteins isolated from homogenates of HCD-fed larvae induced cell spreading as well as ERK1/2, Akt, and JNK phosphorylation in murine macrophages. Removal of apoB-containing lipoproteins from the zebrafish homogenates with an anti-human LDL antibody, as well as reducing lipid hydroperoxides with ebselen, resulted in inhibition of macrophage activation. The TLR4 deficiency in murine macrophages prevented their activation with zebrafish lipoproteins. Using biotinylated homogenates of HCD-fed larvae, we demonstrated that their components bound to murine macrophages, and this binding was effectively competed by minimally oxidized LDL but not by native LDL. These data provide evidence that molecular lipid determinants of proatherogenic macrophage phenotypes are present in large quantities in hypercholesterolemic zebrafish larvae and support the use of the HCD-fed zebrafish as a valuable model to study early events of atherogenesis. PMID:20710028

  16. Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet.

    Directory of Open Access Journals (Sweden)

    Dennis H M Kusters

    Full Text Available To investigate therapeutic effects of annexin A1 (anxA1 on atherogenesis in LDLR-/- mice.Human recombinant annexin A1 (hr-anxA1 was produced by a prokaryotic expression system, purified and analysed on phosphatidylserine (PS binding and formyl peptide receptor (FPR activation. Biodistribution of 99mTechnetium-hr-anxA1 was determined in C57Bl/6J mice. 12 Weeks old LDLR-/- mice were fed a Western Type Diet (WTD during 6 weeks (Group I or 12 weeks (Group P. Mice received hr-anxA1 (1 mg/kg or vehicle by intraperitoneal injection 3 times per week for a period of 6 weeks starting at start of WTD (Group I or 6 weeks after start of WTD (Group P. Total aortic plaque burden and phenotype were analyzed using immunohistochemistry.Hr-anxA1 bound PS in Ca2+-dependent manner and activated FPR2/ALX. It inhibited rolling and adherence of neutrophils but not monocytes on activated endothelial cells. Half lives of circulating 99mTc-hr-anxA1 were <10 minutes and approximately 6 hours for intravenously (IV and intraperitoneally (IP administered hr-anxA1, respectively. Pharmacological treatment with hr-anxA1 had no significant effect on initiation of plaque formation (-33%; P = 0.21(Group I but significantly attenuated progression of existing plaques of aortic arch and subclavian artery (plaque size -50%, P = 0.005; necrotic core size -76% P = 0.015, hr-anxA1 vs vehicle (Group P.Hr-anxA1 may offer pharmacological means to treat chronic atherogenesis by reducing FPR-2 dependent neutrophil rolling and adhesion to activated endothelial cells and by reducing total plaque inflammation.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Microarray Analysis of Human Vascular Smooth Muscle Cell Responses to Bacterial Lipopolysaccharide

    Directory of Open Access Journals (Sweden)

    Joe Minta

    2007-01-01

    Full Text Available Accumulating evidence suggest a causal role of bacterial and viral infections in atherogenesis. Bacterial lipopolysaccharide (LPS has been shown to stimulate resting vascular smooth muscle cells (SMC with the production of inflammatory cytokines and modulation of quiescent cells to the proliferative and synthetic phenotype. To comprehensively identify biologically important genes associated with LPS-induced SMC phenotype modulation, we compared the transcriptomes of quiescent human coronary artery SMC and cells treated with LPS for 4 and 22 h. The SMCs responded robustly to LPS treatment by the differential regulation of several genes involved in chromatin remodeling, transcription regulation, translation, signal transduction, metabolism, host defense, cell proliferation, apoptosis, matrix formation, adhesion and motility and suggest that the induction of clusters of genes involved in cell proliferation, migration and ECM production may be the main force that drives the LPS-induced phenotypic modulation of SMC rather than the differential expression of a single gene or a few genes. An interesting observation was the early and dramatic induction of four tightly clustered interferon-induced genes with tetratricopeptide repeats (IFIT1, 2, 4, 5. siRNA knock-down of IFIT1 in SMC was found to be associated with a remarkable up-regulation of TP53, CDKN1A and FOS, suggesting that IFIT1 may play a role in cell proliferation. Our data provide a comprehensive list of genes involved in LPS biology and underscore the important role of LPS in SMC activation and phenotype modulation which is a pivotal event in the onset of atherogenesis.

  19. Monocytes harboring cytomegalovirus: interactions with endothelial cells, smooth muscle cells, and oxidized low-density lipoprotein. Possible mechanisms for activating virus delivered by monocytes to sites of vascular injury.

    Science.gov (United States)

    Guetta, E; Guetta, V; Shibutani, T; Epstein, S E

    1997-07-01

    Cytomegalovirus (CMV) infection and its periodic reactivation from latency may contribute to atherogenesis and restenosis. It is unknown how CMV is delivered to the vessel wall and is reactivated. We examined the following hypothesis: CMV, present in monocytes recruited to sites of vascular injury, is activated by endothelial cell (EC) or smooth muscle cell (SMC) contact and by oxidized low-density lipoproteins (oxLDLs). The CMV major immediate-early promoter (MIEP) controls immediate-early (IE) gene expression, and thereby viral replication. To determine whether elements of the vessel wall can activate CMV present in monocytes, we transiently transfected the promonocytic cell line HL-60 with a chloramphenicol acetyltransferase reporter gene construct driven by MIEP. MIEP activity increased 1.7 +/- 0.5-fold (P = .02) when the transfected HL-60 cells were cocultured with ECs, 4.5 +/- 1.5-fold when cocultured with SMCs (P = .03), and 2.0 +/- 0.5-fold (P = .01) when exposed to oxLDL. The combination of oxLDL and EC coculture increased MIEP activity over 7-fold. We also found that freshly isolated human monocytes, infected with endothelium-passaged CMV, were capable of transmitting infectious virus to cocultured ECs or SMCs. CMV-related progression of atherosclerosis or restenosis may, at least in part, involve monocyte delivery of the virus to the site of vascular injury, where the vascular milieu, ie, contact with ECs, SMCs, and oxLDL, can contribute to viral reactivation and/or replication by enhancing CMV IE gene expression. The virus may then infect neighboring ECs or SMCs, initiating a cascade of events predisposing to the development of atherogenesis-related processes.

  20. 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.

  1. Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits.

    Science.gov (United States)

    Holm, P; Korsgaard, N; Shalmi, M; Andersen, H L; Hougaard, P; Skouby, S O; Stender, S

    1997-01-01

    The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis. PMID:9259581

  2. Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis

    Science.gov (United States)

    Kim, Hong Seok; Tavakoli, Sina; Piefer, Leigh Ann; Nguyen, Huynh Nga; Asmis, Reto

    2016-01-01

    Diabetes promotes the S-glutathionylation, inactivation and subsequent degradation of mitogen-activated protein kinase phosphatase 1 (MKP-1) in blood monocytes, and hematopoietic MKP-1-deficiency in atherosclerosis-prone mice accelerates atherosclerotic lesion formation, but the underlying mechanisms were not known. Our aim was to determine the mechanisms through which MKP-1 deficiency in monocytes and macrophages promotes atherogenesis. Transplantation of MKP-1-deficient bone marrow into LDL-R−/− (MKP-1LeuKO) mice accelerated high-fat diet (HFD)-induced atherosclerotic lesion formation. After 12 weeks of HFD feeding, MKP-1LeuKO mice showed increased lesion size in both the aortic root (1.2-fold) and the aorta (1.6-fold), despite reduced plasma cholesterol levels. Macrophage content was increased in lesions of MKP-1LeuKO mice compared to mice that received wildtype bone marrow. After only 6 weeks on a HFD, in vivo chemotactic activity of monocytes was already significantly increased in MKP-1LeuKO mice. MKP-1 deficiency in monocytes and macrophages promotes and accelerates atherosclerotic lesion formation by hyper-sensitizing monocytes to chemokine-induced recruitment, predisposing macrophages to M1 polarization, decreased autophagy and oxysterol-induced cell death whereas overexpression of MKP-1 protects macrophages against metabolic stress-induced dysfunction. MKP-1 serves as a master-regulator of macrophage phenotype and function and its dysregulation by metabolic stress may be a major contributor to atherogenesis and the progression of atherosclerotic plaques. PMID:27670844

  3. [Besides fibrinogen, are haemostatic, coagulation and/or fibrinolytic parameters predictors or markers of the risk of cardiovascular events?].

    Science.gov (United States)

    Drouet, Ludovic; Bal dit Sollier, Claire

    2005-01-01

    Most cardiovascular events result from a thrombotic complication of atherosclerotic lesions. In arterial vessels such as the coronary bed, an interrelationship of haemostatic, coagulation and fibrinolytic factors is implicated. While it can be demonstrated that fibrinogen is a risk factor/marker, the role of other factors is not well established. Under arterial flow conditions, platelets are predominantly involved in the thrombotic reaction. Yet, apart from a large increase in the platelet count, the involvement of platelet parameters in cardiovascular risk is not clearly evident. The lack of definitive platelet markers is at least partly due to the difficulty of studying platelet function ex vivo. Several polymorphisms of platelet glycoproteins carrying a moderate increase in risk have been reported, but only in younger patients. One potentially important factor for coagulation is the fibrin structure, which is dependent on fibrinogen, the rate of thrombin generation, the activity of factor XIII and the interrelationship of the cells concerned, all of which act on its sensitivity to thrombosis. Coagulation factors largely affect the rate of thrombin generation. The activity of the fibrinolytic system (and principally any deficiency) has a role in the cardiovascular risk. General markers of cardiovascular risk such as D-dimers are potentially useful, but they increase with thrombin generation and are decreased by a deficiency in fibrinolysis. Furthermore, possibly because they are not indicative of the fibrin structure, they are poorly correlated with clinical events. The poor significance of the available haemostatic, coagulation and/or fibrinolytic parameters is probably due to their lack of representativeness, since haemostatic, coagulation and fibrinolytic systems are all involved in the thrombotic response (and some in atherogenesis itself). Atherogenesis is a multifactorial process and numerous moderate risk factors act in association. Better predictability

  4. Knockdown of GSK3β increases basal autophagy and AMPK signalling in nutrient-laden human aortic endothelial cells

    Science.gov (United States)

    Weikel, Karen A.; Cacicedo, José M.; Ruderman, Neil B.; Ido, Yasuo

    2016-01-01

    High concentrations of glucose and palmitate increase endothelial cell inflammation and apoptosis, events that often precede atherogenesis. They may do so by decreasing basal autophagy and AMP-activated protein kinase (AMPK) activity, although the mechanisms by which this occurs are not clear. Decreased function of the lysosome, an organelle required for autophagy and AMPK, have been associated with hyperactivity of glycogen synthase kinase 3β (GSK3β). To determine whether GSK3β affects nutrient-induced changes in autophagy and AMPK activity, we used a primary human aortic endothelial cell (HAEC) model of type 2 diabetes that we had previously characterized with impaired AMPK activity and autophagy [Weikel et al. (2015) Am. J. Phys. Cell Physiol. 308, C249–C263]. Presently, we found that incubation of HAECs with excess nutrients (25 mM glucose and 0.4 mM palmitate) increased GSK3β activity and impaired lysosome acidification. Suppression of GSK3β in these cells by treatment with a chemical inhibitor or overexpression of kinase-dead GSK3β attenuated these lysosomal changes. Under control and excess nutrient conditions, knockdown of GSK3β increased autophagosome formation, forkhead box protein O1 (FOXO1) activity and AMPK signalling and decreased Akt signalling. Similar changes in autophagy, AMPK and Akt signalling were observed in aortas from mice treated with the GSK3β inhibitor CHIR 99021. Thus, increasing basal autophagy and AMPK activity by inhibiting GSK3β may be an effective strategy in the setting of hyperglycaemia and dyslipidaemia for restoring endothelial cell health and reducing atherogenesis. PMID:27534430

  5. Metabolic effects of oral contraceptives: fact vs. fiction.

    Science.gov (United States)

    1996-01-01

    Many studies show that low-dose OCs have little adverse effect on carbohydrate metabolism and are safe for healthy women, women with a history of gestational diabetes, and women with insulin-dependent diabetes to use. In fact, large epidemiologic studies indicate that OCs, even the high-dose OCs (=or 50 mcg) for long periods, do not increase the risk of diabetes. There is some evidence indicating that OC use does not heighten the progression of diabetic retinopathy, nephropathy, or cardiovascular complications among women with insulin-dependent diabetes. There is no significant difference in carbohydrate metabolism among the different OC formulations. One must carefully consider the risk:benefit ratio of OC use in diabetic women since pregnancy has serious consequences for both mother and fetus. Cardiovascular complications in OC users do not originate from atherogenesis. The androgenic properties of the progestin in low-dose OCs and their effect on lipids are inconsequential for later development of coronary atherogenesis. The estrogen in OCs may protect against atherosclerosis, particularly among women at high risk of atherosclerosis. Former OC users are not at an increased risk of coronary heart disease, stroke, or other heart disease. Lipid changes in OC users tend to remain within the normal range and return to pretreatment values during the pill-free week. All OCs suppress gonadotropins and subsequent ovarian androgen production. They partially suppress androgen production by the adrenals as well. This suppression from two fronts outweighs any androgenic action of the progestin alone. Further, androgenic action probably cannot overpower the estrogen effect. The dose of levonorgestrel used in OCs is too low to express androgenic effects. Since OCs suppress androgen production, all OCs tend to improve acne. OCs reduce free testosterone and increase sex hormone binding globulin levels.

  6. Numerical simulation of pulsatile non-Newtonian flow in the carotid artery bifurcation

    Science.gov (United States)

    Fan, Yubo; Jiang, Wentao; Zou, Yuanwen; Li, Jinchuan; Chen, Junkai; Deng, Xiaoyan

    2009-04-01

    Both clinical and post mortem studies indicate that, in humans, the carotid sinus of the carotid artery bifurcation is one of the favored sites for the genesis and development of atherosclerotic lesions. Hemodynamic factors have been suggested to be important in atherogenesis. To understand the correlation between atherogenesis and fluid dynamics in the carotid sinus, the blood flow in artery was simulated numerically. In those studies, the property of blood was treated as an incompressible, Newtonian fluid. In fact, however, the blood is a complicated non-Newtonian fluid with shear thinning and viscoelastic properties, especially when the shear rate is low. A variety of non-Newtonian models have been applied in the numerical studies. Among them, the Casson equation was widely used. However, the Casson equation agrees well only when the shear rate is less than 10 s-1. The flow field of the carotid bifurcation usually covers a wide range of shear rate. We therefore believe that it may not be sufficient to describe the property of blood only using the Casson equation in the whole flow field of the carotid bifurcation. In the present study, three different blood constitutive models, namely, the Newtonian, the Casson and the hybrid fluid constitutive models were used in the flow simulation of the human carotid bifurcation. The results were compared among the three models. The results showed that the Newtonian model and the hybrid model had very similar distributions of the axial velocity, secondary flow and wall shear stress, but the Casson model resulted in significant differences in these distributions from the other two models. This study suggests that it is not appropriate to only use the Casson equation to simulate the whole flow field of the carotid bifurcation, and on the other hand, Newtonian fluid is a good approximation to blood for flow simulations in the carotid artery bifurcation.

  7. Numerical simulation of pulsatile non-Newtonian flow in the carotid artery bifurcation

    Institute of Scientific and Technical Information of China (English)

    Yubo Fan; Wentao Jiang; Yuanwen Zou; Jinchuan Li; Junkai Chen; Xiaoyan Deng

    2009-01-01

    Both clinical and post mortem studies indicate that, in humans, the carotid sinus of the carotid artery bifurcation is one of the favored sites for the genesis and development of atherosclerotic lesions. Hemodynamic factors have been suggested to be important in atherogenesis. To understand the correlation between atherogenesis and fluid dynamics in the carotid sinus, the blood flow in artery was simulated numerically. In those studies, the property of blood was treated as an incompressible, Newtonian fluid. In fact,however, the blood is a complicated non-Newtonian fluid with shear thinning and viscoelastic properties, especially when the shear rate is low. A variety of non-Newtonian models have been applied in the numerical studies. Among them,the Casson equation was widely used. However, the Casson equation agrees well only when the shear rate is less than 10s-1. The flow field of the carotid bifurcation usually covers a wide range of shear rate. We therefore believe that it may not be sufficient to describe the property of blood only using the Casson equation in the whole flow field of the carotid bifurcation. In the present study, three different blood constitutive models, namely, the Newtonian, the Casson and the hybrid fluid constitutive models were used in the flow simulation of the human carotid bifurcation. The results were compared among the three models. The results showed that the Newtonian model and the hybrid model had very similar distributions of the axial velocity, secondary flow and wall shear stress, but the Casson model resulted in significant differences in these distributions from the other two models. This study suggests that it is not appropriate to only use the Casson equation to simulate the whole flow field of the carotid bifurcation, and on the other hand, Newtonian fluid is a good approximation to blood for flow simulations in the carotid artery bifurcation.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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

  10. CARMA3: A novel scaffold protein in regulation of NF-κB activation and diseases

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    CARD recruited membrane associated protein 3 (CARMA3) is a novel scaffold protein. It belongs to the CARMA protein family, and is known to activate nuclear factor (NF)- κB. However, it is still unknown which receptor functions upstream of CARMA3 to trigger NF-κB activation. Recently, several studies have demonstrated that CARMA3 serves as an indispensable adaptor protein in NF-κB signaling under some G protein-coupled receptors (GP- CRs), such as lysophosphatidic acid (LPA) receptor and angiotensin (Ang) Ⅱ receptor. Mechanistically, CARMA3 recruits its essential downstream molecules Bcl10 and MALT1 to form the CBM (CARMA3-Bcl10-MALT1) signalosome whereby it triggers NF-κB activation. GPCRs and NF-κB play pivotal roles in the regulation of various cellular functions, therefore, aberrant regulation of the GPCR/NF-κB signaling axis leads to the development of many types of diseases, such as cancer and atherogenesis. Recently, the GPCR/CARMA3/NF-κB signaling axis has been confirmed in these specific diseases and it plays crucial roles in the pathogenesis of disease progression. In ovarian cancer cell lines, knockdown of CARMA3 abolishes LPA receptor-induced NF-κB activation, and reduces LPA-induced ovarian cancer invasion. In vascular smooth cells, downregulation of CARMA3 substantially impairs Ang-Ⅱ-receptor-induced NF-κB activation, and in vivo studies have confirmed that Bcl10- deficient mice are protected from developing Ang-Ⅱ-receptor-induced atherosclerosis and aortic aneurysms. In this review, we summarize the biology of CARMA3, describe the role of the GPCR/CARMA3/NF-κB signaling axis in ovarian cancer and atherogenesis, and speculate about the potential roles of this signaling axis in other types of cancer and diseases. With a significant increase in the identification of LPA- and Ang-Ⅱ-like ligands, such as endothelin-1, which also activates NF-κB via CARMA3 and contributes to the development of many diseases, CARMA3 is emerging as a novel

  11. Serum TC/HDL-C,TG/HDL-C and LDL-C/HDL-C in predicting the risk of myocardial infarction in normolipidae-mic patients in South Asia:A case-control study

    Institute of Scientific and Technical Information of China (English)

    Arun Kumar; Ramiah Sivakanesan

    2008-01-01

    Dyslipidemia the major cause of atherosclerosis are suggested to act synergistically with non-lipid risk factors to increase atherogenesis.Low-density lipoprotein cholesterol (LDL-C)is the main therapeutic target in the pre-vention of CVD.Increased triglycerides (TG)and decreased high-density lipoprotein (LDL-C)are considered to be a major risk factor for the development of insulin resistant and metabolic syndrome.Although the TG/HDL-C ratio has been used in recent studies as a clinical indicator for insulin resistance,results were inconsis-tent.The TG/HDL-C ratio is also widely used to assess the lipid atherogenesis.How ever the utility of this rate for predicting coronary heart disease (CHD)risk is not clear.We encountered myocardial infarct patients with normal serum lipid concentration so this study was undertaken to evaluate the usefulness of these lipid ratios in predicting CHD risk in normolipidemic AMI patients and to compare the results with healthy subjects.The aim of the present study was to evaluate serum TC/HDL-C,TG/HDL-C and LDL-C/HDL-C in myocardial infarct subjects with normal lipid profile.To study this,lipid profile was determined in 165 normolipidemic acute myo-cardial infarction patients and 165 age/sex-matched controls.Total cholesterol,triglycerides,and HDL-cho-lesterol were analyzed enzymatically using kits obtained from Randox Laboratories Limited,Crumlin,UK. Plasma LDL-cholesterol was determined from the values of total cholesterol and HDL- cholesterol using the friedwalds formula.The values were expressed as means ± standard deviation (SD)and data from patients and controls was compared using students't'-test.The results and conclusion of the study were:Total cholester-ol,TC:HDL-C ratio,triglycerides,LDL-cholesterol,LDL:HDL-C ratio were higher in MI patients (p<0. 001).HDL-C concentration was significantly lower in MI patients than controls (p<0.001).Higher ratio of TC/HDL-C,TG/HDL-C and LDL-C/HDL-C was observed in AMI patients compared

  12. 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

  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

    Directory of Open Access Journals (Sweden)

    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. Crucial role of interferon-gamma and stimulated macrophages in cardiovascular disease.

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    Schroecksnadel, Katharina; Frick, Barbara; Winkler, Christiana; Fuchs, Dietmar

    2006-07-01

    Inflammation and immune activation are crucially involved in the pathogenesis of atherosclerosis and cardiovascular disease. Accordingly, markers of inflammation such as fibrinogen, ferritin, C-reactive protein or neopterin are found in patients with vascular diseases, correlating strongly with the extent of disease and predicting disease progression. Neopterin formation by human monocyte-derived macrophages and dendritic cells is induced by the pro-inflammatory cytokine interferon-gamma, which is released by activated T-lymphocytes. Human macrophages are centrally involved in plaque formation, and interferon-gamma and macrophages are also of importance in the development of oxidative stress for antimicrobial and antitumoural defence within the cell-mediated immune response. Interferon-gamma also stimulates the enzyme indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine. Again, macrophages are the most important cell type executing this enzyme reaction, but also other cells like dendritic cells, endothelial cells or fibroblasts can contribute to the depletion of tryptophan. Likewise, enhanced tryptophan degradation was reported in patients with coronary heart disease and was found to correlate with enhanced neopterin formation. In chronic diseases such as in cardiovascular disease, biochemical reactions induced by interferon-gamma may have detrimental consequences for host cells. In concert with other pro-inflammatory cytokines, interferon-gamma is the most important trigger for the formation and release of reactive oxygen species (ROS). Chronic ROS-production leads to the depletion of antioxidants like vitamin C and E and glutathione, with a consequence that oxidative stress develop. Oxidative stress plays a major role in the atherogenesis and progression of cardiovascular disease, and it may also account for the irreversible oxidation of other oxidation-sensitive substances like B-vitamins (e.g. folic acid and B12). They are essential cofactors in

  16. Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance.

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    Park, Arick C; Huang, Guorui; Jankowska-Gan, Ewa; Massoudi, Dawiyat; Kernien, John F; Vignali, Dario A; Sullivan, Jeremy A; Wilkes, David S; Burlingham, William J; Greenspan, Daniel S

    2016-02-12

    We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes.

  17. High-density lipoproteincholesterol, reverse cholesterol transport, and cardiovascular risk: a tale of genetics?

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    Giovanni Cimmino

    2013-10-01

    Full Text Available Cholesterol deposition plays a central role in atherogenesis. The accumulation of lipid material is the result of an imbalance between the influx and efflux of cholesterol within the arterial wall. High levels of plasma low-density lipoprotein-cholesterol are considered the major mechanism responsible for the influx and accumulation of cholesterol in the arterial wall, while high-density lipoprotein (HDL- cholesterol seems responsible for its efflux. The mechanism by which cholesterol is removed from extra-hepatic organs and delivered to the liver for its catabolism and excretion is called reverse cholesterol transport (RCT. Epidemiological evidence has associated high levels of HDL-cholesterol/ApoA-I with protection against atherosclerotic disease, but the ultimate mechanism(s responsible for the beneficial effect is not well established. HDLs are synthesized by the liver and small intestine and released to the circulation as a lipid-poor HDL (nascent HDL, mostly formed by ApoA-I and phospholipids. Through their metabolic maturation, HDLs interact with the ABCA1 receptor in the macrophage surface increasing their lipid content by taking phospholipids and cholesterol from macrophages becoming mature HDL. The cholesterol of the HDLs is transported to the liver, via the scavenger receptor class B, type I, for further metabolization and excretion to the intestines in the form of bile acids and cholesterol, completing the process of RCT. It is clear that an inherited mutation or acquired abnormality in any of the key players in RCT mat affect the atherosclerotic process.

  18. Green tea (Camellia sinensis) catechins and vascular function.

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    Moore, Rosalind J; Jackson, Kim G; Minihane, Anne M

    2009-12-01

    The health benefits of green tea (Camellia sinensis) catechins are becoming increasingly recognised. Amongst the proposed benefits are the maintenance of endothelial function and vascular homeostasis and an associated reduction in atherogenesis and CVD risk. The mounting evidence for the influential effect of green tea catechins on vascular function from epidemiological, human intervention and animal studies is subject to review together with exploration of the potential mechanistic pathways involved. Epigallocatechin-3-gallate, one of the most abundant and widely studied catechin found in green tea, will be prominent in the present review. Since there is a substantial inconsistency in the published data with regards to the impact of green tea catechins on vascular function, evaluation and interpretation of the inter- and intra-study variability is included. In conclusion, a positive effect of green tea catechins on vascular function is becoming apparent. Further studies in animal and cell models using physiological concentrations of catechins and their metabolites are warranted in order to gain some insight into the physiology and molecular basis of the observed beneficial effects.

  19. Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis.

    Science.gov (United States)

    Gelosa, Paolo; Sevin, Gulnur; Pignieri, Alice; Budelli, Silvia; Castiglioni, Laura; Blanc-Guillemaud, Vanessa; Lerond, Laurence; Tremoli, Elena; Sironi, Luigi

    2011-03-01

    Thromboxane A(2) and other eicosanoids such as isoprostanes contribute to vascular proliferation and atherosclerosis by binding to the thromboxane/prostaglandin endoperoxide receptors. The effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on aorta remodeling were evaluated in spontaneously hypertensive stroke-prone rats (SHRSPs), a model of severe hypertension, endothelial dysfunction, vascular inflammation, and cerebrovascular diseases. Male SHRSPs were allocated to three groups receiving a standard diet (n = 5) or a high-sodium permissive diet plus vehicle (n = 6) or plus terutroban (30 mg · kg(-1) · day(-1); n = 6). After 6 wk of dietary treatment, all of the animals were injected with bromodeoxyuridine and simultaneously euthanized for aorta collection. The aortic media thickness-to-lumen ratio significantly (P hyperplasia and has beneficial effects on fibrotic processes by affecting TGF-β and heat shock protein-47 expression in SHRSPs. These findings provide mechanistic data supporting the beneficial effects of terutroban in preventing or retarding atherogenesis.

  20. 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.

  1. The burden of type 2 diabetes: strategies to prevent or delay onset

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    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

  2. Eicosapentaenoic Acid Protects against Palmitic Acid-Induced Endothelial Dysfunction via Activation of the AMPK/eNOS Pathway

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    Che-Hsin Lee

    2014-06-01

    Full Text Available Recent studies have shown that free fatty acids are associated with chronic inflammation, which may be involved in vascular injury. The intake of eicosapentaenoic acid (EPA can decrease cardiovascular disease risks, but the protective mechanisms of EPA on endothelial cells remain unclear. In this study, primary human umbilical vein endothelial cells (HUVECs treated with palmitic acid (PA were used to explore the protective effects of EPA. The results revealed that EPA attenuated PA-induced cell death and activation of apoptosis-related proteins, such as caspase-3, p53 and Bax. Additionally, EPA reduced the PA-induced increase in the generation of reactive oxygen species, the activation of NADPH oxidase, and the upregulation of inducible nitric oxide synthase (iNOS. EPA also restored the PA-mediated reduction of endothelial nitric oxide synthase (eNOS and AMP-activated protein kinase (AMPK phosphorylation. Using AMPK siRNA and the specific inhibitor compound C, we found that EPA restored the PA-mediated inhibitions of eNOS and AKT activities via activation of AMPK. Furthermore, the NF-κB signals that are mediated by p38 mitogen-activated protein kinase (MAPK were involved in protective effects of EPA. In summary, these results provide new insight into the possible molecular mechanisms by which EPA protects against atherogenesis via the AMPK/eNOS-related pathway.

  3. 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.

  4. 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.

  5. 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.

  6. In vitro study of the direct effect of extracellular hemoglobin on myelin components.

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    Bamm, Vladimir V; Lanthier, Danielle K; Stephenson, Erin L; Smith, Graham S T; Harauz, George

    2015-01-01

    There is a relationship between cerebral vasculature and multiple sclerosis (MS) lesions: abnormal accumulations of iron have been found in the walls of dilated veins in MS plaques. The sources of this iron can be varied, but capillary and venous hemorrhages leading to blood extravasation have been recorded, and could result in the release of hemoglobin extracellularly. Extracellular hemoglobin oxidizes quickly and is known to become a reactive molecule that triggers low-density lipoprotein oxidation and plays a pivotal role in atherogenesis. In MS, it could lead to local oxidative stress, inflammation, and tissue damage. Here, we investigated whether extracellular hemoglobin and its breakdown products can cause direct oxidative damage to myelin components in a peroxidative environment such as occurs in inflamed tissue. Oxidation of lipids was assessed by the formation of fluorescent peroxidized lipid-protein covalent adducts, by the increase in conjugated diene and malondialdehyde. Oxidation of proteins was analyzed by the change in protein mass. The results suggest that the globin radical could be a trigger of myelin basic protein oxidative cross-linking, and that heme transferred to the lipids is involved in lipid peroxidation. This study provides new insight into the mechanism by which hemoglobin exerts its pathological oxidative activity towards myelin components. This work supports further research into the vascular pathology in MS, to gain insight into the origin and role of iron deposits in disease pathogenesis, or in stimulation of different comorbidities such as cardiovascular disease.

  7. Polyphenols from red wine are potent modulators of innate and adaptive immune responsiveness.

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    Magrone, Thea; Jirillo, Emilio

    2010-08-01

    It is well known that the consumption of dietary polyphenols leads to beneficial effects for human health as in the case of prevention and/or attenuation of cardiovascular, inflammatory, neurodegenerative and neoplastic diseases. This review summarizes the role of polyphenols from red wine in the immune function. In particular, using healthy human peripheral blood mononuclear cells, we have demonstrated the in vitro ability of Negroamaro, an Italian red wine, to induce the release of nitric oxide and both pro-inflammatory and anti-inflammatory cytokines, thus leading to the maintenance of the immmune homeostasis in the host. All these effects were abrogated by deprivation of polyphenols from red wine samples. We have also provided evidence that Negromaro polyphenols are able to activate extracellular regulated kinase and p38 kinase and switch off the NF-kappaB pathway via an increased expression with time of the IkappaBalpha phosphorylated form. These mechanisms may represent key molecular events leading to inhibition of the pro-inflammatory cascade and atherogenesis. In conclusion, according to the current literature and our own data, moderate consumption of red wine seems to be protective for the host in the prevention of several diseases, even including aged-related diseases by virtue of its immunomodulating properties.

  8. Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells.

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    Lin, Xiao-long; Liu, Mi-Hua; Hu, Hui-Jun; Feng, Hong-ru; Fan, Xiao-Juan; Zou, Wei-wen; Pan, Yong-quan; Hu, Xue-mei; Wang, Zuo

    2015-09-01

    Curcumin, a traditional Chinese derivative from the rhizomes of Curcuma longa, is beneficial to health by modulating lipid metabolism and suppressing atherogenesis. A key part of atherosclerosis is the failure of macrophages to restore their cellular cholesterol homeostasis and the formation of foam cells. In this study, results showed that curcumin dramatically increased the expression of ATP-binding cassette transporter 1 (ABCA1), promoted cholesterol efflux from THP-1 macrophage-derived foam cells, and reduced cellular cholesterol levels. Curcumin activated AMP-activated protein kinase (AMPK) and SIRT1, and then activated LXRα in THP-1 macrophage-derived foam cells. Inhibiting AMPK/SIRT1 activity by its specific inhibitor or by small interfering RNA could inhibit LXRα activation and abolish curcumin-induced ABCA1 expression and cholesterol efflux. Thus, curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through activating AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells. This study describes a possible mechanism for understanding the antiatherogenic effects of curcumin on attenuating the progression of atherosclerosis.

  9. Adropin- A Novel Biomarker of Heart Disease: A Systematic Review Article

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    YOSAEE, Somaye; SOLTANI, Sepideh; SEKHAVATI, Eghbal; JAZAYERI, Shima

    2016-01-01

    Background: Heart disease is one of the most common chronic disease and leading cause of morbidity and mortality worldwide. Adropin, a newly identified protein, is important for energy homeostasis and maintaining insulin sensitivity, and has been referred to as a novel regulator of endothelial cells. Endothelial dysfunction is a key early event in atherogenesis and onset of HD. Therefore, this review gives a systematic overview of studies investigating plasma adropin level in patient with heart disease. Methods: Data carried out in PubMed, Scopus, Web of Science, Embase, Google scholar and MEDLINE, from the earliest available online indexing year through 2015. The search restricted to studies conducted in humans. The keyword search was adropin to apply in title, abstract and keywords. References lists of all original published articles were scanned to find additional eligible studies. Results: Heart failure (HF), coronary atherosclerosis acute myocardial infarction and Cardiac Syndrome X (CSX) were type of heart disease acknowledged in this study. Majority of evidences introduced low adropin as an independent risk factor of heart disease. In a case-control study, the plasma level of adropin increased with the severity of HF. Conclusion: Adropinmay be a potential serum biomarker for early diagnosis of HD. PMID:28053922

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  11. Eskimo plasma constituents, dihomo-gamma-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid inhibit the release of atherogenic mitogens.

    Science.gov (United States)

    Smith, D L; Willis, A L; Nguyen, N; Conner, D; Zahedi, S; Fulks, J

    1989-01-01

    Studies in man and laboratory animals suggest that omega 3 polyunsaturated fatty acid constituents of fish oils have antiatherosclerotic properties. We have studied the effects of several such polyunsaturated fatty acids for ability to modify the in vitro release of mitogens from human platelets. Such mitogens may produce the fibro-proliferative component of atherosclerotic plaques. Both 5,8,11,14,17-eicosapentaenoic acid (20:5 omega 3) and 4,7,10,13,16,19-docosahexaenoic acid (22:6 omega 3), major constituents of fish oils, inhibited adenosine diphosphate-induced aggregation of platelets and the accompanying release of mitogens. These effects are dose dependent. Linolenic acid (18:3 omega 3), the biosynthetic precursor of eicosapentaenoic acid, also inhibited platelet aggregation and mitogen release. Eicosapentaenoic acid also inhibited mitogen release from human monocyte-derived macrophages, which, in vivo, are an additional source of mitogens during atherogenesis. Potent inhibition of human platelet aggregation and mitogen release was also seen with dihomo-gamma-linolenic acid (8,11,14-eicosatrienoic acid 20:3 omega 6), whose levels are reportedly elevated in Eskimos subsisting on marine diets. We conclude that diets that elevate plasma and/or tissue levels of eicosapentaenoic acid, docosahexaenoic acid and dihomo-gamma-linolenic acid precursor gamma-linolenic acid (18:3 omega 6) may exert antiatherosclerotic effects by inhibiting the release of mitogens from platelets and other cells.

  12. 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.

  13. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding.

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    Janet Chamberlain

    Full Text Available BACKGROUND: Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1 signaling in the vessel wall would raise arterial blood pressure and promote atheroma. METHODOLOGY/PRINCIPAL FINDINGS: Apoe(-/- and Apoe(-/-/IL-1R1(-/- mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-/IL-R1(-/- mice had a reduced blood pressure and significantly less atheroma than Apoe(-/- mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p < 0.05. This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress. CONCLUSIONS/SIGNIFICANCE: The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man.

  14. Cardiovascular Disease Risk amongst African Black Patients with Rheumatoid Arthritis: The Need for Population Specific Stratification

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    Ahmed Solomon

    2014-01-01

    Full Text Available Rheumatoid arthritis (RA enhances the risk of cardiovascular disease to a similar extent as diabetes. Whereas atherogenesis remains poorly elucidated in RA, traditional and nontraditional risk factors associate similarly and additively with CVD in RA. Current recommendations on CVD risk stratification reportedly have important limitations. Further, reported data on CVD and its risk factors derive mostly from data obtained in the developed world. An earlier epidemiological health transition is intrinsic to persons living in rural areas and those undergoing urbanization. It is therefore conceivable that optimal CVD risk stratification differs amongst patients with RA from developing populations compared to those from developed populations. Herein, we briefly describe current CVD and its risk factor profiles in the African black population at large. Against this background, we review reported data on CVD risk and its potential stratification amongst African black compared to white patients with RA. Routinely assessed traditional and nontraditional CVD risk factors were consistently and independently related to atherosclerosis in African white but not black patients with RA. Circulating concentrations of novel CVD risk biomarkers including interleukin-6 and interleukin-5 adipokines were mostly similarly associated with both endothelial activation and atherosclerosis amongst African black and white RA patients.

  15. Effect of phosphatidylinositol 3-kinase in angiogenesis-related diseases%磷脂酰肌醇3-激酶在血管新生相关性疾病中的作用

    Institute of Scientific and Technical Information of China (English)

    权伟; 张丽莙

    2011-01-01

    @@ 血管新生参与了人体多种生理与病理过程,前者如创伤愈合,后者包括肿瘤、动脉粥样硬化(atherosclerosis,AS)、类风湿性关节炎(rheumatoid arthritis,RA)等多种疾病,血管新生与这些疾病的发生发展密切相关.磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)作为细胞内重要的信号蛋白,可介导细胞迁移、增殖与血管新生等多种生物学行为的信号转导.%Angiogenesis is involved in the pathological processes such as wound healing, atherosclerosis,rheumatoid arthritis and tumor, in which the pathogenesis and development are closely related to the new blood vessel formation. Phosphatidylinositol 3 - kinase ( PI3 K ), one of the important intracellular signaling proteins, mediates many signal transductions in cell migration, proliferation and angiogenesis. The activity of PI3 K and its signaling pathway play a unique role in atherogenesis, unstability of atherosclerotic plaque, tumor metastasis and recurrence, etc. This review summarizes the effect of PI3 K in angiogenesis - related diseases.

  16. 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.

  17. Nanoscale amphiphilic macromolecules with variable lipophilicity and stereochemistry modulate inhibition of oxidized low-density lipoprotein uptake.

    Science.gov (United States)

    Poree, Dawanne E; Zablocki, Kyle; Faig, Allison; Moghe, Prabhas V; Uhrich, Kathryn E

    2013-08-12

    Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs' physicochemical and biological properties, mucic acid-based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability. 2l, the meso analogue of 2b, elicited the highest reported oxLDL uptake inhibition values (89%), highlighting the crucial effect of stereochemistry on biological properties. This study suggests that stereochemistry plays a critical role in modulating oxLDL uptake and must be considered when designing biomaterials for potential cardiovascular therapies.

  18. The impact of chocolate on cardiovascular health.

    Science.gov (United States)

    Fernández-Murga, L; Tarín, J J; García-Perez, M A; Cano, A

    2011-08-01

    Cardiovascular disease is the leading determinant of mortality and morbidity in women. Functional foods are attracting interest as potential regulators of the susceptibility to disease. Supported by epidemiological evidence, chocolate has emerged as a possible modulator of cardiovascular risk. Chocolate, or cocoa as the natural source, contains flavanols, a subclass of flavonoids. The latter years have witnessed an increasing number of experimental and clinical studies that suggest a protective effect of chocolate against atherogenesis. Oxidative stress, inflammation, and endothelial function define three biological mechanisms that have shown sensitivity to chocolate. Moreover, the consumption of chocolate has been involved in the protective modulation of blood pressure, the lipid profile, the activation of platelets, and the sensitivity to insulin. Dark chocolate seems more protective than milk or white chocolate. Despite this array of benefits, there is a lack of well designed clinical studies demonstrating cardiovascular benefit of chocolate. The high caloric content of chocolate, particularly of some less pure forms, imposes caution before recommending uncontrolled consumption.

  19. [Type 2 diabetes complications].

    Science.gov (United States)

    Schlienger, Jean-Louis

    2013-05-01

    People with type 2 diabetes are at increased risk of many complications, which are mainly due to complex and interconnected mechanisms such as hyperglycemia, insulino-resistance, low-grade inflammation and accelerated atherogenesis. Cardi-cerebrovascular disease are frequently associated to type 2 diabetes and may become life threatening, particularly coronaropathy, stroke and heart failure. Their clinical picture are sometimes atypical and silencious for a long time. Type 2 diabetes must be considered as an independent cardiovascular risk factor. Nephropathy is frequent in type 2 diabetes but has a mixed origin. Now it is the highest cause of end-stage renal disease. Better metabolic and blood pressure control and an improved management of microalbuminuria are able to slowdown the course of the disease. Retinopathy which is paradoxically slightly progressive must however be screened and treated in these rather old patients which are globally at high ophthalmologic risk. Diabetic foot is a severe complication secondary to microangiopathy, microangiopathy and neuropathy. It may be considered as a super-complication of several complications. Its screening must be done on a routine basis. Some cancer may be considered as an emerging complication of type 2 diabetes as well as cognitive decline, sleep apnea syndrome, mood disorders and bone metabolism impairments. Most of the type 2 diabetes complications may be prevented by a strategy combining a systematic screening and multi-interventional therapies.

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

    Science.gov (United States)

    Soory, Mena

    2010-01-01

    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.

  1. Silicon dioxide nanoparticles increase macrophage atherogenicity: Stimulation of cellular cytotoxicity, oxidative stress, and triglycerides accumulation.

    Science.gov (United States)

    Petrick, Lauren; Rosenblat, Mira; Paland, Nicole; Aviram, Michael

    2016-06-01

    Nanoparticle research has focused on their toxicity in general, while increasing evidence points to additional specific adverse effects on atherosclerosis development. Arterial macrophage cholesterol and triglyceride (TG) accumulation and foam cell formation are the hallmark of early atherogenesis, leading to cardiovascular events. To investigate the in vitro atherogenic effects of silicon dioxide (SiO2 ), J774.1 cultured macrophages (murine cell line) were incubated with SiO2 nanoparticle (SP, d = 12 nm, 0-20 µg/mL), followed by cellular cytotoxicity, oxidative stress, TG and cholesterol metabolism analyses. A significant dose-dependent increase in oxidative stress (up to 164%), in cytotoxicity (up to 390% measured by lactate dehydrogenase (LDH) release), and in TG content (up to 63%) was observed in SiO2 exposed macrophages compared with control cells. A smaller increase in macrophage cholesterol mass (up to 22%) was noted. TG accumulation in macrophages was not due to a decrease in TG cell secretion or to an increased TG biosynthesis rate, but was the result of attenuated TG hydrolysis secondary to decreased lipase activity and both adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) protein expression (by 42 and 25%, respectively). Overall, SPs showed pro-atherogenic effects on macrophages as observed by cytotoxicity, increased oxidative stress and TG accumulation. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 713-723, 2016.

  2. Development and application of a nonradioactive binding assay of oxidized low-density lipoprotein to macrophage scavenger receptors

    Science.gov (United States)

    Montano, Erica N.; Boullier, Agnès; Almazan, Felicidad; Binder, Christoph J.; Witztum, Joseph L.; Hartvigsen, Karsten

    2013-01-01

    Macrophages play a key role in atherogenesis in part through excessive uptake of oxidized LDL (OxLDL) via scavenger receptors. Binding of OxLDL to macrophages has traditionally been assessed using radiolabeled OxLDL. To allow more efficient and convenient measurements, we developed a nonradioactive binding assay in which biotinylated OxLDL (Bt-OxLDL) is added to macrophages in 96-well microtiter culture plates under various conditions and the extent of binding is determined using solid phase chemiluminescent immunoassay techniques. As examples, we show that Bt-OxLDL displayed high and saturable binding to macrophages in contrast to Bt-LDL, which showed very low binding. In competition assays, unlabeled OxLDL and the anti-OxLDL monoclonal antibody E06 inhibited Bt-OxLDL binding to macrophages in a dose-dependent manner. Specific binding of Bt-OxLDL to ApoE/SR-A/CD36 triple knockout macrophages was reduced by 80% as compared with binding to macrophages from ApoE knockout mice. Binding of Bt-OxLDL to CD36 transfected COS-7 cells showed enhanced saturable binding compared with mock-transfected cells. This assay avoids the use of radioactivity and uses small amounts of materials. It can be used to study binding of OxLDL to macrophages and factors that influence this binding. The techniques described should be readily adaptable to study of other ligands, receptors, and cell types. PMID:23997238

  3. Disruption of mTORC1 in Macrophages Decreases Chemokine Gene Expression and Atherosclerosis

    Science.gov (United States)

    Ai, Ding; Jiang, Hongfeng; Westerterp, Marit; Murphy, Andrew J.; Wang, Mi; Ganda, Anjali; Abramowicz, Sandra; Welch, Carrie; Almazan, Felicidad; Zhu, Yi; Miller, Yury I; Tall, Alan R.

    2014-01-01

    Rationale The mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin, has been shown to decrease atherosclerosis, even while increasing plasma LDL levels. This suggests an anti-atherogenic effect possibly mediated by modulation of inflammatory responses in atherosclerotic plaques. Objective To assess the role of macrophage mTORC1 in atherogenesis. Methods and Results We transplanted bone marrow from mice in which a key mTORC1 adaptor, Raptor, was deleted in macrophages by Cre/loxP recombination (Mac-RapKO mice) into Ldlr-/- mice and then fed them the Western-type diet (WTD). Atherosclerotic lesions from Mac-RapKO mice showed decreased infiltration of macrophages, lesion size and chemokine gene expression compared with control mice. Treatment of macrophages with minimally modified LDL (mmLDL) resulted in increased levels of chemokine mRNAs and STAT3 phosphorylation; these effects were reduced in Mac-RapKO macrophages. While wild-type and Mac-RapKO macrophages showed similar STAT3 phosphorylation on Tyr705, Mac-RapKO macrophages showed decreased STAT3 Ser727 phosphorylation in response to mmLDL treatment and decreased Ccl2 promoter binding of STAT3. Conclusions The results demonstrate cross-talk between nutritionally-induced mTORC1 signaling and mmLDL-mediated inflammatory signaling via combinatorial phosphorylation of STAT3 in macrophages, leading to increased STAT3 activity on the CCL2 (MCP-1)promoter with pro-atherogenic consequences. PMID:24687132

  4. Asociación entre el volumen de grasa epicárdica y las placas coronarias diagnosticadas por tomografía multicorte/ Associationbetweenepicardialfatvolume and coronary plaques diagnosedbymultislicecomputedtomography

    Directory of Open Access Journals (Sweden)

    José A. Morán Quijada

    2015-12-01

    Full Text Available Introduction: Coronary atherosclerotic disease is a major cause of death in Cuba and elsewhere. The volume of epicardial fat is considered a new cardiovascular risk factor because of its association with coronary atherogenesis. Objective: To determine, by multislice computed tomography, the association between epicardial fat volume and the presence of coronary atherosclerotic plaques. Method: A descriptive study was conducted with a universe of 130 patients with chest pain suggestive of ischemic heart disease, of which 117 were selected by opinion sampling. These patients underwent a calcium score study, a coronary angiography and a measurement of the epicardial fat volume. Results: Male patients predominated (54.7% and those aged 60-69 years (32.5%. A high volume of epicardial fat was found in 51.3% of patients, affecting 52.8% of women; 78.9% of patients with a calcium score between 100 and 399 UH had a high volume of epicardial fat, just as 71.2% of those with plaques and 100% of those with 4 or 5 plaques; 41% of patients had various types of plaque, which were mainly located in the anterior descending artery (88.1%. Conclusions: The measurement of the volume of epicardial fat is a useful tool to estimate the presence of coronary disease. When it was high, it was associated with older age, female gender and the presence of a higher calcium score, more plaques, more injuries and a greater involvement of the anterior descending artery.

  5. Chylomicrons metabolism in patients with coronary artery disease; Metabolismo de quilomicrons em pacientes portadores de doenca arterial coronaria

    Energy Technology Data Exchange (ETDEWEB)

    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)

  6. Cholesteryl ester hydrolase activity is abolished in HSL-/- macrophages but unchanged in macrophages lacking KIAA1363.

    Science.gov (United States)

    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; Zechner, Rudolf; Levak-Frank, Sanja; Cravatt, Benjamin; Kratky, Dagmar

    2010-10-01

    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-activating factor (PAF). HSL efficiently cleaved all four substrates, whereas KIAA1363 hydrolyzed only AcMAGE. This contradicts previous studies suggesting that KIAA1363 is a neutral CE hydrolase. Macrophages of KIAA1363(-/-) and wild-type mice exhibited identical neutral CE hydrolase activity, which was almost abolished in tissues and macrophages of HSL(-/-) mice. Conversely, AcMAGE hydrolase activity was diminished in macrophages and some tissues of KIAA1363(-/-) but unchanged in HSL(-/-) mice. CE turnover was unaffected in macrophages lacking KIAA1363 and HSL, whereas cAMP-dependent cholesterol efflux was influenced by HSL but not by KIAA1363. Despite decreased CE hydrolase activities, HSL(-/-) macrophages exhibited CE accumulation similar to wild-type (WT) macrophages. We conclude that additional enzymes must exist that cooperate with HSL to regulate CE levels in macrophages. KIAA1363 affects AcMAGE hydrolase activity but is of minor importance as a direct CE hydrolase in macrophages.

  7. 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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  8. Dysfunction of pulmonary vascular endothelium in chronic obstructive pulmonary disease: basic considerations for future drug development.

    Science.gov (United States)

    Yang, Qin; Underwood, Malcolm J; Hsin, Michael K Y; Liu, Xiao-Cheng; He, Guo-Wei

    2008-09-01

    Chronic obstructive pulmonary disease (COPD) is one of the leading health problems worldwide and continues to be a major cause of morbidity and mortality in developed countries. The clinical features of COPD are chronic obstructive bronchiolitis and emphysema. Pulmonary vascular endothelial dysfunction is a characteristic pathological finding of COPD at different stages of the disease. Functional changes of pulmonary endothelial cells in COPD include antiplatelet abnormalities, anticoagulant disturbances, endothelial activation, atherogenesis, and compromised regulation of vascular tone which may adversely affect the ventilation-perfusion match in COPD. As the most important risk factor of COPD, cigarette smoking may initiate pulmonary vascular impairment through direct injury of endothelial cells or release of inflammatory mediators. Morphological changes such as denudation of endothelium and endothelial cell apoptosis have been observed in the pulmonary vasculature in COPD patients as well as functional alterations. Changes in the expression of tissue factor pathway inhibitor (TFPI), thrombomodulin, selectins, and adhesion molecules in pulmonary endothelial cells as well as complex regulation and interaction of vasoactive substances and growth factors released from endothelium may underlie the mechanisms of pulmonary endothelial dysfunction in COPD. The mechanism of endothelial repair/regeneration in COPD, although not fully understood, may involve upregulation of vascular endothelial growth factors in the early stages along with an increased number of bone marrow-derived progenitor cells. These factors should be taken into account when developing new strategies for the pharmacological therapy of patients with COPD.

  9. 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.

  10. Omega-3 fatty acids, inflammation and angiogenesis: nutrigenomic effects as an explanation for anti-atherogenic and anti-inflammatory effects of fish and fish oils.

    Science.gov (United States)

    Massaro, Marika; Scoditti, Egeria; Carluccio, Maria Annunziata; Montinari, Maria Rosa; De Caterina, Raffaele

    2008-01-01

    Atherosclerosis is a dynamic process with inflammatory aspects playing a considerable pathogenetic role. In this process, the vascular endothelium is the key regulator of vascular function, promoting the maintenance of vascular homeostasis or the progression towards vascular disease. In the past 30 years, the dietary intake of omega-3 (n-3) polyunsaturated fatty acids - mainly derived from fish - has emerged as an important way to modify cardiovascular risk through beneficial effects on all stages of atherosclerosis. This review specifically focuses on the modulating effects of n-3 fatty acids on molecular events involved in early and late atherogenesis, including effects on endothelial expression of adhesion molecules, as well as pro-inflammatory and pro-angiogenic enzymes. By accumulating in endothelial membrane phospholipids, omega-3 fatty acids have been shown to decrease the transcriptional activation of several genes through a decreased activation of the nuclear factor-kappaB system of transcription factors. This occurs secondary to decreased generation of intracellular reactive oxygen species. This series of investigations configures a clear example of nutrigenomics, i.e. how nutrients may affect gene expression, ultimately affecting a wide spectrum of human diseases.

  11. Omega-3 fatty acids and atorvastatin affect connexin 43 expression in the aorta of hereditary hypertriglyceridemic rats.

    Science.gov (United States)

    Dlugosová, Katarína; Weismann, Peter; Bernátová, Iveta; Sotníková, Ruzena; Slezák, Ján; Okruhlicová, Ludmila

    2009-12-01

    Statins and omega-3 polyunsaturated fatty acids (n-3 PUFA) reduce cardiovascular disease incidence during hypertriglyceridemia (HTG). To elucidate possible cardioprotective mechanisms, we focused on gap junction protein connexin 43 (Cx43). Its expression is disturbed during atherogenesis, but little information is available on its expression during HTG. Experiments were performed on adult male hereditary HTG (hHTG) rats treated with n-3 PUFA (30 mg/day) and atorvastatin (0.5 mg/100 g body weight per day) for 2 months. Cx43 expression and distribution in the aorta were investigated by using Western blotting and immunolabeling, followed by quantitative analysis. Transmission electronmicroscopy was used to study ultrastructure of endothelial contact sites. In contrast to age-matched Wistar, Cx43 expression in aorta of hHTG rats was significantly higher (p < 0.05), and prominent Cx43 immunospots were seen in tunica media and less in endothelium of hHTG rats. Changes in Cx43 expression were accompanied by local qualitative subcellular alterations of interendothelial connections. Treatment of hHTG rats with n-3 PUFA and atorvastatin markedly lowered Cx43 expression in aorta and modified connexin distribution in endothelium and media (p < 0.05 vs. untreated hHTG). The protective effect of treatment of HTG was observed on the structural integrity of the endothelium and was readily visible at the molecular level. Results indicate the involvement of altered Cx43 expression in vascular pathophysiology during HTG and during HTG treatment.

  12. 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.

  13. [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.

  14. Tuberculosis and Cardiovascular Disease: Linking the Epidemics.

    Science.gov (United States)

    Huaman, Moises A; Henson, David; Ticona, Eduardo; Sterling, Timothy R; Garvy, Beth A

    The burden of tuberculosis and cardiovascular disease (CVD) is enormous worldwide. CVD rates are rapidly increasing in low- and middle-income countries. Public health programs have been challenged with the overlapping tuberculosis and CVD epidemics. Monocyte/macrophages, lymphocytes and cytokines involved in cellular mediated immune responses against Mycobacterium tuberculosis are also main drivers of atherogenesis, suggesting a potential pathogenic role of tuberculosis in CVD via mechanisms that have been described for other pathogens that establish chronic infection and latency. Studies have shown a pro-atherogenic effect of antibody-mediated responses against mycobacterial heat shock protein-65 through cross reaction with self-antigens in human vessels. Furthermore, subsets of mycobacteria actively replicate during latent tuberculosis infection (LTBI), and recent studies suggest that LTBI is associated with persistent chronic inflammation that may lead to CVD. Recent epidemiologic work has shown that the risk of CVD in persons who develop tuberculosis is higher than in persons without a history of tuberculosis, even several years after recovery from tuberculosis. Together, these data suggest that tuberculosis may play a role in the pathogenesis of CVD. Further research to investigate a potential link between tuberculosis and CVD is warranted.

  15. Cardiovascular disease in haemodialysis: role of the intravascular innate immune system.

    Science.gov (United States)

    Ekdahl, Kristina N; Soveri, Inga; Hilborn, Jöns; Fellström, Bengt; Nilsson, Bo

    2017-02-27

    Haemodialysis is a life-saving renal replacement modality for end-stage renal disease, but this therapy also represents a major challenge to the intravascular innate immune system, which is comprised of the complement, contact and coagulation systems. Chronic inflammation is strongly associated with cardiovascular disease (CVD) in patients on haemodialysis. Biomaterial-induced contact activation of proteins within the plasma cascade systems occurs during haemodialysis and initially leads to local generation of inflammatory mediators on the biomaterial surface. The inflammation is spread by soluble activation products and mediators that are generated during haemodialysis and transported in the extracorporeal circuit back into the patient together with activated leukocytes and platelets. The combined effect is activation of the endothelium of the cardiovascular system, which loses its anti-thrombotic and anti-inflammatory properties, leading to atherogenesis and arteriosclerosis. This concept suggests that maximum suppression of the intravascular innate immune system is needed to minimize the risk of CVD in patients on haemodialysis. A potential approach to achieve this goal is to treat patients with broad-specificity systemic drugs that target more than one of the intravascular cascade systems. Alternatively, 'stealth' biomaterials that cause minimal cascade system activation could be used in haemodialysis circuits.

  16. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Association between epicardial fat volume and coronary plaques diagnosed by multislice computed tomography

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    José A. Morán Quijada

    2016-01-01

    Full Text Available Introduction: Coronary atherosclerotic disease is a major cause of death in Cuba and elsewhere. The volume of epicardial fat is considered a new cardiovascular risk factor because of its association with coronary atherogenesis.Objective: To determine, by multislice computed tomography, the association between epicardial fat volume and the presence of coronary atherosclerotic plaques.Method: A descriptive study was conducted with a universe of 130 patients with chest pain suggestive of ischemic heart disease, of which 117 were selected by opinion sampling. These patients underwent a calcium score study, a coronary angiography and a measurement of the epicardial fat volume.Results: Male patients predominated (54.7% and those aged 60-69 years (32.5%. A high volume of epicardial fat was found in 51.3% of patients, affecting 52.8% of women; 78.9% of patients with a calcium score between 100 and 399 UH had a high volume of epicardial fat, just as 71.2% of those with plaques and 100% of those with 4 or 5 plaques; 41% of patients had various types of plaque, which were mainly located in the anterior descending artery (88.1%.Conclusions: The measurement of the volume of epicardial fat is a useful tool to estimate the presence of coronary disease. When it was high, it was associated with older age, female gender and the presence of a higher calcium score, more plaques, more injuries and a greater involvement of the anterior descending artery.

  19. Did we finally slay the evil dragon of cigarette smoking in the late 20th century?: unfortunately, the answer is no - the dragon is still alive and well in the 21st century and living in the third world. Shame on us!

    Science.gov (United States)

    Hurt, Richard D; Murphy, Joseph G; Dunn, William F

    2014-12-01

    If cigarettes were introduced as a new consumer product today, it is unlikely they would receive government regulatory approval. Cigarettes have proven biologic toxicities (carcinogenesis, atherogenesis, teratogenesis) and well-established causal links to human disease. Things were very different in 1913 when the R. J. Reynolds Tobacco Company introduced the first modern cigarette, the iconic Camel. By the early 1950s, definitive scientific reports linked cigarettes and human disease, but it was more than a half century later (2006) that cigarette manufacturers were found guilty by a federal court of deceptive product marketing regarding the health hazards of tobacco use. In the United States, cigarette smoking remains a major but slowly declining problem. But in developing countries, cigarette use is expanding tremendously. In global terms, the epidemic of smoking-caused disease is projected to increase rapidly in coming decades, not decline. Society may have begun to slowly win the smoking battle in the developed world, but we are resoundingly losing the global war on smoking. All is not lost! There is some good news! The 2003 Framework Convention on Tobacco Control, supported strongly by the American College of Chest Physicians, is the first global public health treaty of the new millennium. Many developed societies have begun planning to rid their countries of cigarettes in what is called the Endgame Strategy, and now is the time for the international medical community to help change tobacco policy to a worldwide endgame approach to rid all humanity of smoking-related diseases.

  20. 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.

  1. Emerging role of IL-17 in atherosclerosis.

    Science.gov (United States)

    Chen, Shuang; Crother, Timothy R; Arditi, Moshe

    2010-01-01

    The IL-23-IL-17 axis is emerging as a critical regulatory system that bridges the innate and adaptive arms of the immune system. Th17 cells have been linked to the pathogenesis of several chronic inflammatory and autoimmune diseases. However, the role of Th17 cells and IL-17 in various stages of atherogenesis remains poorly understood and is only beginning to be elucidated. While IL-17 is a predominantly proinflammatory cytokine, it has a pleiotropic function and it has been implicated both as an instigator in the pathogenesis of several inflammatory disorders as well as being protective in certain inflammatory disease models. Therefore, it is not surprising that the current literature is conflicting on the role of IL-17 during atherosclerotic lesion development. Various approaches have been used by several groups to discern the involvement of IL-17 in atherosclerosis. While one study found that IL-17 is protective against atherosclerosis, several other recent studies have suggested that IL-17 plays a proatherogenic role. Thus, the function of IL-17 remains controversial and awaits more direct studies to address the issue. In this review, we will highlight all the latest studies involving IL-17 and atherosclerosis, including both clinical and experimental research.

  2. Effects of Low Carbohydrate High Protein (LCHP) diet on atherosclerotic plaque phenotype in ApoE/LDLR-/- mice: FT-IR and Raman imaging.

    Science.gov (United States)

    Wrobel, T P; Marzec, K M; Chlopicki, S; Maślak, E; Jasztal, A; Franczyk-Żarów, M; Czyżyńska-Cichoń, I; Moszkowski, T; Kostogrys, R B; Baranska, M

    2015-09-22

    Low Carbohydrate High Protein (LCHP) diet displays pro-atherogenic effects, however, the exact mechanisms involved are still unclear. Here, with the use of vibrational imaging, such as Fourier transform infrared (FT-IR) and Raman (RS) spectroscopies, we characterize biochemical content of plaques in Brachiocephalic Arteries (BCA) from ApoE/LDLR(-/-) mice fed LCHP diet as compared to control, recomended by American Institute of Nutrition, AIN diet. FT-IR images were taken from 6-10 sections of BCA from each mice and were complemented with RS measurements with higher spatial resolution of chosen areas of plaque sections. In aortic plaques from LCHP fed ApoE/LDLR(-/-) mice, the content of cholesterol and cholesterol esters was increased, while that of proteins was decreased as evidenced by global FT-IR analysis. High resolution imaging by RS identified necrotic core/foam cells, lipids (including cholesterol crystals), calcium mineralization and fibrous cap. The decreased relative thickness of the outer fibrous cap and the presence of buried caps were prominent features of the plaques in ApoE/LDLR(-/-) mice fed LCHP diet. In conclusion, FT-IR and Raman-based imaging provided a complementary insight into the biochemical composition of the plaque suggesting that LCHP diet increased plaque cholesterol and cholesterol esters contents of atherosclerotic plaque, supporting the cholesterol-driven pathogenesis of LCHP-induced atherogenesis.

  3. Dual AAV/IL-10 Plus STAT3 Anti-Inflammatory Gene Delivery Lowers Atherosclerosis in LDLR KO Mice, but without Increased Benefit

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    Maohua Cao

    2012-01-01

    Full Text Available Both IL-10 and STAT3 are in the same signal transduction pathway, with IL-10-bound IL10 receptor (R acting through STAT3 for anti-inflammatory effect. To investigate possible therapeutic synergism, we delivered both full-length wild-type human (h STAT3 and hIL-10 genes by separate adenoassociated virus type 8 (AAV8 tail vein injection into LDLR KO on HCD. Compared to control Neo gene-treated animals, individual hSTAT3 and hIL-10 delivery resulted in significant reduction in atherogenesis, as determined by larger aortic lumen size, thinner aortic wall thickness, and lower blood velocity (all statistically significant. However, dual hSTAT3/hIL-10 delivery offered no improvement in therapeutic effect. Plasma cholesterol levels in dual hSTAT3/hIL-10-treated animals were statistically higher compared to hIL-10 alone. While no advantage was seen in this case, we consider that the dual gene approach has intrinsic merit, but properly chosen partnered genes must be used.

  4. C242T Polymorphism in CYBA Gene (p22phox) and Risk of Coronary Artery Disease in a Population of Caucasian Italians

    Science.gov (United States)

    Nasti, Sabina; Spallarossa, Paolo; Altieri, Paola; Garibaldi, Silvano; Fabbi, Patrizia; Polito, Luisa; Bacino, Luca; Brunelli, Michele; Brunelli, Claudio; Barsotti, Antonio; Ghigliotti, Giorgio

    2006-01-01

    Background: specific polymorphisms of genes regulating intracellular redox balance and oxidative stress are related to atherogenesis. Some studies have identified a relationship between progression of atherosclerosis and C242T mutation in CYBA gene coding for p22phox, a subunit of the NADH/NADPH oxidase system. Design: we investigated whether the C242T nucleotide transition is associated with the presence of coronary artery disease (CAD) in a population of 494 Caucasian Italians undergoing coronary angiography to diagnose the cause of chest pain. Results: the frequency of the T mutant allele that we found in 276 patients with angiographically documented CAD was significantly higher compared to what we observed in 218 subjects with normal coronary arteries (Controls) (respectively: 0.400 and 0.332, p < 0.01). The prevalence of the T allele was even stronger when we compared: 1) early onset (age ≤55) vs late onset (age ≥65) single-vessel CAD patients (respectively: 0.75 and 0.48, p < 0.05), and 2) the subgroup of CAD patients with at least one ≥98% stenosis in a coronary vessel vs those with no ≥98% stenosis in a coronary vessel (respectively: 0.425 and 0.365, p < 0.05). Conclusions: these results support the increased risk of developing early CAD and of having rapid progression of coronary stenosis in subjects carrying the C242T nucleotide transition among the Italian population. PMID:16788250

  5. Effect of Quercetin on Paraoxonase 2 Levels in RAW264.7 Macrophages and in Human Monocytes—Role of Quercetin Metabolism

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    Manfred James Mueller

    2009-09-01

    Full Text Available There is increasing evidence that the intracellular antioxidant enzyme paraoxonase 2 (PON2 may have a protective function in the prevention of atherogenesis. An enhancement of PON2 activity by dietary factors including flavonoids is therefore of interest. In the present study we determined the effect of quercetin on paraoxonase 2 levels in cultured murine macrophages in vitro and in overweight subjects with a high cardiovascular risk phenotype supplemented with 150 mg quercetin/day for 42 days in vivo. Supplementation of murine RAW264.7 macrophages in culture with increasing concentrations of quercetin (1, 10, 20 μmol/L resulted in a significant increase in PON2 mRNA and protein levels, as compared to untreated controls. Unlike quercetin, its glucuronidated metabolite quercetin-3-glucuronide did not affect PON2 gene expression in cultured macrophages. However the methylated quercetin derivative isorhamnetin enhanced PON2 gene expression in RAW264.7 cells to similar extent like quercetin. Although supplementing human volunteers with quercetin was accompanied by a significant increase in plasma quercetin concentration, dietary quercetin supplementation did not change PON2 mRNA levels in human monocytes in vivo. Current data indicate that quercetin supplementation increases PON2 levels in cultured monocytes in vitro but not in human volunteers in vivo.

  6. Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells.

    Science.gov (United States)

    Feldmann, Radmila; Fischer, Cornelius; Kodelja, Vitam; Behrens, Sarah; Haas, Stefan; Vingron, Martin; Timmermann, Bernd; Geikowski, Anne; Sauer, Sascha

    2013-04-01

    Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.

  7. The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease.

    Science.gov (United States)

    Debreceni, Balazs; Debreceni, Laszlo

    2014-06-01

    Cardiovascular disease (CVD) is the leading cause of mortality in the Western world. The effort of research should aim at the primary prevention of CVD. Alongside statin therapy, which is maintained to be an effective method of CVD prevention, there are alternative methods such as vitamin B substitution therapy with folic acid (FA), and vitamins B12 and B6 . B-vitamins may inhibit atherogenesis by decreasing the plasma level of homocysteine (Hcy)-a suspected etiological factor for atherosclerosis-and by other mechanisms, primarily through their antioxidant properties. Although Hcy-lowering vitamin trials have failed to demonstrate beneficial effects of B-vitamins in the prevention of CVD, a meta-analysis and stratification of a number of large vitamin trials have suggested their effectiveness in cardiovascular prevention (CVP) in some aspects. Furthermore, interpretation of the results from these large vitamin trials has been troubled by statin/aspirin therapy, which was applied along with the vitamin substitution, and FA fortification, both of which obscured the separate effects of vitamins in CVP. Recent research results have accentuated a new approach to vitamin therapy for CVP. Studies undertaken with the aim of primary prevention have shown that vitamin B substitution may be effective in the primary prevention of CVD and may also be an option in the secondary prevention of disease if statin therapy is accompanied by serious adverse effects. Further investigations are needed to determine the validity of vitamin substitution therapy before its introduction in the protocol of CVD prevention.

  8. The status of glutathione peroxidase, superoxide dismutase, vitamins A, C, E and malondialdehyde in patients with cardiovascular disease in Zahedan, Southeast Iran.

    Science.gov (United States)

    Karajibani, Mansour; Hashemi, Mohammad; Montazerifar, Farzaneh; Bolouri, Ahmad; Dikshit, Madhurima

    2009-08-01

    Growing evidence has demonstrated that oxidative stress and increased altered oxygen utilization contribute to atherogenesis and cardiovascular disease (CVD) progression. Antioxidants protect the body from damage caused by free radicals. The objective of this study was to determine antioxidants status in CVD patients. This cross-sectional study was performed on 71 patients clinically diagnosed with CVD and 63 healthy individuals. Plasma malondialdehyde (MDA) level was measured for lipid peroxidation product and erythrocyte SOD and GPx activities as enzymatic antioxidants. The serum levels of vitamins A and E were assayed using HPLC and vitamin C by the photometric method. Total antioxidant capacity (TAC) was measured using the ferric reducing ability of plasma (FRAP) method. The results showed a significant reduction in antioxidant status (enzymatic and non-enzymatic) with a concomitant increase in the concentrations of lipid peroxidation products in CVD patients. There was a significant inverse correlation among TAC, SOD, GPx and vitamin C with MDA. It can be concluded that the antioxidant defense system plays an important role in preventing the development and progression of CVD with the ability to control oxidative stress.

  9. The role of vitamin supplementation in the prevention of cardiovascular disease events.

    Science.gov (United States)

    Desai, Chirag K; Huang, Jennifer; Lokhandwala, Adil; Fernandez, Aaron; Riaz, Irbaz Bin; Alpert, Joseph S

    2014-09-01

    The production, sale, and consumption of multiple vitamins is a multibillion-dollar industry. Most Americans take some form of supplement ostensibly for prevention of cardiovascular disease. It has been claimed that vitamin A retards atherogenesis. Vitamin C is an antioxidant and is thought to possibly decrease free radical-induced endothelial injury, which can lead to atherosclerotic plaque formation. Vitamin E has been extensively studied for its possible effects on platelet function as well as inhibition of foam-cell formation. Low levels of vitamin D have been thought to negatively impact myocardial structure and increase the risk for cardiovascular events. Increased intake of vitamin B6, B12, and folate has been associated with reduction of homocysteine levels; elevated homocysteine blood levels have been associated with the occurrence of stroke, heart attack, and cardiovascular death. The purpose of this study was to review the currently available literature for vitamin supplementation with respect to prevention of cardiovascular disease. Unfortunately, the current evidence suggests no benefit exists with vitamin supplementation in the general US population. Further research is needed to evaluate whether there are specific populations that might benefit from vitamin supplementation.

  10. B cell subsets in atherosclerosis

    Directory of Open Access Journals (Sweden)

    Heather M. Perry

    2012-12-01

    Full Text Available Atherosclerosis, the underlying cause of heart attacks and strokes, is a chronic inflammatory disease of the artery wall. Immune cells, including lymphocytes modulate atherosclerotic lesion development through interconnected mechanisms. Elegant studies over the past decades have begun to unravel a role for B cells in atherosclerosis. Recent findings provide evidence that B cell effects on atherosclerosis may be subset-dependent. B-1a B cells have been reported to protect from atherosclerosis by secretion of natural IgM antibodies. Conventional B-2 B cells can promote atherosclerosis through less clearly defined mechanism that may involve CD4 T cells. Yet, there may be other populations of B cells within these subsets with different phenotypes altering their impact on atherosclerosis. Additionally, the role of B cell subsets in atherosclerosis may depend on their environmental niche and/or the stage of atherogenesis. This review will highlight key findings in the evolving field of B cells and atherosclerosis and touch on the potential and importance of translating these findings to human disease.

  11. Propylthiouracil, independent of its antithyroid effect, decreases VSMC collagen expression.

    Science.gov (United States)

    Chen, Wei-Jan; Pang, Jong-Hwei S; Lin, Kwang-Huei; Yang, Su-Hui

    2009-01-01

    Propylthiouracil (PTU), in addition to its antithyroid effect, is recently found to have a potent antiatherosclerotic effect. Because collagen accumulation is the major contributor to the growth of atherosclerotic lesions and the neointimal formation after arterial injury, the aim of this study is to investigate the impact of PTU on collagen regulation. In the rat carotid injury model, PTU administration reversed the up-regulation of collagen in the neointima induced by balloon injury. In vitro, vascular smooth muscle cells (VSMCs), the main origin of arterial collagen, were treated with PTU. Propylthiouracil caused a concentration-dependent decrease in collagen I and III steady-state protein and mRNA levels, as determined by immuno-cytochemistry, Western, and/or Northern blot analyses. Transient transfection experiments using rat type I collagen promoter construct showed that PTU failed to affect collagen gene transcription in VSMCs. Actinomycin D studies demonstrated that the half-life of collagens mRNA decreased with PTU treatment, suggesting that PTU down-regulates collagen expression predominantly at the post-transcriptional level. Taken together, these data suggest that PTU inhibits VSMC collagen production via destabilization of collagen mRNA that contributes to its beneficial effect on atherogenesis and neointimal formation after arterial injury. However, whether the destabilization of collagen may induce plaque rupture in PTU-treated arteries merits further investigation.

  12. Propylthiouracil, independent of its antithyroid effect, promotes vascular smooth muscle cells differentiation via PTEN induction.

    Science.gov (United States)

    Chen, Wei-Jan; Pang, Jong-Hwei S; Lin, Kwang-Huei; Lee, Dany-Young; Hsu, Lung-An; Kuo, Chi-Tai

    2010-01-01

    Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial injury.

  13. 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.

  14. Prevalence of Metabolic Syndrome in Patients with Psoriasis

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    Ilkin Zindancı

    2012-01-01

    Full Text Available Background. Psoriasis is a chronic inflammatory skin disorder in which proinflammatory cytokines including IL-6 and TNF-α increase both locally and systematically. It is thought that chronic inflammation results in metabolic diseases and proinflammatory cytokines give rise to the development of atherogenesis, peripheral insulin resistance, hypertension, and type 2 diabetes. Our aim was to investigate the prevalence of metabolic syndrome in patients with psoriasis vulgaris. Methods. Study consisted of 115 plaque-type psoriasis patients and 140 healthy individuals. Data including body weight, height, waist circumference, body-mass index, and arterial blood pressure were collected. Fasting blood glucose, triglyceride, and HDL levels were determined. International Diabetes Federation Criteria for Metabolic Syndrome and Insulin Resistance were used for evaluating patients with metabolic syndrome and diabetes. Results. Compared to the control group, metabolic syndrome, diabetes mellitus, and hypertension were found to be higher in psoriasis patients. Metabolic syndrome was increased by 3-folds in psoriasis patients and was more prevalent in women than in men. It was determined that the prevalence of metabolic syndrome was higher in psoriasis patients after the age of 40. Metabolic syndrome was not related to smoking, severity of psoriasis, and duration of disease. Conclusions. Our findings suggest that psoriasis preconditions occurrence of a group of diseases such as diabetes mellitus, hypertension, and metabolic syndrome. For this reason, patients with psoriasis should be treated early and they should be followed with respect to metabolic diseases.

  15. Atherosclerosis in vascular grafts for peripheral vascular disease. Part 2. Synthetic arterial prostheses.

    Science.gov (United States)

    Walton, K W; Slaney, G; Ashton, F

    1986-08-01

    Thirty-nine synthetic (32 Dacron and 7 Teflon) arterial prostheses (from 38 patients with peripheral arterial disease) removed after periods between 2 months and 18 years, were examined by histology and immuno-histology. The grafts were initially permeated by thrombus containing platelet antigens and this became organised and converted to granulation, and then to fibrous, tissue. The newly-formed tissue contained 'foreign-body' giant-cells in contact with the plastic prosthesis and showed evidence of permeation by plasma proteins. In grafts of over 2 years duration, this reactive tissue no longer contained platelet antigens but invariably revealed bound lipid, identifiable as apolipoprotein-B-containing lipoproteins (LpB), and fibrinogen-related antigens (FRA), in a distribution resembling that seen in atherosclerotic arteries. LpB and FRA were also seen in organised, or partially organised, mural thrombi in older grafts. The oldest grafts additionally showed stenosis, calcification or aneurysm formation. Lipid deposition increases with the age of grafts; is independent of the nature of the plastic fibre used or its mode of fabrication; and sometimes contributes to graft failure. Immuno-histology indicates that this is an insudative process indistinguishable from 'true' atherosclerosis which occurs in graft-linings of prostheses of long duration and in old mural thrombi in grafts and that the lipid in these lesions derives from plasma LpB rather than from platelets. This source for the lipid suggests that the insudative and thrombogenic theories of atherogenesis can be reconciled.

  16. INSULIN RESISTANCE AND CAROTID ATHEROSCLEROSIS IN 221 PATIENTS WITH POTENTIAL HYPERGLYCEMIA

    Institute of Scientific and Technical Information of China (English)

    Bo Yang; Tian-de Li; Jin-song Wang; Guang Zhi; Wen-sheng Jin; Yong Xu

    2005-01-01

    Objective To investigate the relationship between insulin resistance and carotid atherosclerosis in patients with potential hyperglycemia.Methods A total of 221 patients were recruited among those with potential hyperglycemia. All participants underwent physical examination, medical history interview, and 75 g oral glucose tolerance test. Venous blood was sampled for measurement of insulin and cholesterol levels. The intima-media thickness (IMT) in bilateral common carotid arteries was observed by B-mode ultrasound. Insulin resistance index was calculated by homeostasis model assessment (HOMA-IR).Subjects were stratified in quintiles according to HOMA-IR values. Risk factors and atherosclerotic parameters were analyzed.Results With HOMA-IR value increase, incidence of impaired glucose tolerance, diabetes mellitus, hypertension, and coronary artery disease increased, the levels of triglyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose, 2 hour plasma glucose, and fasting insulin increased as well, while the level of high density lipoprotein cholesterol (HDL-C) decreased. Meanwhile, all atherosclerotic parameters increased. Multivariate regression analysis showed that TG, total cholesterol, HDL-C, LDL-C levels, and In(HOMA-IR) were related to IMT, hence were risk factors for IMT increase.Conchsion Insulin resistance is implicated in atherogenesis.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  18. Unsaturated Fatty Acids Drive Disintegrin and Metalloproteinase (ADAM)-dependent Cell Adhesion, Proliferation, and Migration by Modulating Membrane Fluidity*

    Science.gov (United States)

    Reiss, Karina; Cornelsen, Isabell; Husmann, Matthias; Gimpl, Gerald; Bhakdi, Sucharit

    2011-01-01

    The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers. PMID:21642425

  19. Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity.

    Science.gov (United States)

    Reiss, Karina; Cornelsen, Isabell; Husmann, Matthias; Gimpl, Gerald; Bhakdi, Sucharit

    2011-07-29

    The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers.

  20. Jellyfish skin polysaccharides: extraction and inhibitory activity on macrophage-derived foam cell formation.

    Science.gov (United States)

    Zhang, Hai-Lin; Cui, Shao-Hua; Zha, Xue-Qiang; Bansal, Vibha; Xue, Lei; Li, Xiao-Long; Hao, Ran; Pan, Li-Hua; Luo, Jian-Ping

    2014-06-15

    In this work, response surface methodology was used to determine optimum conditions for extraction of polysaccharides from jellyfish skin (JSP). The optimum parameters were found to be raw material to water ratio 1:7.5 (w/v), extraction temperature 100°C and extraction time 4h. Under these conditions, the JSP yield reached 1.007 mg/g. Papain (15 U/mL) in combination with Sevag reagent was beneficial in removing proteins from JSP. After precipitation with ethanol at final concentration of 40%, 60% and 80% in turn, three polysaccharide fractions of JSP1, JSP2 and JSP3 were obtained from JSP, respectively. The three fractions exhibited different physicochemical properties with respect to molecular weight distribution, monosaccharide composition, infrared absorption spectra, and glycosyl bond composition. In addition, JSP3 showed strong inhibitory effects on oxidized low-density lipoprotein (oxLDL) induced conversion of macrophages into foam cells, which possibly attributed to the down-regulation of some atherogenesis-related gene expressions.

  1. Rosiglitazone inhibits expression of acyl-coenzyme A:cholesterol acyltransferase-1 in THP-1 macrophages induced by advanced glycation end-products

    Institute of Scientific and Technical Information of China (English)

    Yang Qihong; Xu Qiang; Zhang Hong; Si Liangyi

    2008-01-01

    Objective: To investigate the effects of rosiglitazone, a synthetic ligand of peroxisome proliferators-activated receptor gamma (PPARγ), on the expression of acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) in phorbol myristate acetate (PMA)-pretreated THP-1 cells after the inducement of advanced glycation end products (AGEs). Methods: After THP-1 cells were cultured in the presence of 0.1 umol/L PMA for 72 h to induce phagocytic differentiation, the obtained THP-1 macrophages were treated with rosiglitazone for 4 h at different concentrations (1,5 or 10 μmol/L) and then exposed to AGEs-modified bovine serum albumin (AGEs-BSA) for 24 h at a concentration of 200 mg/L. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis were performed to detect the mRNA and protein expressions of ACAT-1 respectively. Results: Administration of AGEs-BSA (200 mg/L) into the THP-1 macrophages resulted in up-regulation of ACAT-1 at mRNA and protein levels when compared with the expressions in macrophages incubated with serum-free RPM11640. Pretreatment of rosiglitazone inhibited significantly the increased expression of ACAT-1 induced by AGEs-BSA in a concentration-dependent manner. Conclusion: PPARγ activation by rosiglitazone down-regulates ACAT-1 expression induced by AGEs in THP-1 macrophages, which might provide a new way for treating atherogenesis in diabetic patients.

  2. Apolipoproteins A-I and B in Kuwaiti children.

    Science.gov (United States)

    Moussa, M A; Shaltout, A A; Nkansa-Dwamena, D; Mourad, M

    1998-01-01

    To assess the relation of apolipoproteins (Apos) A-I and B (the carrier proteins for high and low density lipoprotein cholesterol, respectively) with the degree of obesity, body fat distribution, serum lipids, glucose and insulin levels, a case-control study was carried out and included 460 Kuwaiti obese children, 6-13 years old, matched by age and sex to 460 normal-weight controls. Obese children were ascertained in a representative cross-sectional study of 2,400 school children. The Apo A-I levels were not different between obese and non-obese boys, while they were significantly lower in obese girls (p < 0.01). The Apo B mean concentrations were significantly higher in obese boys and girls (p < 0.001), while the Apo A-I:B ratio was significantly lower in obese children (p < 0.001). Apo A-I levels were positively correlated with total cholesterol, high- and low-density lipoprotein cholesterol, but were not correlated with very low-density lipoprotein cholesterol, triglycerides, insulin, glucose or insulin:glucose ratio. Apo B levels were negatively correlated with high-density lipoprotein cholesterol and positively correlated with insulin and insulin:glucose ratio (p < 0.01) in obese children. The study documented an adverse Apo profile in obese Kuwaiti children. Since Apo changes are correctable through management of obesity, their identification in childhood offers prospects for prevention of early onset atherogenesis in adulthood.

  3. Food restriction normalizes chylomicron remnant metabolism in murine models of obesity as assessed by a novel stable isotope breath test.

    Science.gov (United States)

    Martins, Ian J; Tran, J M L; Redgrave, Trevor G

    2002-02-01

    Evidence is increasing that defective metabolism of postprandial remnants of triglyceride-rich lipoproteins contributes to atherogenesis. In obesity, postprandial lipemia is increased by mechanisms that are not currently established. In the present study, a recently developed (13)CO(2) breath test was used to assess the metabolism of chylomicron remnants (CR) in obese mice. Six murine obese models ob/ob, fat/fat, New Zealand Obese (NZO), db/db, gold thioglucose (GTG)-treated and agouti (A(y)) were studied. All obese mice were hyperphagic and their breath test metabolism was markedly impaired (P obese models such as db/db were diabetic, our data suggest that the defective breath test was independent of diabetes because all obese and diabetic models responded similarly to food restriction. Impaired hepatic catabolism of CR was excluded as a cause of the abnormal breath tests. In summary, the impairment (P < 0.05) in remnant metabolism as assessed by the breath test in obese mice was corrected by food restriction, associated with improvements in plasma glucose, triglyceride and cholesterol levels.

  4. Commensal Microbe-specific Activation of B2 Cell Subsets Contributes to Atherosclerosis Development Independently of Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Lin Chen

    2016-11-01

    Full Text Available The relation between B2 cells and commensal microbes during atherosclerosis remains largely unexplored. Here we show that under hyperlipidemic conditions intestinal microbiota resulted in recruitment and ectopic activation of B2 cells in perivascular adipose tissue, followed by an increase in circulating IgG, promoting disease development. In contrast, disruption of the intestinal microbiota by a broad-spectrum antibiotic cocktail (AVNM led to the attenuation of atherosclerosis by suppressing B2 cells, despite the persistence of serum lipid abnormalities. Furthermore, pharmacological depletion of B2 cells with an anti-B2-cell surface CD23 antibody also attenuated commensal microbe-induced atherosclerosis. Moreover, expression analysis of TLR-signaling-related genes in the activated B2 cell subsets, assessed using the Toll-Like Receptor Signaling Pathway RT2 Profiler PCR Array, confirmed activation of the B2-cell autoantibody-production axis, which was associated with an increased capacity of B2 cells to bind to intestinal microbiota. Together, our findings reveal the critical role of commensal microbe-specific activation of B2 cells in the development of atherogenesis through lipid metabolism-independent mechanisms.

  5. Antithrombotic lipid minor constituents from vegetable oils. Comparison between olive oils and others.

    Science.gov (United States)

    Karantonis, Haralabos C; Antonopoulou, Smaragdi; Demopoulos, Constantinos A

    2002-02-27

    Many epidemiological studies suggest that vegetable oils and especially olive oil present a protective effect against atherosclerosis. In this study, total lipids (TL) of Greek olive oils and seed oils of four kinds, namely, soybean, corn, sunflower, and sesame oil, were separated into total polar lipids (TPL) and total neutral lipids (TNL) via a novel extraction procedure. TPL and TNL of olive oil were fractionated by HPLC for further study. Each lipid fraction from HPLC separation along with TL, TPL, and TNL lipid samples from oils were tested in vitro for their capacity to induce or to inhibit washed rabbit platelet aggregation. Comparison between olive and seed oils supports the superiority of olive oil as high levels of platelet activating factor (PAF) antagonists have been detected, mainly in TPL. In addition, the structure of the most active fraction from olive oil was elucidated, as a glycerol-glycolipid. Because it has already been reported that PAF plays a pivotal role in atherogenesis, the existence of PAF agonists and antagonists in vegetable oils may explain their protective role against atherosclerosis.

  6. Methylglyoxal Causes Cell Death in Neural Progenitor Cells and Impairs Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Chun, Hye Jeong; Lee, Yujeong; Kim, Ah Hyun; Lee, Jaewon

    2016-04-01

    Methylglyoxal (MG) is formed during normal metabolism by processes like glycolysis, lipid peroxidation, and threonine catabolism, and its accumulation is associated with various degenerative diseases, such as diabetes and arterial atherogenesis. Furthermore, MG has also been reported to have toxic effects on hippocampal neurons. However, these effects have not been studied in the context of neurogenesis. Here, we report that MG adversely affects hippocampal neurogenesis and induces neural progenitor cell (NPC) death. MG significantly reduced C17.2 NPC proliferation, and high concentration of MG (500 μM) induced cell death and elevated oxidative stress. Further, MG was found to activate the ERK signaling pathway, indicating elevated stress response. To determine the effects of MG in vivo, mice were administrated with vehicle or MG (0.5 or 1 % in drinking water) for 4 weeks. The numbers of BrdU-positive cells in hippocampi were significantly lower in MG-treated mice, indicating impaired neurogenesis, but MG did not induce neuronal damage or glial activations. Interestingly, MG reduced memory retention when administered to mice at 1 % but not at 0.5 %. In addition, the levels of hippocampal BDNF and synaptophysin were significantly lower in the hippocampi of mice treated with MG at 1 %. Collectively, our findings suggest MG could be harmful to NPCs and to hippocampal neurogenesis.

  7. 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...

  8. Leishmania major Self-Limited Infection Increases Blood Cholesterol and Promotes Atherosclerosis Development

    Directory of Open Access Journals (Sweden)

    Luciana R. Fernandes

    2013-01-01

    Full Text Available Leishmania major infection of resistant mice causes a self-limited lesion characterized by macrophage activation and a Th1 proinflammatory response. Atherosclerosis is an inflammatory disease involving hypercholesterolemia and macrophage activation. In this study, we evaluated the influence of L. major infection on the development of atherosclerosis using atherosclerosis-susceptible apolipoprotein E-deficient (apoE KO mice. After 6 weeks of infection, apoE KO mice exhibited reduced footpad swelling and parasitemia similar to C57BL/6 controls, confirming that both strains are resistant to infection with L. major. L. major-infected mice had increased plasma cholesterol levels and reduced triacylglycerols. With regard to atherosclerosis, noninfected mice developed only fatty streak lesions, while the infected mice presented with advanced lesions containing a necrotic core and an abundant inflammatory infiltrate. CD36 expression was increased in the aortic valve of the infected mice, indicating increased macrophage activation. In conclusion, L. major infection, although localized and self-limited in resistant apoE KO mice, has a detrimental effect on the blood lipid profile, increases the inflammatory cell migration to atherosclerotic lesions, and promotes atherogenesis. These effects are consequences of the stimulation of the immune system by L. major, which promotes the inflammatory components of atherosclerosis, which are primarily the parasite-activated macrophages.

  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

    Directory of Open Access Journals (Sweden)

    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.

  10. 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 CO(2) 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Inhibition of Cholesterol Esterification Influences Cytokine Exspression in Lypopolisaccharide-activated P388D1 Macrophages

    Directory of Open Access Journals (Sweden)

    Rosa Rita Bonatesta

    2007-01-01

    Full Text Available Several in vivo and in vitro studies have demonstrated the involvement of infectious agents in the development of atherosclerosis. However, the mechanisms by which micro-organisms induce and/or aggravate atherosclerosis, are so far unclear. Accumulation of cholesterol esters and lipid laden cell formation are hallmark of the atherogenesis, however, the possible relationship between cholesterol esterification and the signal-transducing component of LPS recognition complex inducing cytokine secretion has not been yet investigated. In the present study, we investigated the effect of mevinolin, the ACAT inhibitor, Sandoz 58035, and plasma from statin-treated hypercholesterolemic patients on cholesterol metabolism and cytokine expression in LPS activated P388D1 macrophages. In P388D1 macrophages cholesterol synthesis and uptake, as well as cholesterol ester synthesis, were unchanged following LPS-activation. When cells were grown in presence of serum from patients under statin therapy, cholesterol esterification was lower compared to cells grown with plasma from healthy subjects, independently from the type of statin used. This effect was accompanied by inhibition of IL-1β expression in LPS activated cells. The ACAT inhibitor, Sandoz 58035, which completely blocked cholesterol esterification in normal and LPS-activated macrophages, prevented IL-1β and IL-6 over-expression in LPS activated cells. Although preliminary, these data point to a possible relationship between cholesterol esterification and cytokine production in macrophages, prospecting new possible mechanisms by which microbial or inflammatory agents may induce and/or accelerate the atherosclerotic process.

  13. Reduction in circulating markers of endothelial dysfunction in HIV-infected patients during antiretroviral therapy

    DEFF Research Database (Denmark)

    Kjær, Andreas; Kristoffersen, U S; Kofoed, K;

    2009-01-01

    OBJECTIVES: Antiretroviral therapy (ART) in HIV-infected patients is associated with increased cardiovascular risk. Circulating markers of endothelial dysfunction may be used to study early atherogenesis. The aim of our study was to investigate changes in such markers during initiation of ART....... METHODS: In 115 HIV-positive treatment-naïve patients, plasma lipids, E-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), tissue-type plasminogen activator inhibitor 1 (tPAI-1) and high-sensitivity C-reactive protein (hsCRP) were measured...... before and after 2 and 14 months of ART. A control group of 30 healthy subjects was included. Values are mean+/-standard error of the mean. RESULTS: Prior to treatment, HIV-infected patients had elevated levels of sICAM-1 (296+/-24 vs. 144+/-12 ng/mL), tPAI-1 (18 473+/-1399 vs. 5490+/-576 pg/mL) and hs...

  14. Dubin-Johnson syndrome coinciding with colon cancer and atherosclerosis.

    Science.gov (United States)

    Sticova, Eva; Elleder, Milan; Hulkova, Helena; Luksan, Ondrej; Sauer, Martin; Wunschova-Moudra, Irena; Novotny, Jan; Jirsa, Milan

    2013-02-14

    Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress. Dubin-Johnson syndrome is a rare, autosomal recessive, inherited disorder characterized by biphasic, predominantly conjugated hyperbilirubinemia with no progression to end-stage liver disease. The molecular basis in Dubin-Johnson syndrome is absence or deficiency of human canalicular multispecific organic anion transporter MRP2/cMOAT caused by homozygous or compound heterozygous mutation(s) in ABCC2 located on chromosome 10q24. Clinical onset of the syndrome is most often seen in the late teens or early adulthood. In this report, we describe a case of previously unrecognized Dubin-Johnson syndrome caused by two novel pathogenic mutations (c.2360_2366delCCCTGTC and c.3258+1G>A), coinciding with cholestatic liver disease in an 82-year-old male patient. The patient, suffering from advanced atherosclerosis with serious involvement of coronary arteries, developed colorectal cancer with nodal metastases. The subsequent findings do not support the protective role of Dubin-Johnson type hyperbilirubinemia.

  15. Decreased Regulatory T Cells in Vulnerable Atherosclerotic Lesions: Imbalance between Pro- and Anti-Inflammatory Cells in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Ilonka Rohm

    2015-01-01

    Full Text Available Atherosclerosis is a chronic inflammatory disease of the arterial wall in which presentation of autoantigens by dendritic cells (DCs leads to the activation of T cells. Anti-inflammatory cells like Tregs counterbalance inflammation in atherogenesis. In our study, human carotid plaque specimens were classified as stable (14 and unstable (15 according to established morphological criteria. Vessel specimens (n=12 without any signs of atherosclerosis were used as controls. Immunohistochemical staining was performed to detect different types of DCs (S100, fascin, CD83, CD209, CD304, and CD123, proinflammatory T cells (CD3, CD4, CD8, and CD161, and anti-inflammatory Tregs (FoxP3. The following results were observed: in unstable lesions, significantly higher numbers of proinflammatory cells like DCs, T helper cells, cytotoxic T cells, and natural killer cells were detected compared to stable plaques. Additionally, there was a significantly higher expression of HLA-DR and more T cell activation (CD25, CD69 in unstable lesions. On the contrary, unstable lesions contained significantly lower numbers of Tregs. Furthermore, a significant inverse correlation between myeloid DCs and Tregs was shown. These data suggest an increased inflammatory state in vulnerable plaques resulting from an imbalance of the frequency of local pro- and anti-inflammatory immune cells.

  16. Coffee polyphenols protect human plasma from postprandial carbonyl modifications.

    Science.gov (United States)

    Sirota, Roman; Gorelik, Shlomit; Harris, Raviv; Kohen, Ron; Kanner, Joseph

    2013-05-01

    The antioxidant capability of coffee polyphenols to inhibit red-meat lipid peroxidation in stomach medium and absorption into blood of malondialdehyde (MDA) in humans was studied. Roasted-ground coffee polyphenols that were found to inhibit lipid peroxidation in stomach medium are 2- to 5-fold more efficient antioxidant than those found in instant coffee. Human plasma from ten volunteers analyzed after a meal of red-meat cutlets (250 g) revealed a rapid accumulation of MDA. The accumulation of MDA in human plasma modified low-density lipoprotein is known to trigger atherogenesis. Consumption of 200 mL roasted coffee by ten volunteers during a meal of red-meat cutlets, resulted after 2 and 4 h in the inhibition by 80 and 50%, respectively, of postprandial plasma MDA absorption. The results obtained in vitro simulated stomach model on MDA accumulation were predictive for the amount of MDA absorbed into circulating human plasma, in vivo. Timing the consumption of coffee during the meals may make it a very active functional food.

  17. Actual position of interleukin(IL)-33 in atherosclerosis and heart failure: Great Expectations or En attendant Godot?

    Science.gov (United States)

    Kunes, P; Mandak, J; Holubcova, Z; Kolackova, M; Krejsek, J

    2015-07-01

    Atherosclerosis has been recognized as an inflammatory/autoimmune disease. The long-standing low-grade inflammation which fuels its development is primarily focused on the components of the vessel wall. Originally, inflammation in atherogenesis was supposed to be driven by the pro-inflammatory Th1 cellular and cytokine immune response. On the basis of accumulating evidence, this view has been re-evaluated to include the Th17/Th1 axis which is shared by most diseases of sterile inflammation. The anti-inflammatory Th2 cellular and cytokine immune response is initiated concomitantly with the former two, the latter dampening their harmful reactions which culminate in full-blown atherosclerosis. Interleukin-33, a novel member of the IL-1 cytokine superfamily, was suggested to take part in the anti-atherogenic response by mediating the Th1-to-Th2 switch of the immune reactions. However, IL-33 is a multifaceted mediator with both pro- and anti-inflammatory activities, also called a "dual factor" or a "Janus face" interleukin. IL-33 occurs both in an extracellular (cytokine-like) and in a nuclear-bound (transcription factor-like) form, each of them performing distinct activities of their own. This review article presents the latest data relevant to IL-33's role in atherosclerosis and cardiac diseases as perceived by a cardiologist and a cardiac surgeon.

  18. Native low density lipoprotein promotes lipid raft formation in macrophages.

    Science.gov (United States)

    Song, Jian; Ping, Ling-Yan; Duong, Duc M; Gao, Xiao-Yan; He, Chun-Yan; Wei, Lei; Wu, Jun-Zhu

    2016-03-01

    Oxidized low‑density lipoprotein (LDL) has an important role in atherogenesis; however, the mechanisms underlying cell‑mediated LDL oxidation remain to be elucidated. The present study investigated whether native‑LDL induced lipid raft formation, in order to gain further insight into LDL oxidation. Confocal microscopic analysis revealed that lipid rafts were aggregated or clustered in the membrane, which were colocalized with myeloperoxidase (MPO) upon native LDL stimulation; however, in the presence of methyl‑β‑cyclodextrin (MβCD), LDL‑stimulated aggregation, translocation, and colocalization of lipid rafts components was abolished.. In addition, lipid raft disruptors MβCD and filipin decreased malondialdehyde expression levels. Density gradient centrifugation coupled to label‑free quantitative proteomic analysis identified 1,449 individual proteins, of which 203 were significantly upregulated following native‑LDL stimulation. Functional classification of the proteins identified in the lipid rafts revealed that the expression levels of translocation proteins were upregulated. In conclusion, the results of the present study indicated that native‑LDL induced lipid raft clustering in macrophages, and the expression levels of several proteins were altered in the stimulated macrophages, which provided novel insights into the mechanism underlying LDL oxidation.

  19. Chronic vitamin C deficiency increases the risk of cardiovascular diseases.

    Science.gov (United States)

    Ginter, E

    2007-01-01

    The studies on experimental animals (guinea pigs, monkeys, fish) have confirmed the important role of ascorbic acid deficiency in the development of hypercholesterolemia and atherosclerosis, but the clinical experience is not quite uniform. Metaanalyses of randomized controlled trials performed on subjects without established vitamin C-deficiency conclud that the evidence of the presence or absence of benefits derived from the ability of ascorbic acid to prevent cardiovascular diseases is not sufficient. This review is an outline of numerous clinical, epidemiological and prospective studies that have found a positive role of vitamin C in the prevention of atherosclerosis. If we admit the possibility that vitamin C deficiency is a significant risk factor of atherogenesis, due to ethical reasons it is impossible to perform long-term controlled trials on subjects with proved vitamin C deficiency, to recommend them not to change their nutrition and lifestyle, and to administer placebo to the control group. Therefore the proof of atherogenic effect of chronic vitamin C deficiency is limited to indirect evidence only. In this review many new data on the positive effects of ascorbic acid on human cardiovascular system are summarized and the mechanisms of its protective influence on blood vessels are discussed (Fig.5, Ref. 45). Full Text (Free, PDF) www.bmj.sk.

  20. Antiatherogenic effects of n-3 fatty acids - evidence and mechanisms

    Directory of Open Access Journals (Sweden)

    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

  1. The monoterpene terpinolene from the oil of Pinus mugo L. in concert with alpha-tocopherol and beta-carotene effectively prevents oxidation of LDL.

    Science.gov (United States)

    Grassmann, J; Hippeli, S; Spitzenberger, R; Elstner, E F

    2005-06-01

    Antioxidants from several nutrients, e.g. vitamin E, beta-carotene, or flavonoids, inhibit the oxidative modification of low-density lipoproteins. This protective effect could possibly retard atherogenesis and in consequence avoid coronary heart diseases. Some studies have shown a positive effect of those antioxidants on cardiovascular disease. Another class of naturally occurring antioxidants are terpenoids, which are found in essential oils. The essential oil of Pinus mugo and the contained monoterpene terpinolene effectively prevent low-density lipoprotein (LDL)-oxidation. In order to test the mechanism by which terpinolene protects LDL from oxidation, LDL from human blood plasma enriched in terpinolene was isolated. In this preparation not only the lipid part of LDL is protected against copper-induced oxidation--as proven by following the formation of conjugated dienes, but also the oxidation of the protein part is inhibited, since loss of tryptophan fluorescence is strongly delayed. This inhibition is due to a retarded oxidation of intrinsic carotenoids of LDL, and not, as in the case of some flavonoids, attributable to a protection of intrinsic alpha-tocopherol. These results are in agreement with our previous results, which showed the same effects for a monoterpene from lemon oil, i.e. gamma-terpinene.

  2. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans.

    Science.gov (United States)

    Chou, Meng-Yun; Fogelstrand, Linda; Hartvigsen, Karsten; Hansen, Lotte F; Woelkers, Douglas; Shaw, Peter X; Choi, Jeomil; Perkmann, Thomas; Bäckhed, Fredrik; Miller, Yury I; Hörkkö, Sohvi; Corr, Maripat; Witztum, Joseph L; Binder, Christoph J

    2009-05-01

    Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of oxidized lipoproteins and apoptotic cells. Adaptive immune responses to various oxidation-specific epitopes play an important role in atherogenesis. However, accumulating evidence suggests that these epitopes are also recognized by innate receptors, such as scavenger receptors on macrophages, and plasma proteins, such as C-reactive protein (CRP). Here, we provide multiple lines of evidence that oxidation-specific epitopes constitute a dominant, previously unrecognized target of natural Abs (NAbs) in both mice and humans. Using reconstituted mice expressing solely IgM NAbs, we have shown that approximately 30% of all NAbs bound to model oxidation-specific epitopes, as well as to atherosclerotic lesions and apoptotic cells. Because oxidative processes are ubiquitous, we hypothesized that these epitopes exert selective pressure to expand NAbs, which in turn play an important role in mediating homeostatic functions consequent to inflammation and cell death, as demonstrated by their ability to facilitate apoptotic cell clearance. These findings provide novel insights into the functions of NAbs in mediating host homeostasis and into their roles in health and diseases, such as chronic inflammatory diseases and atherosclerosis.

  3. Site-specific influence of polyunsaturated fatty acids on atherosclerosis in immune incompetent LDL receptor deficient mice.

    Science.gov (United States)

    Reardon, Catherine A; Blachowicz, Lydia; Gupta, Gaorav; Lukens, John; Nissenbaum, Michael; Getz, Godfrey S

    2006-08-01

    Polyunsaturated fatty acids (PUFA) are thought to influence plasma lipid levels, atherosclerosis, and the immune system. In this study, we fed male LDL receptor deficient (LDLR(-/-)) mice and immune incompetent LDLR(-/-) RAG2(-/-) mice diets containing predominantly saturated fats (milk fat) or PUFA (safflower oil) to determine if the response to diet was influenced by immune status. Relative to milk fat diet, plasma lipid and VLDL levels in both the LDLR(-/-) and LDLR(-/-) RAG2(-/-) mice fed safflower oil diet were lower, suggesting that the primary effect of PUFA on plasma lipids was not due to its inhibition of the immune system. Neither diet nor immune status influenced hepatic triglyceride production and post-heparin lipase activity, suggesting that the differences in triglyceride levels are due to differences in rates of catabolism of triglyceride-rich lipoproteins. While both diets promoted atherogenesis, both aortic root and innominate artery atherosclerosis in LDLR(-/-) mice was less in safflower oil fed animals. In contrast, a site-specific effect of PUFA was observed in the immune incompetent LDLR(-/-) RAG2(-/-). In these mice, aortic root atherosclerosis, but not innominate artery atherosclerosis, was less in PUFA fed animal. These results suggest that PUFA and the immune system may influence innominate artery atherosclerosis by some overlapping mechanisms.

  4. Characterization of the natural killer T-cell response in an adoptive transfer model of atherosclerosis.

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    VanderLaan, Paul A; Reardon, Catherine A; Sagiv, Yuval; Blachowicz, Lydia; Lukens, John; Nissenbaum, Michael; Wang, Chyung-Ru; Getz, Godfrey S

    2007-03-01

    Natural killer T (NKT) cells have recently been implicated in atherogenesis, primarily for their ability to recognize and respond to lipid antigens. Because the atherosclerotic lesion is characterized by the retention and modification of lipids in the vascular wall, NKT cells may be involved in promoting the local vascular inflammatory response. Here, we investigate the proatherogenic role of NKT cells in an adoptive transfer model of atherosclerosis, using as recipients immune-deficient, atherosclerosis-susceptible RAG1(-/-)LDLR(-/-) mice. The adoptive transfer of an NKT cell-enriched splenocyte population from Valpha14Jalpha18 T-cell receptor transgenic mice resulted in a 73% increase in aortic root lesion area compared with recipients of NKT cell-deficient splenocytes derived from CD1d(-/-) mice after 12 weeks of Western-type diet feeding. The total serum from hypercholesterolemic mice leads to a small but significant activation of Valpha14Jalpha18 T-cell receptor-expressing hybridoma line by dendritic cells that is CD1d-dependent. Therefore, these studies demonstrate that NKT cells are proatherogenic in the absence of exogenous stimulation, and this activity is likely associated with endogenous lipid antigens carried by lipoproteins in the circulation and perhaps also in the atherosclerotic plaque.

  5. Acrolein impairs the cholesterol transport functions of high density lipoproteins.

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    Chadwick, Alexandra C; Holme, Rebecca L; Chen, Yiliang; Thomas, Michael J; Sorci-Thomas, Mary G; Silverstein, Roy L; Pritchard, Kirkwood A; Sahoo, Daisy

    2015-01-01

    High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway.

  6. High-Density Lipoprotein-Mediated Transcellular Cholesterol Transport in Mouse Aortic Endothelial Cells

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    Miao, LiXia; Okoro, Emmanuel U.; Cao, ZhiJan; Yang, Hong; Motley-Johnson, Evangeline; Guo, Zhongmao

    2015-01-01

    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 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, ABCA1 and SR-B1 but not involving PI3K and Akt. PMID:26255968

  7. Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease

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    Lackner Karl J

    2006-01-01

    Full Text Available Abstract Background Sphingomyelin (SM is the major phospholipid in cell membranes and in lipoproteins. In human plasma, SM is mainly found in atherogenic lipoproteins; thus, high levels of SM may promote atherogenesis. Methods We investigated in a median follow up of 6.0 years the association of SM with the incidence of a combined endpoint (myocardial infarction and cardiovascular death in stable and unstable patients, and its relation to other marker of atherosclerosis in 1,102 patients with angiographically documented CAD and 444 healthy controls. Results and discussion Logistic regression analysis showed that SM categorized by median was associated with an elevated risk for CAD (HR 3.2, 95%CI 2.5–4.0, p Conclusion The results of our study reveal that 1 human plasma SM levels are a risk factor for CAD; 2 the pro-atherogenic property of plasma SM might be related to metabolism of apoB-containing or triglyceride-rich lipoproteins; and 3 plasma SM levels are a predictor for outcome of patients with acute coronary syndrome.

  8. 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.

  9. [Role of secreted and lipoprotein-associated phospholipase A2 in cardiovascular risk].

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    Ferri, Nicola; Corsini, Alberto

    2014-12-01

    Phospholipase A(2) (PLA(2)) are enzymes that hydrolyze the ester bond of glycerophospholipids releasing free fatty acids and lysophospholipids, including the arachidonic acid, the precursor of the eicosanoids and the inflammatory cascades. PLA(2) are present in the atherosclerotic plaques and their direct involvement in the proatherogenic inflammatory response is well documented. Epidemiological and genetic studies have demonstrated the correlation of the PLA(2) mass and enzymatic activity with the incidence of cardiovascular diseases. The potential pro-atherogenic role of PLA(2) led to the development of two small molecules, varespladib, a reversible sPLA(2) inhibitor, and darapladib, a selective Lp-PLA(2) inhibitor. Both molecules have demonstrated antiatherosclerotic properties in animal models, and positive effects on atherosclerotic plaque composition evaluated in phase 2 clinical trials. On these grounds, the results of three phase 3 studies have recently been published: the VISTA-16 study with varespladib in patients with acute coronary syndrome, and the STABILITY and SOLID-TIMI 52 studies with darapladib in patients with stable coronary heart disease and acute coronary syndrome, respectively. Unexpectedly, both studies did not demonstrate an additional protective action of PLA 2 inhibitors over the standard of care treatment with statins, antiplatelet drugs, and coronary revascularization. In the present article, the enzymatic properties and the involvement of sPLA(2) and Lp-PLA(2) in atherogenesis are reviewed, with a focus on the results of experimental studies and clinical studies with both varespladib and darapladib inhibitors.

  10. The role of lipoprotein-associated phospholipase A2 (Lp-PLA₂) in cardiovascular disease.

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    Ikonomidis, Ignatios; Michalakeas, Christos A; Lekakis, John; Parissis, John; Anastasiou-Nana, Maria

    2011-05-01

    Lipoprotein-associated Phospholipase A2 (Lp-PLA(2)) is an enzyme that belongs to the A2 Phospholipase superfamily and is produced by inflammatory cells that are involved in the process of atherogenesis. Even though there is controversy in current bibliography whether Lp-PLA(2) exerts proatherogenic or anti-atherogenic properties, the weight of evidence suggests a pro-atherogenic role for this protein. Lp-PLA(2) is detected in human atherosclerotic lesions and elevated Lp-PLA(2) levels are associated with an increased risk of cardiovascular events and adverse events in patients with coronary artery disease independently of traditional risk factors and other markers of inflammation. It has been recently shown that direct pharmacological inhibition of Lp-PLA(2) activity exerts beneficiary effects on the atherosclerotic process. This finding is most interesting since it could offer a novel target for therapeutic intervention in patients suffering from cardiovascular disease. The purpose of this review article is to report on the role of Lp-PLA(2) in cardiovascular diseases and to enlighten the putative pathophysiologic mechanisms by which this protein exerts its effect on cardiovascular function. Additionally, the pharmacological interventions that influence Lp-PLA(2) activity and may offer a new approach for the treatment of atherosclerosis will be analyzed.

  11. Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE−/− Mice

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    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.

  12. Wall Shear Stress in Aorta with Coarctation and Post-Stenotic Dilatation - Scale Resolved Simulation of Pulsatile Blood Flow

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    Gardhagen, Roland; Karlsson, Matts

    2012-11-01

    Large eddy simulations of pulsating blood flow in an idealized model of a human aorta with a coarctation and a post-stenotic dilatation were conducted before and after treatment of the stenosis using Ansys Fluent. The aim was to study wall shear stress (WSS), which influences the function of endothelial cells, and turbulence, which may play a role in thrombus formation. Phase average values of WSS before the treatment revealed high shear in the stenosis at peak systole, as expected, but also at the end of the dilatation. In the dilatation backflow causes a negative peak. Diastolic WSS is characterized by low amplitude oscillations, which promotes atherogenesis. Also noticeable is the asymmetric pattern between the inner and outer sides of the vessel caused by the arch upstream of the stenosis. Thus, large spatial, temporal, and probably asymmetric WSS gradients in the already diseased region suggest increased risk for further endothelial dysfunction. This reflects a complex, partly turbulent, flow pattern that may disturb the blood flow in the abdominal aorta. After treatment of the stenosis, but not the dilatation, fluctuations of velocity and WSS were still found, thus harmful flow conditions still exist.

  13. ROCK2 associates with lectin-like oxidized LDL receptor-1 and mediates oxidized LDL-induced IL-8 production.

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    Mattaliano, Mark D; Wooters, Joe; Shih, Heather H; Paulsen, Janet E

    2010-05-01

    Oxidatively modified low-density lipoprotein (OxLDL) is a contributing factor of endothelial dysfunction, an early cellular event during atherogenesis. In endothelial cells, OxLDL has been shown to stimulate proinflammatory responses, increase lipid accumulation, and induce the expression of adhesion and extracellular matrix degrading molecules. The primary receptor for OxLDL on endothelial cells has been identified as a member of the scavenger receptor family called lectin-like OxLDL receptor-1 (LOX-1). A number of studies on LOX-1 have implicated its role in multiple cardiovascular diseases including atherosclerosis. To better understand the molecular mechanisms underlying the role of LOX-1 in endothelial cells, we identified interacting proteins in an affinity-purified LOX-1 receptor complex from human aortic endothelial HAECT cells by mass spectrometry. Two molecules involved in Rho signaling pathway, ARHGEF1 and ROCK2, were identified, and their associations with LOX-1 were confirmed in reciprocal immunoprecipitation studies. Particularly, ROCK2 was found to dynamically associate with LOX-1 in the presence of OxLDL. In addition, OxLDL treatment stimulated ROCK2 catalytic activity, and ROCK2 inhibition attenuated NF-kappaB activation and IL-8 production resulting from OxLDL activation of LOX-1. In summary, a functional proteomics approach has enabled us to identify novel LOX-1 interactors that potentially contribute to the cellular and signaling functions of LOX-1.

  14. Detection of Fungal Elements in Atherosclerotic Plaques Using Mycological, Pathological and Molecular Methods

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    Omid MASOUMI

    2015-10-01

    Full Text Available Background: The aim of this study was to detect fungi in atherosclerotic plaques and investigate their possible role in atherosclerosis.Methods: Coronary atherosclerotic plaques specimen were obtained from patients with atherosclerosis. Direct exami-nation, culture, histopathology study, PCR and sequencing were performed to detect/identify the mycotic elements in the plaques. Age, sex, smoking, obesity, hypertension, hyperlipidemia, family history of heart diseases and diabetes were considered and data were analyzed using Chi Square test by SPSS version 15.Results: A total of 41 specimens were analyzed. Direct examination for fungal elements was negative in all cases but in culture only one specimen grew as a mold colony. The presence of fungal elements were confirmed in 6 and 2 tissue sections stained by Gomori methenamine silver and Hematoxylin and Eosin methods, respectively. Using PCR, 11 cases were positive for fungi. The DNA sequence analysis of six positive specimens which were randomly selected revealed fungi as Candida albicans (n=3, Candida guilliermondii (n=2 and Monilia sp. (n=1.Conclusion: A significant association between the presence of fungi in atherosclerotic plaques and severity of athero-genesis and atherosclerotic disease was not found. This could be due to limited numbers of patients included in our study. However, the presence of fungal elements in 26.8% of our specimens is considerable and the results does not exclude the correlation between the presence of fungi with atherosclerosis and coronary artery disease.

  15. Lipidomics in longevity and healthy aging.

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    Gonzalez-Covarrubias, Vanessa

    2013-12-01

    The role of classical lipids in aging diseases and human longevity has been widely acknowledged. Triglyceride and cholesterol concentrations are clinically assessed to infer the risk of cardiovascular disease while larger lipoprotein particle size and low triglyceride levels have been identified as markers of human longevity. The rise of lipidomics as a branch of metabolomics has provided an additional layer of accuracy to pinpoint specific lipids and its association with aging diseases and longevity. The molecular composition and concentration of lipid species determine their cellular localization, metabolism, and consequently, their impact in disease and health. For example, low density lipoproteins are the main carriers of sphingomyelins and ceramides, while high density lipoproteins are mostly loaded with ether phosphocholines, partly explaining their opposing roles in atherogenesis. Moreover, the identification of specific lipid species in aging diseases and longevity would aid to clarify how these lipids alter health and influence longevity. For instance, ether phosphocholines PC (O-34:1) and PC (O-34:3) have been positively associated with longevity and negatively with diabetes, and hypertension, but other species of phosphocholines show no effect or an opposite association with these traits confirming the relevance of the identification of molecular lipid species to tackle our understanding of healthy aging and disease. Up-to-date, a minor fraction of the human plasma lipidome has been associated to healthy aging and longevity, further research would pinpoint toward specific lipidomic profiles as potential markers of healthy aging and metabolic diseases.

  16. [Glycation of extracellular matrix proteins and its role in atherosclerosis].

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    Kuzan, Aleksandra; Chwiłkowska, Agnieszka; Kobielarz, Magdalena; Pezowicz, Celina; Gamian, Andrzej

    2012-10-29

    Glycation consists in formation of advanced glycation end-products (AGE) during non-enzymatic reaction between reducing sugars and proteins, lipids or nucleic acids. This review is focused mainly on glycation of collagen and its role in acceleration of vascular disease. Collagen is an extracellular matrix protein characterized by unique structure forming fibrils with great anti-tensile and anti-breaking strength. The protein builds the connective tissue and is responsible for biomechanical properties of blood vessels. It is reported that higher content of glycated collagen correlates with lower elasticity and greater toughness of the vessel walls and, as a consequence, a faster rate of atherosclerosis development. Numerous mechanisms connected with AGE formation are involved in atherogenesis, among others: receptor-mediated production of free radicals, triggering an inflammatory process, activation of leukocytes and thrombocytes, facilitation of LDL binding, change in level of growth factors, adhesion molecules, MMP and some other proteins' expression. The coverages allow the development of therapeutic strategies to prevent or slow down the pathological processes connected with glycation of collagen and other proteins in the artery wall. The main strategies are based on limitation of exogenous AGE, consumption of products which contain rutin, treatment with drugs which inhibit AGE formation, such as pyridoxamine, and chemicals which are able to cleave already formed AGE protein-protein crosslinks, such as ALT-711.

  17. 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.

  18. Paraoxonase 2 Induces a Phenotypic Switch in Macrophage Polarization Favoring an M2 Anti-Inflammatory State

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    Koren-Gluzer, Marie; Rosenblat, Mira; Hayek, Tony

    2015-01-01

    Inflammatory processes are involved in atherosclerosis development. Macrophages play a major role in the early atherogenesis, and they are present in the atherosclerotic lesion in two phenotypes: proinflammatory (M1) or anti-inflammatory (M2). Paraoxonase 2 (PON2) is expressed in macrophages, and it was shown to protect against atherosclerosis. Thus, the aim of our study was to analyze the direct effect of PON2 on macrophage inflammatory phenotypes. Ex vivo studies were performed with murine peritoneal macrophages (MPM) harvested from control C57BL/6 and PON2-deficient (PON2KO) mice. PON2KO MPM showed an enhanced proinflammatory phenotype compared to the control, both in the basal state and following M1 activation by IFNγ and lipopolysaccharide (LPS). In parallel, PON2KO MPM also showed reduced anti-inflammatory responses in the basal state and also following M2 activation by IL-4. Moreover, the PON2-null MPM demonstrated enhanced phagocytosis and reactive oxygen species (ROS) production in the basal state and following M1 activation. The direct effect of PON2 was shown by transfecting human PON2 (hPON2) into PON2KO MPM. PON2 transfection attenuated the macrophages' response to M1 activation and enhanced M2 response. These PON2 effects were associated with attenuation of macrophages' abilities to phagocyte and to generate ROS. We conclude that PON2 promotes an M1 to M2 switch in macrophage phenotypes. PMID:26779262

  19. Paraoxonase 2 Induces a Phenotypic Switch in Macrophage Polarization Favoring an M2 Anti-Inflammatory State

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    Marie Koren-Gluzer

    2015-01-01

    Full Text Available Inflammatory processes are involved in atherosclerosis development. Macrophages play a major role in the early atherogenesis, and they are present in the atherosclerotic lesion in two phenotypes: proinflammatory (M1 or anti-inflammatory (M2. Paraoxonase 2 (PON2 is expressed in macrophages, and it was shown to protect against atherosclerosis. Thus, the aim of our study was to analyze the direct effect of PON2 on macrophage inflammatory phenotypes. Ex vivo studies were performed with murine peritoneal macrophages (MPM harvested from control C57BL/6 and PON2-deficient (PON2KO mice. PON2KO MPM showed an enhanced proinflammatory phenotype compared to the control, both in the basal state and following M1 activation by IFNγ and lipopolysaccharide (LPS. In parallel, PON2KO MPM also showed reduced anti-inflammatory responses in the basal state and also following M2 activation by IL-4. Moreover, the PON2-null MPM demonstrated enhanced phagocytosis and reactive oxygen species (ROS production in the basal state and following M1 activation. The direct effect of PON2 was shown by transfecting human PON2 (hPON2 into PON2KO MPM. PON2 transfection attenuated the macrophages’ response to M1 activation and enhanced M2 response. These PON2 effects were associated with attenuation of macrophages’ abilities to phagocyte and to generate ROS. We conclude that PON2 promotes an M1 to M2 switch in macrophage phenotypes.

  20. 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

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

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    Narendra Tuteja

    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. 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.

  3. Induction of interleukin-8 production by angiotensin Ⅱ in rat vascular smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    Zhi Wang; Lili Zhang; Baogui Sun; Qiuyan Dai

    2009-01-01

    Objective:Interleukin-8(IL-8) represents the prototypical chemokine that is made by a wide variety of cell types.Previously studies have suggested that angiotensin Ⅱ(Ang Ⅱ) is involved in atherogenesis through induction ofproinflammatory cytokines such as interleukin-6 or monocyte chemoattractant protein-1 (MCP-1) in vascular smooth muscle cells(VSMCs),while the role orang Ⅱ on IL-8 expression in VSMCs is poorly studied.Methods:In this study,VSMCs were isolated from the thoracic aorta of Sprague-Dawley rats.The expression of smooth muscle α-actin was confirmed by an immunohistochemical method.Semi-quantitative RT-PCR and enzyme-linked immunosorbent assay (ELISA) analyses were conducted to detect IL-8 expression.Results:In the present study we found that Ang Ⅱ significantly increased the expression of IL-8 both at the mRNA and protein levels in rat VSMCs in a dose- and time-dependent manner.Conclusion:These findings suggested that Ang Ⅱ may participate in atherosclerosis through induction of inflammatory mediator in VSMCs.

  4. Influence of anti-VEGF about cardiovascular biomarkers in age related macular degeneration.

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    Manresa, N; Mulero, J; Losada, M; Zafrilla, P

    2015-02-01

    Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates the atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. The objective of the current study was to analyze the effect of anti-VEGF therapy on cardiovascular risk factors in patients with exudative age related macular degeneration. A total of 73 patients with exudative age related macular degeneration (without previous anti-VEGF therapy) were treated with two anti-VEGF: Ranibizumab and Pegaptanib sodium. The follow up was 6 months. The following parameters were determined before and after treatment: homocysteine, lipids (total cholesterol, triglycerides, HDL-c, LDL-c), C-Reactive Protein and fibrinogen. There were not statistically significant differences in parameters studied before and after treatment with both Pegaptanib sodium and Ranibizumab, except C-Reactive Protein. Of all patients analyzed, only 3 of them have initially C-Reactive Protein levels above normal levels and after antiangiogenic therapy, there was a significant increase in C-Reactive Protein. We have not found results in our study who to suspect that treatment with anti-VEGF in the patients with exudative age related macular degeneration increases cardiovascular risk predictors. However, after therapy was increased the CRP and fibrinogen may mean that anti-VEGF contribute an alteration of endothelial homeostasis in exudative AMD.

  5. Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis.

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    Verhoeven, Frank; Prati, Clément; Maguin-Gaté, Katy; Wendling, Daniel; Demougeot, Céline

    2016-11-05

    Rheumatoid arthritis (RA) is the most common systemic autoimmune disease characterized by articular and extra-articular manifestations involving cardiovascular (CV) diseases. RA increases the CV mortality by up to 50 % compared with the global population and CV disease is the leading cause of death in patients with RA. There is growing evidence that RA favors accelerated atherogenesis secondary to endothelial dysfunction (ED) that occurs early in the course of the disease. ED is a functional and reversible alteration of endothelial cells, leading to a shift of the actions of the endothelium towards reduced vasodilation, proinflammatory state, proliferative and prothrombotic properties. The mechanistic links between RA and ED have not been fully explained, but growing evidence suggests a role for traditional CV factors, auto-antibodies, genetic factors, oxidative stress, inflammation and iatrogenic interventions such as glucocorticoids (GCs) use. GCs have been used in RA for several decades. Whilst their deleterious CV side effects were described in the 1950s, their effect on CV risk associated with inflammatory arthritis remains subject for debate. GC might induce negative effects on endothelial function, via a direct effect on endothelium or via increasing CV risk factors. Conversely, they might actually improve endothelial function by decreasing systemic and/or vascular inflammation. The present review summarizes the available data on the impact of GCs on endothelial function, both in normal and inflammatory conditions, with a special focus on RA patients.

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

    Science.gov (United States)

    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.

  7. Heme oxygenase-1 against vascular insufficiency: roles of atherosclerotic disorders.

    Science.gov (United States)

    Ishikawa, Kazunobu

    2003-01-01

    Heme oxygenase (HO), an enzyme essential for heme degradation, shows anti-oxidative and anti-inflammatory properties via the production of bile pigments, carbon monoxide (CO) and ferritin induction under various pathophysiological conditions. A number of recent studies have shown biological effects of HO reaction in cardiovascular disorders. An inducible form of HO, HO-1, is induced by a variety of stresses such as oxidized lipoproteins, cytokines, hemodynamic changes, angiotensin II and nitric oxide (NO) in vascular wall. HO-1 induction seems to function as an adaptive response against these injurious stimuli. HO-1 induction in artery wall scavenges reactive oxygen species, which leads to the attenuation of monocyte adhesion and chemotaxis. HO-1 induction also reduces lipid peroxidation in plasma and artery wall. These properties of HO-1 suggest anti-atherogenic roles of this enzyme. In this review, roles of endothelial HO-1 expression and bilirubin in atherogenesis are also discussed. HO-1 also seems to play a significant role in restenosis after angioplasty, which is a major clinical problem associated with atherosclerosis. Recent progress in human HO-1 genetics supports these experimental results. This review aims to reaffirm current problems in the biological aspects of HO and suggest future research direction and clinical application.

  8. Effect of barnidipine on blood pressure and serum metabolic parameters in patients with essential hypertension: a pilot study.

    Science.gov (United States)

    Spirou, Athanasia; Rizos, Evangelos; Liberopoulos, Evangelos N; Kolaitis, Nikolaos; Achimastos, Apostolos; Tselepis, Alexandros D; Elisaf, Moses

    2006-12-01

    The effect of barnidipine, a calcium channel blocker, on metabolic parameters is not well known. The authors conducted the present pilot study to evaluate the possible effects of barnidipine on parameters involved in atherogenesis, oxidative stress, and clotting activity. This open-label intervention study included 40 adult patients with essential hypertension who received barnidipine 10 mg once daily. Barnidipine significantly reduced systolic and diastolic blood pressure as well as isoprostane levels, which represent a reliable marker of oxidative stress. In contrast, barnidipine had a neutral effect on lipid profile and apolipoprotein levels, did not influence glucose homeostasis, had no effect on renal function, and did not cause any changes in electrolyte levels. Moreover, barnidipine did not affect either the clotting/fibrinolytic status (evaluated by measurement of fibrinogen, total plasminogen activator inhibitor, tissue plasminogen activator, and a2 antiplasmin) or the enzymatic activity of the inflammatory/anti-inflammatory mediators lipoprotein-associated phospholipase A2 and paraoxonase 1, respectively. Barnidipine should be mainly considered as an antihypertensive agent with neutral effects on most of the studied metabolic parameters in hypertensive patients. Any antioxidant effect of barnidipine needs further investigation.

  9. Recent advances in apolipoprotein M and atherosclerosis%载脂蛋白M与动脉粥样硬化的研究进展

    Institute of Scientific and Technical Information of China (English)

    刘杨; 张晓膺; 罗光华

    2011-01-01

    @@ 心、脑血管疾病的发生率及死亡率居各种疾病前列,动脉粥样硬化(atherosclerosis,AS)是其重要的病理基础,因此对动脉粥样硬化的研究具有极其重要的临床意义.动脉粥样硬化研究范围广泛,近年来,载脂蛋白与动脉粥样硬化关系的研究进展尤为迅速.%Atherosclerosis is a complex pathological process, which has a close relationship with inflammatory response and disorder of lipid metabolism.The cardioprotective role of high - density lipoprotein ( HDL ) is related to its characters of protecting the vascular endothelial cells and the properties of anti - inflammation and anti - oxidation.Low density lipoprotein ( LDL ) and very - low - density lipoprotein ( VLDL ) are thought to have the adverse effects on human atherosclerosis.Apolipoprotein M ( apoM, found in 1999 ) is an apolipoprotein mainly associated with HDLs.ApoM has a remarkable property of anti - atherosclerosis in animal experiment.However, recent studies have not yet been able to establish that apoM is a defining risk factor for human coronary heart disease, and the biological functions of apoM, including its potential role in human atherogenesis, need to be established.

  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. 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).

  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.

  13. What is metabolic syndrome, and why are children getting it?

    Science.gov (United States)

    Weiss, Ram; Bremer, Andrew A; Lustig, Robert H

    2013-04-01

    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.

  14. Alginic acid cell entrapment: a novel method for measuring in vivo macrophage cholesterol homeostasis

    Science.gov (United States)

    Sontag, Timothy J.; Chellan, Bijoy; Bhanvadia, Clarissa V.; Getz, Godfrey S.; Reardon, Catherine A.

    2015-01-01

    Macrophage conversion to atherosclerotic foam cells is partly due to the balance of uptake and efflux of cholesterol. Cholesterol efflux from cells by HDL and its apoproteins for subsequent hepatic elimination is known as reverse cholesterol transport. Numerous methods have been developed to measure in vivo macrophage cholesterol efflux. Most methods do not allow for macrophage recovery for analysis of changes in cellular cholesterol status. We describe a novel method for measuring cellular cholesterol balance using the in vivo entrapment of macrophages in alginate, which retains incorporated cells while being permeable to lipoproteins. Recipient mice were injected subcutaneously with CaCl2 forming a bubble into which a macrophage/alginate suspension was injected, entrapping the macrophages. Cells were recovered after 24 h. Cellular free and esterified cholesterol mass were determined enzymatically and normalized to cellular protein. Both normal and cholesterol loaded macrophages undergo measureable changes in cell cholesterol when injected into WT and apoA-I-, LDL-receptor-, or apoE-deficient mice. Cellular cholesterol balance is dependent on initial cellular cholesterol status, macrophage cholesterol transporter expression, and apolipoprotein deficiency. Alginate entrapment allows for the in vivo measurement of macrophage cholesterol homeostasis and is a novel platform for investigating the role of genetics and therapeutic interventions in atherogenesis. PMID:25465389

  15. Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE−/− Mice

    Science.gov (United States)

    Gonzalez, Jaime; Donoso, Wendy; Sandoval, Nathalie; Reyes, María; Gonzalez, Priscila; Gajardo, Monica; Morales, Erik; Neira, Amalia; Razmilic, Iván; Yuri, José A.

    2015-01-01

    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. PMID:26075004

  16. Cardiovascular physiology of androgens and androgen testosterone therapy in postmenopausal women.

    Science.gov (United States)

    Ling, Shanhong; Komesaroff, Paul A; Sudhir, Krishnankutty

    2009-03-01

    Women before menopause are at relatively lower risk of cardiovascular disease (CVD) compared with age-matched men and after menopause this gender advantage disappears. Androgen has been known to be an independent factor contributing to the higher male susceptibility to CVD, through adverse effects on lipids, blood pressure, and glucose metabolism. High androgen levels also contribute to CVD development in women with polycystic ovary syndrome as well as androgen abusing athletes and body builders. On the other hand, decline in androgen levels, as a result of ageing in men, is associated with hypertension, diabetes and atherosclerosis. Postmenopausal women, particularly those with oophorectomy are generally in low levels of sex hormones and androgen insufficiency is independently associated with the higher incidence of atherosclerosis in postmenopausal women. Androgen testosterone therapy (ATT) has been commonly used to improve well-being and libido in aging men with low androgen levels. The therapy has been demonstrated also to effectively reduce atherogenesis in these people. The use of ATT in postmenopausal women has increased in recent years and to date, however, the cardiovascular benefits of such therapy in these women remain uncertain. This review focuses on research regarding the impact of endogenous androgens and ATT on the cardiovascular physiology and CVD development in postmenopausal women.

  17. Roles of lysophosphatidic acid in cardiovascular physiology and disease.

    Science.gov (United States)

    Smyth, Susan S; Cheng, Hsin-Yuan; Miriyala, Sumitra; Panchatcharam, Manikandan; Morris, Andrew J

    2008-09-01

    The bioactive lipid mediator lysophosphatidic acid (LPA) exerts a range of effects on the cardiovasculature that suggest a role in a variety of critical cardiovascular functions and clinically important cardiovascular diseases. LPA is an activator of platelets from a majority of human donors identifying a possible role as a regulator of acute thrombosis and platelet function in atherogenesis and vascular injury responses. Of particular interest in this context, LPA is an effective phenotypic modulator of vascular smooth muscle cells promoting the de-differentiation, proliferation and migration of these cells that are required for the development of intimal hyperplasia. Exogenous administration of LPA results in acute and systemic changes in blood pressure in different animal species, suggesting a role for LPA in both normal blood pressure regulation and hypertension. Advances in our understanding of the molecular machinery responsible for the synthesis, actions and inactivation of LPA now promise to provide the tools required to define the role of LPA in cardiovascular physiology and disease. In this review we discuss aspects of LPA signaling in the cardiovasculature focusing on recent advances and attempting to highlight presently unresolved issues and promising avenues for further investigation.

  18. Connexin37: a potential modifier gene of inflammatory disease.

    Science.gov (United States)

    Chanson, Marc; Kwak, Brenda R

    2007-08-01

    There is an increasing appreciation of the importance of gap junction proteins (connexins) in modulating the severity of inflammatory diseases. Multiple epidemiological gene association studies have detected a link between a single nucleotide polymorphism in the human connexin37 (Cx37) gene and coronary artery disease or myocardial infarction in various populations. This C1019T polymorphism causes a proline-to-serine substitution (P319S) in the regulatory C terminal tail of Cx37, a protein that is expressed in the vascular endothelium as well as in monocytes and macrophages. Indeed, these three cell types are key players in atherogenesis. In the early phases of atherosclerosis, blood monocytes are recruited to the sites of injury in response to chemotactic factors. Monocytes adhere to the dysfunctional endothelium and transmigrate across endothelial cells to penetrate the arterial intima. In the intima, monocytes proliferate, mature, and accumulate lipids to progress into macrophage foam cells. This review focuses on Cx37 and its impact on the cellular and molecular events underlying tissue function, with particular emphasis of the contribution of the C1019T polymorphism in atherosclerosis. We will also discuss evidence for a potential mechanism by which allelic variants of Cx37 are differentially predictive of increased risk for inflammatory diseases.

  19. The relationship between wall shear stress distributions and intimal thickening in the human abdominal aorta

    Directory of Open Access Journals (Sweden)

    Butany Jagdish

    2003-11-01

    Full Text Available Abstract Purpose The goal of this work was to determine wall shear stress (WSS patterns in the human abdominal aorta and to compare these patterns to measurements of intimal thickness (IT from autopsy samples. Methods The WSS was experimentally measured using the laser photochromic dye tracer technique in an anatomically faithful in vitro model based on CT scans of the abdominal aorta in a healthy 35-year-old subject. IT was quantified as a function of circumferential and axial position using light microscopy in ten human autopsy specimens. Results The histomorphometric analysis suggests that IT increases with age and that the distribution of intimal thickening changes with age. The lowest WSS in the flow model was found on the posterior wall inferior to the inferior mesenteric artery, and coincided with the region of most prominent IT in the autopsy samples. Local geometrical features in the flow model, such as the expansion at the inferior mesenteric artery (common in younger individuals, strongly influenced WSS patterns. The WSS was found to correlate negatively with IT (r2 = 0.3099; P = 0.0047. Conclusion Low WSS in the abdominal aorta is co-localized with IT and may be related to atherogenesis. Also, rates of IT in the abdominal aorta are possibly influenced by age-related geometrical changes.

  20. Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells

    Directory of Open Access Journals (Sweden)

    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.

  1. Translational atherosclerosis research: From experimental models to coronary artery disease in humans.

    Science.gov (United States)

    Gleissner, Christian A

    2016-05-01

    Atherosclerosis is the leading cause of death worldwide. Research on the pathophysiological mechanisms of atherogenesis has made tremendous progress over the past two decades. However, despite great advances there is still a lack of therapies that reduce adverse cardiovascular events to an acceptable degree. This review addresses successes, but also questions, challenges, and chances regarding the translation of basic science results into clinical practice, i.e. the capability to apply the results of basic and/or clinical research in order to design therapies suitable to improve patient outcome. Specifically, it discusses problems in translating findings from the most broadly used murine models of atherosclerosis into clinically feasible therapies and strategies potentially improving the results of clinical trials. Most likely, the key to success will be a multimodal approach employing novel imaging methods as well as large scale screening tools-summarized as "omics" approach. Using individually tailored therapies, plaque stabilization and regression could prevent adverse cardiovascular events thereby improving outcome of a large number of patients.

  2. Atherosclerosis induced by diabetogenic diet in New Zealand white rabbits

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    To observe the effects of diabetogenic (high fat high sucrose, lacking choleserol) diet on atherogenesis in New Zealand white rabbits. Two groups of New Zealand white rabbits received regular rabbit chow (the normal control), or high fat high sucrose diet for 4 months. The levels of plasma total cholesterol, HDL cholesterol, triglycerides, insulin, and glucose were investigated, the areas of fatty streak of the aortae were measured after staining with Sodan IV, and the aortic, coronary specimens were observed with light and electron microscopies. The plasma glucose, triglycerides, and total cholesterol were increased significantly by high fat high sucrose feeding. At the end of 4 months, the early charateristics of atherosclerosis were present in the animals' vascular specimens. Our findings suggest that high fat high sucrose feeding can induce hyperglycemia, hypertriglyceridemia and atherosclerosis in New Zealand white rabbits, and this could be a potential animal model for studying the mechanisms of diabetes-accelerated atherosclerosis. This study raised a question: What is the mechanism by which high fat high sucrose feeding induces atherosclerosis?. The related hypothesis was given in this article.

  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

    Directory of Open Access Journals (Sweden)

    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. Effect of reuse of polysulfone membrane on oxidative stress during hemodialysis.

    Science.gov (United States)

    Ramakrishna, P; Reddy, E Prabhakar; Suchitra, M M; Bitla, A R; Rao, P V Srinivasa; Sivakumar, V

    2012-05-01

    Patients with chronic renal failure, especially those on long-term hemodialysis (HD), have a high incidence of premature cardiovascular disease. Oxidative stress, which occurs when there is an excessive free radical production or low antioxidant level, has recently been implicated as a causative factor in atherogenesis. Hourly changes in malondialdehyde (MDA) and antioxidant enzymes, vitamins, lipid profile and ferric reducing ability of plasma (FRAP) were studied with the first use and immediate subsequent reuse of polysulfone dialysis membrane in 27 patients on regular HD treatment. Data were corrected for hemoconcentration and standardized to measure the rate of change. Increase in MDA and erythrocyte catalase along with decrease in plasma vitamin E and FRAP levels and no change in glutathione peroxidase levels were observed as a result of both fresh and reuse dialysis. These findings indicate a net oxidative stress in both fresh as well as dialyzer reuse sessions. There was no significant change in oxidative stress in both fresh and reuse sessions. The oxidative stress with reuse dialysis was less when compared to first use dialysis, but the difference was not statistically significant.

  5. The effect of a spatially heterogeneous transmural water flux on concentration polarization of low density lipoprotein in arteries.

    Science.gov (United States)

    Vincent, Peter E; Sherwin, Spencer J; Weinberg, Peter D

    2009-04-22

    Uptake of low density lipoprotein (LDL) by the arterial wall is likely to play a key role in atherogenesis. A particular process that may cause vascular scale heterogeneity in the rate of transendothelial LDL transport is the formation of a flow-dependent LDL concentration polarization layer on the luminal surface of the arterial endothelium. In this study, the effect of a spatially heterogeneous transmural water flux (that traverses the endothelium only via interendothelial cell clefts) on such concentration polarization is investigated numerically. Unlike in previous investigations, realistic intercellular cleft dimensions are used here and several values of LDL diffusivity are considered. Particular attention is paid to the spatially averaged LDL concentration adjacent to different regions of the endothelial surface, as such measures may be relevant to the rate of transendothelial LDL transport. It is demonstrated in principle that a heterogeneous transmural water flux can act to enhance such measures, and cause them to develop a shear dependence (in addition to that caused by vascular scale flow features, affecting the overall degree of LDL concentration polarization). However, it is shown that this enhancement and additional shear dependence are likely to be negligible for a physiologically realistic transmural flux velocity of 0.0439 mum s(-1) and an LDL diffusivity (in blood plasma) of 28.67 mum(2) s(-1). Hence, the results imply that vascular scale studies of LDL concentration polarization are justified in ignoring the effect of a spatially heterogeneous transmural water flux.

  6. Vascular wall function in insulin-resistant JCR:LA-cp rats: role of male and female sex.

    Science.gov (United States)

    O'Brien, S F; Russell, J C; Dolphin, P J; Davidge, S T

    2000-08-01

    Vascular wall function was assessed in obese insulin-resistant (cp/cp) and lean normal (+/?), male and female, JCR:LA-cp rats. Both male and female cp/cp rats showed enhanced maximum contractility in response to norepinephrine; impaired smooth muscle in response to sodium nitroprusside, a nitric oxide (NO) donor; and impaired relaxation in response to acetylcholine (ACh), compared with their lean counterparts. The abnormalities were similar in male and female cp/cp rats. The NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), inhibited ACh-mediated relaxation significantly in male rats, both cp/cp and +/?. The inhibition of ACh-mediated relaxation by L-NAME in +/? females was less, with no reduction in maximal relaxation, and was absent in cp/cp females. These effects suggest that the relative importance of NO in the endothelial modulation of smooth muscle contractility is greater in male rats. The results are consistent with a decreased role for endothelial NO in the cp/cp rats of both sexes and a reduction in NO-independent cholinergic relaxation in the male cp/cp rat. This NO-independent mechanism is not affected in the female cp/cp rats. The relatively small differences between males and females in smooth muscle cell and vascular function may contribute to sex-related differences in the atherogenesis, vasospasm, and ischemic damage associated with the obese insulin-resistant state.

  7. 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.

  8. The Impact of Hypoglycemia on the Cardiovascular System: Physiology and Pathophysiology.

    Science.gov (United States)

    Yang, Shi-Wei; Park, Kyoung-Ha; Zhou, Yu-Jie

    2016-10-01

    Intensive glycemic control may increase cardiovascular (CV) risk and mortality due to hypoglycemia. The pathophysiology of glucose counter-regulation in patients with type 1 or type 2 diabetes for over 15 years is characterized by impairment of the defense mechanisms against hypoglycemia. Hypoglycemia causes pronounced physiological and pathophysiological effects on the CV system as consequences of autonomic system activation and counter regulatory hormones release. These effects provoke a series of hemodynamic changes that include an increase in heart rate and peripheral systolic blood pressure, a decrease in central blood pressure, reduced peripheral arterial resistance, and increased myocardial contractility and cardiac output. Cardiac electrophysiological changes including flattening or inversion of T waves, QT prolongation, and ST segment depression were observed in both insulin-induced and spontaneous hypoglycemia. Sympathoadrenal activation is the main cause of these changes through mechanisms that involve, but are not limited to, catecholamine-mediated hypokalemia. Hypoglycemia is also involved in platelet activation. There is growing concern about the long-term effects of hypoglycemia, especially as related to inflammation and atherogenesis.

  9. Inhibition of pseudoperoxiadse activity of human red blood cell hemoglobin by methocarbamol.

    Science.gov (United States)

    Minai-Tehrani, Dariush; Toofani, Sara; Yazdi, Fatemeh; Minai-Tehrani, Arash; Mollasalehi, Hamidreza; Bakhtiari Ziabari, Kourosh

    2017-01-01

    After red blood cells lysis, hemoglobin is released to blood circulation. Hemoglobin is carried in blood by binding to haptoglobin. In normal individuals, no free hemoglobin is observed in the blood, because most of the hemoglobin is in the form of haptoglobin complex. In some diseases that are accompanied by hemolysis, the amount of released hemoglobin is higher than its complementary haptoglobin. As a result, free hemoglobin appears in the blood, which is a toxic compound for these patients and may cause renal failure, hypertensive response and risk of atherogenesis. Free hemoglobin has been determined to have peroxidase activity and considered a pseudoenzyme. In this study, the effect of methocarbamol on the peroxidase activity of human hemoglobin was investigated. Our results showed that the drug inhibited the pseudoenzyme by un-competitive inhibition. Both Km and Vmax decreased by increasing the drug concentration. Ki and IC50 values were determined as 6 and 10mM, respectively. Docking results demonstrated that methocarbamol did not attach to heme group directly. A hydrogen bond linked NH2 of carbamate group of methocarbamol to the carboxyl group of Asp126 side chain. Two other hydrogen bonds could be also observed between hydroxyl group of the drug and Ser102 and Ser133 residues of the pseudoenzyme.

  10. Electromobility Shift Analysis (EMSA) Applied to the Study of NF-kappa B Binding Interactions in Vascular Smooth Muscle Cells.

    Science.gov (United States)

    Bourcier, T

    1999-01-01

    The nuclear factor-kappa B (NFκB) family of transcription factors has emerged as a signaling pathway that figures prominently in a cell's initial response to a plethora of inflammatory stimuli. Modified lipids, oxidative stress, bacterial endotoxins, growth factors and cytokines, such as platelet-derived growth factor (PDGF) and interleukin-1 (IL-1), are among the stimuli that free NFκB dimers from their cytosolic inhibitor proteins leading to nuclear translocation of NFκB and transactivation of target genes (1-3). The smooth muscle cells (SMC) of the vasculature express components of this pathway and are activated by these stimuli, promoting dysregulation of gene expression by cells within the atherosclerotic vessel. Indeed, NFκB proteins have been localized within the nuclei of vascular SMC at sites of human atherosclerotic lesions, suggesting a role for NFκB in activation of this cell type in vivo (4-6). NFκB participates in dysregulated gene expression not only by SMC but also by endothelial cells and macrophages, prominent cell types within atherosclerotic lesions, thus much attention has focused on the workings of this signaling pathway within vascular cells and its role in atherogenesis.

  11. 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.

  12. The immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability?

    Science.gov (United States)

    Montecucco, Fabrizio; Steffens, Sabine; Mach, François

    2007-01-01

    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 (NF)kappaB ligand (RANKL)/receptor activator of nuclear factor (NF)kappaB (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.

  13. The relationship between atherosclerosis and pulmonary emphysema

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    Vučević Danijela

    2014-01-01

    Full Text Available Introduction. The etiopathogenesis of atherosclerosis and subsequent pulmonary emphysema has not been fully elucidated. Experimental Studies Foam cells are of great importance in the development of these diseases. It is known that local cytokine secretion and modification of native lipoprotein particles, which are internalized by the vascular and alveolar macrophages via the scavenger receptors on the surfaces of these cells, lead to the formation of foam cells. Thus, the exacerbation of local inflammatory process in the vascular and lung tissue ensues due to a generation of reactive oxygen species, resulting in further lipoprotein modification and cytokine production. Accumulating evidence suggests that oxidants may facilitate the inflammatory response by impairing antiprotease function, directly attacking vascular and lung matrix proteins and by inactivating enzymes involved in elastin synthesis and vascular and lung repair. Clinical Studies Cigarette smoke is recognized as a rich source of oxidants. Nearly 90% of all patients with chronic obstructive pulmonary disease are smokers. The process of atherogenesis is also influenced by tobacco smoke. Conclusion The role of vascular and alveolar macrophages has become increasingly important in understanding the development of atherosclerosis and resulting pulmonary emphysema.[Projekat Ministarstva nauke Republike Srbije, br. 175015

  14. Blood flow characteristics in the aortic arch

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    Prahl Wittberg, Lisa; van Wyk, Stevin; Mihaiescu, Mihai; Fuchs, Laszlo; Gutmark, Ephraim; Backeljauw, Philippe; Gutmark-Little, Iris

    2012-11-01

    The purpose with this study is to investigate the flow characteristics of blood in the aortic arch. Cardiovascular diseases are associated with specific locations in the arterial tree. Considering atherogenesis, it is claimed that the Wall Shear Stress (WSS) along with its temporal and spatial gradients play an important role in the development of the disease. The WSS is determined by the local flow characteristics, that in turn depends on the geometry as well as the rheological properties of blood. In this numerical work, the time dependent fluid flow during the entire cardiac cycle is fully resolved. The Quemada model is applied to account for the non-Newtonian properties of blood, an empirical model valid for different Red Blood Cell loading. Data obtained through Cardiac Magnetic Resonance Imaging have been used in order to reconstruct geometries of the the aortic arch. Here, three different geometries are studied out of which two display malformations that can be found in patients having the genetic disorder Turner's syndrome. The simulations show a highly complex flow with regions of secondary flow that is enhanced for the diseased aortas. The financial support from the Swedish Research Council (VR) and the Sweden-America Foundation is gratefully acknowledged.

  15. Enhanced anti-inflammatory activities of Monascus pilosus fermented products by addition of ginger to the medium.

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    Chen, Chin-Chu; Chyau, Charng-Cherng; Liao, Chen-Chung; Hu, Tzu-Jung; Kuo, Chia-Feng

    2010-11-24

    Hypercholesterolemia initiates the atherogenic process; however, chronic inflammation promotes atherogenesis. Monascus spp. fermented products are recognized for their anti-hypercholesterolemic effect, but their anti-inflammatory activity is not as significant as that of many plant-derived foods. To enhance the anti-inflammatory function of Monascus pilosus fermented products, ginger was added to the PDB medium at a ratio of 20% (v/v). The mycelia and broth were collected, freeze-dried, and extracted by ethanol for assays. Macrophage RAW264.7 was challenged with lipopolysaccharide (LPS) and coincubated with the extracts of fermented product cultured in ginger-supplemented medium (MPG) or extracts of fermented product cultured in regular PDB medium (MP) for 18 h. Human umbilical vein endothelial cell HUVEC was challenged with tumor necrosis factor (TNF)-α and coincubated with the extracts of either MPG or MP for 6 h. The results showed that MPG significantly (pMonascus spp. fermented products as antiatherosclerotic nutraceuticals.

  16. p66(Shc) protein, oxidative stress, and cardiovascular complications of diabetes: the missing link.

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    Francia, Pietro; Cosentino, Francesco; Schiavoni, Marzia; Huang, Yale; Perna, Enrico; Camici, Giovani G; Lüscher, Thomas F; Volpe, Massimo

    2009-09-01

    Diabetes affects more than 150 million people worldwide, and it is estimated that this would increase to 299 million by the year 2025. The incidence of and mortality from cardiovascular disease are two- to eightfold higher in subjects with diabetes than in those without, coronary artery disease accounting for the large majority of deaths. Among the full spectrum of biochemical effects of high glucose, generation of oxygen-derived free radicals is one of the main pathophysiological mechanisms linking hyperglycemia to atherosclerosis, nephropathy, and cardiomyopathy. The adaptor protein p66(Shc) is implicated in mitochondrial reactive oxygen species (ROS) generation and translation of oxidative signals into apoptosis. Indeed, p66(Shc-/-) mice display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress-induced apoptosis. Accordingly, a series of studies defined the pathophysiological role of p66(Shc) in cardiovascular disease where ROS represent a substantial triggering component. As p66(Shc) modulates the production of cellular ROS, it represents a proximal node through which high glucose exerts its deleterious effects on different cell types; indeed, several studies tested the hypothesis that deletion of the p66(Shc) gene may confer protection against diabetes-related cardiovascular complications. The present review focuses on the reported evidence linking p66(Shc) signaling pathway to high glucose-associated endothelial dysfunction, atherogenesis, nephropathy, and cardiomyopathy.

  17. Molecular Targeting of Proteins by l-Homocysteine: Mechanistic Implications for Vascular Disease

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    Glushchenko, Alla V.; Jacobsen, Donald W.

    2010-01-01

    Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, complications of pregnancy, cognitive impairment, and osteoporosis. That elevated homocysteine leads to vascular dysfunction may be the linking factor between these apparently unrelated pathologies. Although a growing body of evidence suggests that homocysteine plays a causal role in atherogenesis, specific mechanisms to explain the underlying pathogenesis have remained elusive. This review focuses on chemistry unique to the homocysteine molecule to explain its inherent cytotoxicity. Thus, the high pKa of the sulfhydryl group (pKa, 10.0) of homocysteine underlies its ability to form stable disulfide bonds with protein cysteine residues, and in the process, alters or impairs the function of the protein. Studies in this laboratory have identified albumin, fibronectin, transthyretin, and metallothionein as targets for homocysteinylation. In the case of albumin, the mechanism of targeting has been elucidated. Homocysteinylation of the cysteine residues of fibronectin impairs its ability to bind to fibrin. Homocysteinylation of the cysteine residues of metallothionein disrupts zinc binding by the protein and abrogates inherent superoxide dismutase activity. Thus, S-homocysteinylation of protein cysteine residues may explain mechanistically the cytotoxicity of elevated l-homocysteine. PMID:17760510

  18. POSSIBLE ROLE OF MITOCHONDRIAL GENOME MUTATIONS IN CORONARY HEART DISEASE

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    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.

  19. High glucose enhance expression of matrix metalloproteinase—2 in smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    HAOFeng; YUJin-De

    2003-01-01

    AIM:To investigate the effects of high glucose on expression of matrix metalloproteinase-2(MMP-2) in rat aortic smooth muscle cells and the influence of matrix remodeling on atherogenesis in diabetic patients. METHODS: The smooth muscle cells were cultured from the thoracic aorta of Sprague-Dawley (SD) rat. MMP-2 mRNA was determined by reverse transcriptase-polymerase chain reaction(RT-PCR),MMP-2 protein was measured by Western blotting, and MMP-2 activity in conditioned medium was observed by zymography. RESULTS:In comparison with the control, there was no difference in the expression of MMP-2 when glucose concentration was 1g/L,whereas MMP-2 activity in smooth muscle cells was significantly increased by the glucose 5 g/L(P<0.01). CONCLUSION:High glucose enhanced the expression and activity of MMP-2 in smooth muscle cells, which may provide an explanation for the phenomenon that diabetes patients are prone to have atherosclerotic lesions.

  20. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice.

    Science.gov (United States)

    Koenen, Rory R; von Hundelshausen, Philipp; Nesmelova, Irina V; Zernecke, Alma; Liehn, Elisa A; Sarabi, Alisina; Kramp, Birgit K; Piccinini, Anna M; Paludan, Søren R; Kowalska, M Anna; Kungl, Andreas J; Hackeng, Tilman M; Mayo, Kevin H; Weber, Christian

    2009-01-01

    Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.

  1. Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease

    Science.gov (United States)

    Pechlaner, Raimund; Willeit, Peter; Summerer, Monika; Santer, Peter; Egger, Georg; Kronenberg, Florian; Demetz, Egon; Weiss, Günter; Tsimikas, Sotirios; Witztum, Joseph L.; Willeit, Karin; Iglseder, Bernhard; Paulweber, Bernhard; Kedenko, Lyudmyla; Haun, Margot; Meisinger, Christa; Gieger, Christian; Müller-Nurasyid, Martina; Peters, Annette; Willeit, Johann; Kiechl, Stefan

    2015-01-01

    Objective The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat (VNTR) polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease (CVD). We examined this association prospectively in the general population. Approach and Results Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 VNTR length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared to the rest of the population (recessive trait) featured substantially increased CVD risk (hazard ratio [95% confidence interval], 5.45 (2.39, 12.42); PSAPHIR, and KORA prospective studies (HR [95% CI], 3.26 [1.50, 7.33]; P=0.0043). Conclusions This study found a strong association between the HO-1 VNTR polymorphism and CVD risk confined to subjects with a high number of repeats on both HO-1 alleles, and provides evidence for accelerated atherogenesis and decreased anti-oxidant defence in this vascular high-risk group. PMID:25359861

  2. Dietary Inflammatory Index and Incidence of Cardiovascular Disease in the SUN Cohort

    Science.gov (United States)

    Ramallal, Raúl; Toledo, Estefanía; Martínez-González, Miguel A.; Hernández-Hernández, Aitor; García-Arellano, Ana; Shivappa, Nitin; Hébert, James R.; Ruiz-Canela, Miguel

    2015-01-01

    Background Diet is known to play a key role in atherogenesis and in the development of cardiovascular events. Dietary factors may mediate these processes acting as potential modulators of inflammation. Potential Links between inflammatory properties of diet and the occurrence of cardiovascular events have not been tested previously. Objective We aimed to assess the association between the dietary inflammatory index (DII), a method to assess the inflammatory potential of the diet, and incident cardiovascular disease. Methods In the prospective, dynamic SUN cohort, 18,794 middle-aged, Spanish university graduates were followed up for 8.9 years (median). A validated 136-item food-frequency questionnaire was used to calculate the DII. The DII is based on scientific evidence about the relationship between diet and inflammatory biomarkers (C-reactive protein, IL-1β, IL-4, IL-6, IL-10 and TNF-α). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between the DII and incident cardiovascular disease (myocardial infarction, stroke or cardiovascular death). Results The risk for cardiovascular events progressively increased with each increasing quartile of DII (ptrend = 0.017). The multivariable-adjusted HR for participants in the highest (most pro-inflammatory) vs. the lowest quartile of the DII was 2.03 (95% CI 1.06–3.88). Conclusions A pro-inflammatory diet was associated with a significantly higher risk for developing cardiovascular events. PMID:26340022

  3. Erythrocyte Duffy antigen receptor for chemokines (DARC):diagnostic and therapeutic implications in atherosclerotic Cardiovascular disease

    Institute of Scientific and Technical Information of China (English)

    Stavros APOSTOLAKIS; Georgios K CHALIKIAS; Dimitrios N TZIAKAS; Stavros KONSTANTINIDES

    2011-01-01

    Atherosclerosis is an inflammatory disease.The last three decades efforts have been made to elucidate the biochemical pathways that are implicated in the process of atherogenesis and plaque development.Chemokines are crucial mediators in every step of this process.Additionally.cellular components of the peripheral blood have been proved important mediators in the formation and progression of atherosclerotic lesions.However,until recently data were mostly focusing on leukocytes and platelets.Erythrocytes were considered unreceptive bystanders and limited data supported their importance in the progression and destabilization of the atherosclerotic plaque.Recently erythrocytes, through their Duffy antigen receptor for chemokines(DARC),have been proposed as appealing regulators of chemokine-induced pathways.Dissimilar to every other chemokine receptor DARC possesses high affinity for severalligands from both CC and CXC chemokine sub-families.Moreover,DARC is not coupled to a G-protein or any other intracellular signalling system;thus it is incapable of generating second messages.The exact biochemical role of erythrocyte DARC remains to be determined.It is however challenging the fact that DARC is a regulator of almost every CC and CXC chemokine ligand and therefore DARC antagonism could efiectively block the complex pre-inflammatory chemokine network.In the present review we intent to provid recent evidence supporting the role of erythrocytes in atherosclerosis focusing on the erythrocyte-chemokine interaction through the Duffy antigen system.

  4. Recent advances in lipoprotein and atherosclerosis: A nutrigenomic approach

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    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

  5. BR 08-3 MANAGEMENT OF DYSLIPIDEMIA IN HYPERTENSION.

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    Muthusamy, V V

    2016-09-01

    Cardiovascular disease burden is increasing all over the world. The diagnosis of hypertension is considered when a person has persistently elevated BP (Systolic BP more than 140 mmHg and/or Diastolic BP more than 90 mmHg). Dyslipidemia denotes abnormal levels of lipids in the blood (Total Cholesterol >200 mg%, Low density lipoprotein (LDL) >100 mg%, Triglycerides (TGL) >150 mg% and High density lipoprotein (HDL) metabolic syndrome as per the definition of NCEP Guidelines-Adult Treatment Panel III (ATP III). The prevalence of the co-existence of hypertension and dyslipidemia is in the range of 15-31%. The co-existence of these two risk factors has more than the additive effect for endothelial dysfunction resulting in enhanced atherosclerosis leading to CVD. The term dyslipidemic hypertension (DH) was used in the context of familial DH. Non-familial forms of DH are more common than familial form. Some authors name this combination as Lipitension for easy understanding. Framingham Heart study shows that the majority of hypertension population have more than one risk factor predominantly atherogenic in nature. Dyslipidemia causes endothelial damage and loss of vasomotor activity. The damage may manifest as elevated BP. MRFIT study reveals that mild to moderate elevation of BP and Dyslipidemia can lead to multiplicative adverse impact on CVD. Framingham study results also reveal that moderately elevated BP and cholesterol had a similar risk.RAAS promotes atherogenesis. Angiotensin II promotes atherogenesis through stimulation AT1 receptor, which increases lipid uptake in cells, vasoconstriction and free radical production to foster both hypertension and atherosclerosis. Hypertension damages vascular endothelium through altered shear stress and oxidative stress resulting in increased synthesis of collagen and fibronectin, reduced nitric oxide-dependent vascular relaxation and increased permeability to lipoproteins. Hypertension is also associated with up regulation of

  6. 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

  7. 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.

  8. Effect of Nateglinide and Glibenclamide on Endothelial Cells and Smooth Muscle Cells from Human Coronary Arteries

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    Seeger H

    2004-01-01

    Full Text Available In the present work the effect of nateglinide and glibenclamide, two different substances used for therapy of diabetes mellitus type 2, were investigated on the synthesis of markers of endothelial function and on the proliferation of smooth muscle cells in vitro. As cell models endothelial and smooth muscle cells from human coronary arteries were used. Both substances were tested at concentrations of 0.1, 1 and 10 mmol/l. As markers of endothelial function prostacyclin, endothelin and plasminogen-activator-inhibitor-1 (PAI-1 were tested. Nateglinide and glibenclamide were similarly able to inhibit endothelial endothelin and PAI-1 synthesis, but only at the highest concentration tested. Endothelial prostacyclin synthesis and proliferation of smooth muscle cells were not significantly changed by both substances. These results indicate that both nateglinide and glibenclamide may have potential in reducing negative long-term effects of diabetes such as atherogenesis. Kurzfassung: Effekt von Nateglinid und Glibenclamid auf Endothel- und Muskelzellen humaner Koronararterien. In der vorliegenden Arbeit wurde die Wirkung von Nateglinid und Glibenclamid, zweier unterschiedlicher Substanzen zur Behandlung des Diabetes mellitus Typ 2, auf die Synthese von Markern der Endothelfunktion und auf die Proliferation glatter Muskelzellen untersucht. Als Zellmodell dienten Endothelzellen und glatte Muskelzellen menschlicher Koronararterien. Beide Substanzen wurden in den Konzentrationen 0,1, 1 und 10 mmol/l getestet. Als Marker der Endothelfunktion dienten Prostazyklin, Endothelin und Plasminogen-Aktivator-Inhibitor-1 (PAI-1. Sowohl Nateglinid als auch Glibenclamid konnten die endotheliale Endothelin- und PAI-1-Produktion in ähnlichem Ausmaß senken, allerdings nur in der höchsten Konzentration. Die Prostazyklinsynthese und die Muskelzellproliferation wurden nicht signifikant beeinflußt. Diese Ergebnisse deuten daraufhin, daß sowohl Nateglinid als auch

  9. Cloning and expression of an anti-LDL(-) single-chain variable fragment, and its inhibitory effect on experimental atherosclerosis.

    Science.gov (United States)

    Kazuma, Soraya M; Cavalcante, Marcela F; Telles, Andréia E R; Maranhão, Andrea Queiroz; Abdalla, Dulcineia S P

    2013-01-01

    The in vivo modified forms of low-density lipoprotein (LDL) are important for the formation of foam cells and as mediators of the immuno-inflammatory process involved in the progression of atherosclerosis. Electronegative LDL, LDL(-), is a LDL subfraction with pro-inflammatory properties that is present in human blood. To investigate possible atheroprotective effects, an anti-LDL(-) single-chain variable fragment (scFv) was expressed in the methylotrophic yeast Pichia pastoris and its activity was evaluated in vitro against macrophages and in experimental atherosclerosis in Ldlr(-/-) mice. The recombinant 2C7 scFv was produced in a yield of 9.5 mg of protein/L. The specificity and affinity of purified 2C7 scFv against LDL(-) was confirmed by ELISA. To assess the activity of 2C7 scFv on foam cell formation, RAW 264.7 macrophages were exposed to LDL(-) in the presence or absence of 2C7 scFv. The 2C7 scFv inhibited the uptake of LDL(-) by macrophages in a dose-dependent manner, and internalization of LDL(-) by these cells was found to be mediated by the CD36 and CD14 receptor. In addition, compared with untreated cells, lipid accumulation in macrophages was decreased, and the expression of Cd36, Tlr-4 and Cox-2 was downregulated in macrophages treated with 2C7 scFv. Importantly, compared with untreated mice, the treatment of Ldlr(-/-) mice with 2C7 scFv decreased the atherosclerotic lesion area at the aortic sinus. In conclusion, our data show that 2C7 scFv inhibits foam cell formation and atherosclerotic plaque development by modulating the expression of genes relevant to atherogenesis. These results encourage further use of this antibody fragment in the development of new therapeutic strategies that neutralize the pro-atherogenic effects of LDL(-).

  10. Wall Shear Stress Distribution in Patient Specific Coronary Artery Bifurcation

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    Vahab Dehlaghi

    2010-01-01

    Full Text Available Problem statement: Atherogenesis is affected by hemodynamic parameters, such as wall shear stress and wall shear stress spatial gradient. These parameters are largely dependent on the geometry of arterial tree. Arterial bifurcations contain significant flow disturbances. Approach: The effects of branch angle and vessel diameter ratio at the bifurcations on the wall shear stress distribution in the coronary arterial tree based on CT images were studied. CT images were digitally processed to extract geometrical contours representing the coronary vessel walls. The lumen of the coronary arteries of the patients was segmented using the open source software package (VMTK. The resulting lumens of coronary arteries were fed into a commercial mesh generator (GAMBIT, Fluent Inc. to generate a volume that was filled with tetrahedral elements. The FIDAP software (Fluent Corp. was used to carry out the simulation by solving Navier-Stokes equations. The FIELDVIEW software (Version 10.0, Intelligent Light, Lyndhurst, NJ was used for the visualization of flow patterns and the quantification of wall shear stress. Post processing was done with VMTK and MATLAB. A parabolic velocity profile was prescribed at the inlets and outlets, except for 1. Stress free outlet was assigned to the remaining outlet. Results: The results show that for angle lower than 90°, low shear stress regions are observed at the non-flow divider and the apex. For angle larger than 90°, low shear stress regions only at the non-flow divider. By increasing of diameter of side branch ratio, low shear stress regions in the side branch appear at the non-flow divider. Conclusion: It is concluded that not only angle and diameter are important, but also the overall 3D shape of the artery. More research is required to further quantify the effects angle and diameter on shear stress patterns in coronaries.

  11. Engagement of specific innate immune signaling pathways during Porphyromonas gingivalis induced chronic inflammation and atherosclerosis.

    Science.gov (United States)

    Gibson, Frank C; Ukai, Takashi; Genco, Caroline A

    2008-01-01

    Toll-like receptors (TLRs) are a group of pathogen-associated molecular pattern receptors, which play an important role in innate immune signaling in response to microbial infection. It has been demonstrated that TLRs are differentially up regulated in response to microbial infection and chronic inflammatory diseases such as atherosclerosis. The expression of TLRs are markedly augmented in human atherosclerotic lesions and this occurs preferentially by endothelial cells and macrophages in areas infiltrated with inflammatory cells. Furthermore polymorphisms in the human gene encoding one TLR receptor (TLR4) which attenuates receptor signaling and diminishes the inflammatory response to gram-negative pathogens, is associated with low levels of certain circulating mediators of inflammation and a decreased risk for atherosclerosis in humans. Recent advances have established a fundamental role for inflammation in mediating all stages of atherosclerosis. However, the triggers that initiate and sustain the inflammatory process have not been definitively identified. Although definitive proof of a role of infection contributing to atherogenesis is lacking, multiple investigations have demonstrated that infectious agents evoke cellular and molecular changes supportive of such a role. Evidence in humans suggesting that periodontal infection predisposes to atherosclerosis is derived from studies demonstrating that the periodontal pathogen Porphyromonas gingivalis resides in the wall of atherosclerotic vessels and seroepidemiological studies demonstrating an association between pathogen-specific IgG antibodies and atherosclerosis. Our recent work with P. gingivalis has demonstrated the effectiveness of specific intervention strategies (immunization) in the prevention of pathogen-accelerated atherosclerosis. We have also established that the inflammatory signaling pathways that P. gingivalis utilizes is dependent on the cell type and this specificity clearly influences innate

  12. Group IVA phospholipase A2-associated production of MMP-9 in macrophages and formation of atherosclerotic lesions.

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    Ii, Hiromi; Hontani, Naoya; Toshida, Issei; Oka, Mayuko; Sato, Takashi; Akiba, Satoshi

    2008-03-01

    Matrix metalloproteinase-9 (MMP-9) is involved in atherogenesis, and the production of MMP-9 in macrophages is considered to be mediated by the arachidonic acid cascade. The present study examined the possible involvement of group IVA phospholipase A2 (IVA-PLA2), a key enzyme in the arachidonic acid cascade, in the production of MMP-9 induced by oxidized low-density lipoprotein (oxLDL) in macrophages and high-fat diet-induced formation of atherosclerotic lesions using IVA-PLA2-deficient mice (C57BL/6 background). In wild-type mouse peritoneal macrophages, oxLDL induced an increase in MMP-9 in the culture medium. The oxLDL-promoted production of MMP-9 was markedly reduced in IVA-PLA2-deficient macrophages compared to wild-type macrophages. Feeding of wild-type mice with a high-fat diet caused the formation of early atherosclerotic lesions in the aortic root with increases in MMP-9 and macrophages in the lesions and with higher serum levels of total cholesterol. Such lesions were apparently less severe in IVA-PLA2-deficient mice fed a high-fat diet, despite higher total cholesterol levels. Under the conditions, a high-fat diet reduced the serum levels of high-density lipoprotein-cholesterol (HDL-C) in wild-type mice. However, IVA-PLA2-deficient mice fed a high-fat diet were protected against the decrease in HDL-C levels. The present results suggest that IVA-PLA2 is involved in the oxLDL-induced production of MMP-9 in macrophages and the high-fat diet-induced formation of early atherosclerotic lesions. The protection against the lesions in IVA-PLA2-deficient mice may be ascribable, in part, to the impaired production of MMP-9 and/or the maintained levels of HDL-C.

  13. Imaging Atherosclerotic Plaque Inflammation via Folate Receptor Targeting Using a Novel 18F-Folate Radiotracer

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    Adrienne Müller

    2014-03-01

    Full Text Available Folate receptor β (FR-β is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. A pivotal step in atherogenesis is the subendothelial accumulation of macrophages. In nascent lesions, they coordinate the scavenging of lipids and cellular debris to define the likelihood of plaque inflammation and eventually rupture. In this study, we determined the presence of FR-β-expressing macrophages in atherosclerotic lesions by the use of a fluorine-18-labeled folate-based radiotracer. Human endarterectomized specimens were used to measure gene expression levels of FR-β and CD68. Increased FR-β and CD68 levels were found in atherosclerotic plaques compared to normal artery walls by quantitative real-time polymerase chain reaction. Western blotting and immunohistochemistry demonstrated prominent FR-β protein levels in plaques. FR- β-positive cells colocalized with activated macrophages (CD68 in plaque tissue. Carotid sections incubated with 3′-aza-2′- [18F]fluorofolic acid displayed increased accumulation in atherosclerotic plaques through in vitro autoradiography. Specific binding of the radiotracer correlated with FR-β-expressing macrophages. These results demonstrate high FR-β expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. Areas of high 3′-aza-2′-[18F]fluorofolic acid binding within the lesions represented FR-β-expressing macrophages. Selectively targeting FR-β-positive macrophages through folate-based radiopharmaceuticals may be useful for noninvasive imaging of plaque inflammation.

  14. Dietary antioxidants and cardioprotection--fact or fallacy?

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    Steinbrecher, U P

    1997-03-01

    The emerging dogma that low density lipoprotein (LDL) oxidation is a contributing cause and not simply a consequence of atherosclerosis is based on three lines of experimental evidence: (i) lipid peroxidation products and oxidized LDLs are present in atherosclerotic lesions; (ii) oxidized LDL has an array of potentially proatherogenic properties in vitro, including uptake by macrophages via a number of distinct "scavenger" receptors; and (iii) treatment of hypercholesterolemic animals with potent antioxidant drugs can retard the development of atherosclerosis. Additional support for the role of lipoprotein oxidation in atherogenesis was provided by cross-cultural dietary comparisons, which suggested an inverse correlation between antioxidant vitamin intake and coronary mortality. As well, several large case-control studies indicated that antioxidant vitamin intake, particularly vitamin E, was associated with reduced coronary risk. However, these studies do not indicate whether this association is causal, or if vitamin supplementation is merely a marker for some other protective factor. To test this properly, randomized controlled intervention studies are required. In several animal models, a number of different antioxidant drugs have been shown to retard atherosclerosis, but results with vitamin supplementation are unclear. Results of intervention trials in humans show no benefit to long-term beta-carotene supplementation, and the only published study of vitamin E found a reduction of nonfatal myocardial infarction but no reduction (actually an increase) in fatal myocardial infarction and total mortality. Several other large antioxidant intervention trials are underway. Until the results of these studies are available, there appears to be insufficient evidence on which to base recommendations regarding antioxidant supplements for the prevention of atherosclerosis.

  15. Characterization of VCAM-1-binding peptide-functionalized quantum dots for molecular imaging of inflamed endothelium.

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    Yun Chen

    Full Text Available Inflammation-induced activation of endothelium constitutes one of the earliest changes during atherogenesis. New imaging techniques that allow detecting activated endothelial cells can improve the identification of persons at high cardiovascular risk in early stages. Quantum dots (QDs have attractive optical properties such as bright fluorescence and high photostability, and have been increasingly studied and developed for bio-imaging and bio-targeting applications. We report here the development of vascular cell adhesion molecule-1 binding peptide (VCAM-1 binding peptide functionalized QDs (VQDs from amino QDs. It was found that the QD fluorescence signal in tumor necrosis factor [Formula: see text] (TNF-[Formula: see text] treated endothelial cells in vitro was significantly higher when these cells were labeled with VQDs than amino QDs. The VQD labeling of TNF-[Formula: see text]-treated endothelial cells was VCAM-1 specific since pre-incubation with recombinant VCAM-1 blocked cells' uptake of VQDs. Our ex vivo and in vivo experiments showed that in the inflamed endothelium, QD fluorescence signal from VQDs was also much stronger than that of amino QDs. Moreover, we observed that the QD fluorescence peak was significantly blue-shifted after VQDs interacted with aortic endothelial cells in vivo and in vitro. A similar blue-shift was observed after VQDs were incubated with recombinant VCAM-1 in tube. We anticipate that the specific interaction between VQDs and VCAM-1 and the blue-shift of the QD fluorescence peak can be very useful for VCAM-1 detection in vivo.

  16. Systems Biology Reveals Cigarette Smoke-Induced Concentration-Dependent Direct and Indirect Mechanisms That Promote Monocyte-Endothelial Cell Adhesion.

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    Poussin, Carine; Laurent, Alexandra; Peitsch, Manuel C; Hoeng, Julia; De Leon, Hector

    2015-10-01

    Cigarette smoke (CS) affects the adhesion of monocytes to endothelial cells, a critical step in atherogenesis. Using an in vitro adhesion assay together with innovative computational systems biology approaches to analyze omics data, our study aimed at investigating CS-induced mechanisms by which monocyte-endothelial cell adhesion is promoted. Primary human coronary artery endothelial cells (HCAECs) were treated for 4 h with (1) conditioned media of human monocytic Mono Mac-6 (MM6) cells preincubated with low or high concentrations of aqueous CS extract (sbPBS) from reference cigarette 3R4F for 2 h (indirect treatment, I), (2) unconditioned media similarly prepared without MM6 cells (direct treatment, D), or (3) freshly generated sbPBS (fresh direct treatment, FD). sbPBS promoted MM6 cells-HCAECs adhesion following I and FD, but not D. In I, the effect was mediated at a low concentration through activation of vascular inflammation processes promoted in HCAECs by a paracrine effect of the soluble mediators secreted by sbPBS-treated MM6 cells. Tumor necrosis factor α (TNFα), a major inducer, was actually shed by unstable CS compound-activated TNFα-converting enzyme. In FD, the effect was triggered at a high concentration that also induced some toxicity. This effect was mediated through an yet unknown mechanism associated with a stress damage response promoted in HCAECs by unstable CS compounds present in freshly generated sbPBS, which had decayed in D unconditioned media. Aqueous CS extract directly and indirectly promotes monocytic cell-endothelial cell adhesion in vitro via distinct concentration-dependent mechanisms.

  17. Arterial pulse wave velocity, inflammatory markers, pathological GH and IGF states, cardiovascular and cerebrovascular disease

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    Michael R Graham

    2008-12-01

    Full Text Available Michael R Graham1, Peter Evans2, Bruce Davies1, Julien S Baker11Health and Exercise Science Research Unit, Faculty of Health Sport and Science, University of Glamorgan, Pontypridd, Wales, United Kingdom; 2Royal Gwent Hospital, Newport, Gwent, United KingdomAbstract: Blood pressure (BP measurements provide information regarding risk factors associated with cardiovascular disease, but only in a specific artery. Arterial stiffness (AS can be determined by measurement of arterial pulse wave velocity (APWV. Separate from any role as a surrogate marker, AS is an important determinant of pulse pressure, left ventricular function and coronary artery perfusion pressure. Proximal elastic arteries and peripheral muscular arteries respond differently to aging and to medication. Endogenous human growth hormone (hGH, secreted by the anterior pituitary, peaks during early adulthood, declining at 14% per decade. Levels of insulin-like growth factor-I (IGF-I are at their peak during late adolescence and decline throughout adulthood, mirror imaging GH. Arterial endothelial dysfunction, an accepted cause of increased APWV in GH deficiency (GHD is reversed by recombinant human (rh GH therapy, favorably influencing the risk for atherogenesis. APWV is a noninvasive method for measuring atherosclerotic and hypertensive vascular changes increases with age and atherosclerosis leading to increased systolic blood pressure and increased left ventricular hypertrophy. Aerobic exercise training increases arterial compliance and reduces systolic blood pressure. Whole body arterial compliance is lowered in strength-trained individuals. Homocysteine and C-reactive protein are two infl ammatory markers directly linked with arterial endothelial dysfunction. Reviews of GH in the somatopause have not been favorable and side effects of treatment have marred its use except in classical GHD. Is it possible that we should be assessing the combined effects of therapy with rhGH and rh

  18. Vitamins, Minerals and Flavonoids Intake and the Risk of Cardiovascular Diseases

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    Seyed Ali Keshavarz

    2007-06-01

    Full Text Available Diseases of heart and stroke cause most deaths in both sexes of all ethnic groups. For more than 40 years epidemiological studies, experimental studies, and clinical trials have shown that numerous dietary risk factors affect serum lipids, atherogenesis and coronary heart disease (CHD. Substantial interest has recently focused on the hypothesis that the naturally occurring antioxidant vitamins such as vitamin E, vitamin C, and ß-carotene may prevent myocardial infarction, progression of coronary heart disease. Substantial laboratory, animal, and human data suggest that oxidation of low-density lipoprotein (LDL cholesterol is an important step in the pathogenesis of atherosclerotic lesions. Oxidation of LDL cholesterol is important in both the initiation and progression of plaque or increases the risk for plaque rupture. The major lipid-soluble antioxidant vitamins are vitamin E ( -tocopherol and ß-carotene, a precursor of vitamin A. The major water-soluble antioxidant vitamin is vitamin C (ascorbic acid. Vitamin E is important in preventing oxidation of LDL cholesterol. ß-Carotene prevents oxidation of LDL cholesterol. Vitamin C prevents oxidation of LDL cholesterol and preserves vitamin E and ß-carotene levels during oxidative stress. It is increasingly recognized that folate and vitamin B6 may play a role in the prevention of cardiovascular disease. The primary mechanism proposed for their effect on coronary vascular disease (CVD is a reduction in plasma homocysteine concentration by remethylation of homocysteine back to methionine. Minerals like magnesium, Potassium and calcium and also vitamin D have protective effect in blood pressure. Selenium is an important component of antioxidant defence and flavonoids which are derived from plants have been shown to inhibit platelet aggregation and adhesion, which may be another way they lower the risk of heart disease. In this article the role of micronutrients in prevention of cardiovascular

  19. Lipocalin (LCN 2 Mediates Pro-Atherosclerotic Processes and Is Elevated in Patients with Coronary Artery Disease.

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    Raghav Oberoi

    Full Text Available Lipocalin (LCN 2 is associated with multiple acute and chronic inflammatory diseases but the underlying molecular and cellular mechanisms remain unclear. Here, we investigated whether LCN2 is released from macrophages and contributes to pro-atherosclerotic processes and whether LCN2 plasma levels are associated with the severity of coronary artery disease progression in humans.In an autocrine-paracrine loop, tumor necrosis factor (TNF-α promoted the release of LCN2 from murine bone-marrow derived macrophages (BMDM and vice versa. Moreover, LCN2 stimulation of BMDM led to up-regulation of M1 macrophage markers. In addition, enhanced migration of monocytic J774A.1 cells towards LCN2 was observed. Furthermore, LCN2 increased the expression of the scavenger receptors Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 as well as scavenger receptor class A-1 (SRA-1 and induced the conversion of macrophages to foam cells. In atherosclerotic lesions of low density lipoprotein receptor-deficient (ldlr-/- mice fed a high fat, high cholesterol diet, LCN2 was found to be co-localized with macrophages in the shoulder region of the atherosclerotic plaque. In addition, LCN2 plasma levels were significantly increased in plasma samples of these mice. Finally, LCN2 plasma levels correlated with the severity of coronary artery disease (CAD in patients as determined by coronary angiography.Here we demonstrated that LCN2 plays a pivotal role in processes involved in atherogenesis by promoting polarization and migration of monocytic cells and development of macrophages towards foam cells. Moreover, LCN2 may be used as a prognostic marker to determine the status of CAD progression.

  20. An immune response network associated with blood lipid levels.

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    Michael Inouye

    2010-09-01

    Full Text Available While recent scans for genetic variation associated with human disease have been immensely successful in uncovering large numbers of loci, far fewer studies have focused on the underlying pathways of disease pathogenesis. Many loci which are associated with disease and complex phenotypes map to non-coding, regulatory regions of the genome, indicating that modulation of gene transcription plays a key role. Thus, this study generated genome-wide profiles of both genetic and transcriptional variation from the total blood extracts of over 500 randomly-selected, unrelated individuals. Using measurements of blood lipids, key players in the progression of atherosclerosis, three levels of biological information are integrated in order to investigate the interactions between circulating leukocytes and proximal lipid compounds. Pair-wise correlations between gene expression and lipid concentration indicate a prominent role for basophil granulocytes and mast cells, cell types central to powerful allergic and inflammatory responses. Network analysis of gene co-expression showed that the top associations function as part of a single, previously unknown gene module, the Lipid Leukocyte (LL module. This module replicated in T cells from an independent cohort while also displaying potential tissue specificity. Further, genetic variation driving LL module expression included the single nucleotide polymorphism (SNP most strongly associated with serum immunoglobulin E (IgE levels, a key antibody in allergy. Structural Equation Modeling (SEM indicated that LL module is at least partially reactive to blood lipid levels. Taken together, this study uncovers a gene network linking blood lipids and circulating cell types and offers insight into the hypothesis that the inflammatory response plays a prominent role in metabolism and the potential control of atherogenesis.

  1. Connective tissue diseases and noninvasive evaluation of atherosclerosis

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    Ardita G

    2014-06-01

    Full Text Available Giorgio Ardita, Giacomo Failla, Paolo Maria Finocchiaro, Francesco Mugno, Luigi Attanasio, Salvatore Timineri, Michelangelo Maria Di SalvoCardiovascular Department, Angiology Unit, Ferrarotto Hospital, Catania, ItalyAbstract: Connective tissue diseases (CTDs are associated with increased risk of cardiovascular disease due to accelerated atherosclerosis. In patients with autoimmune disorders, in addition to traditional risk factors, an immune-mediated inflammatory process of the vasculature seems to contribute to atherogenesis. Several pathogenetic mechanisms have been proposed, including chronic inflammation and immunologic abnormalities, both able to produce vascular damage. Macrovascular atherosclerosis can be noninvasively evaluated by ultrasound measurement of carotid or femoral plaque. Subclinical atherosclerosis can be evaluated by well-established noninvasive techniques which rely on ultrasound detection of carotid intima-media thickness. Flow-mediated vasodilatation and arterial stiffness are considered markers of endothelial dysfunction and subclinical atherosclerosis, respectively, and have been recently found to be impaired early in a wide spectrum of autoimmune diseases. Carotid intima-media thickness turns out to be a leading marker of subclinical atherosclerosis, and many studies recognize its role as a predictor of future vascular events, both in non-CTD individuals and in CTD patients. In rheumatic diseases, flow-mediated dilatation and arterial stiffness prove to be strongly correlated with inflammation, disease damage index, and with subclinical atherosclerosis, although their prognostic role has not yet been conclusively shown. Systemic lupus erythematosus, rheumatoid arthritis, and likely antiphospholipid syndrome are better associated with premature and accelerated atherosclerosis. Inconclusive results were reported in systemic sclerosis.Keywords: rheumatic disease, subclinical atherosclerosis, arterial stiffness

  2. Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis.

    Science.gov (United States)

    Sergin, Ismail; Bhattacharya, Somashubhra; Emanuel, Roy; Esen, Emel; Stokes, Carl J; Evans, Trent D; Arif, Batool; Curci, John A; Razani, Babak

    2016-01-05

    Autophagy is a catabolic cellular mechanism that degrades dysfunctional proteins and organelles. Atherosclerotic plaque formation is enhanced in mice with macrophages deficient for the critical autophagy protein ATG5. We showed that exposure of macrophages to lipids that promote atherosclerosis increased the abundance of the autophagy chaperone p62 and that p62 colocalized with polyubiquitinated proteins in cytoplasmic inclusions, which are characterized by insoluble protein aggregates. ATG5-null macrophages developed further p62 accumulation at the sites of large cytoplasmic ubiquitin-positive inclusion bodies. Aortas from atherosclerotic mice and plaques from human endarterectomy samples showed increased abundance of p62 and polyubiquitinated proteins that colocalized with plaque macrophages, suggesting that p62-enriched protein aggregates were characteristic of atherosclerosis. The formation of the cytoplasmic inclusions depended on p62 because lipid-loaded p62-null macrophages accumulated polyubiquitinated proteins in a diffuse cytoplasmic pattern. Lipid-loaded p62-null macrophages also exhibited increased secretion of interleukin-1β (IL-1β) and had an increased tendency to undergo apoptosis, which depended on the p62 ubiquitin-binding domain and at least partly involved p62-mediated clearance of NLRP3 inflammasomes. Consistent with our in vitro observations, p62-deficient mice formed greater numbers of more complex atherosclerotic plaques, and p62 deficiency further increased atherosclerotic plaque burden in mice with a macrophage-specific ablation of ATG5. Together, these data suggested that sequestration of cytotoxic ubiquitinated proteins by p62 protects against atherogenesis, a condition in which the clearance of protein aggregates is disrupted.

  3. 干细胞心肌移植的研究进展%Progress of cardiac stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    魏丽; 黄星原

    2010-01-01

    Cardiomyopathy is a serious disease for children's health.With the development of medical methods,cardiac stem cell transplantation has brought hopes for treatment of cardiovascular diseases,it has also become a research hotspot in recent years.Several different types of cells have been used in cardiac stem cell transplantation currently,including embryonic stem cells,bone marrow derived stem cells,skeletal myoblasts,umbilical cord blood stem cells,adipose stem cells,etc.The delivery is including intramyocardial injection,intracoronary injection,intravenous injection,and tissue-engineered constructs.The adverse reactions are ventricular arrhythmias,oncogenic transformation,multiorgan seeding,unintended cell differentiation,accelerated atherogenesis and coronary thrombosis.%心肌病是严重威胁小儿健康的一类疾病,随着医学手段的不断发展,干细胞心肌移植给心血管疾病的治疗带来了希望,也成为近年来学者们研究的热点.目前用于心肌移植的干细胞包括胚胎干细胞、骨髓源性干细胞、骨骼肌成肌细胞、心肌干细胞、脐血干细胞、脂肪干细胞等,移植途径包括心肌内注射、冠状动脉内注射、静脉注射和组织工程.移植干细胞引起的不良反应包括室性心律失常、癌基因转化、多器官种植、意外细胞分化及加速动脉粥样硬化和冠状动脉血栓形成.

  4. Importance of Primary Capture and L-Selectin–Dependent Secondary Capture in Leukocyte Accumulation in Inflammation and Atherosclerosis in Vivo

    Science.gov (United States)

    Eriksson, Einar E.; Xie, Xun; Werr, Joachim; Thoren, Peter; Lindbom, Lennart

    2001-01-01

    In the multistep process of leukocyte extravasation, the mechanisms by which leukocytes establish the initial contact with the endothelium are unclear. In parallel, there is a controversy regarding the role for L-selectin in leukocyte recruitment. Here, using intravital microscopy in the mouse, we investigated leukocyte capture from the free flow directly to the endothelium (primary capture), and capture mediated through interactions with rolling leukocytes (secondary capture) in venules, in cytokine-stimulated arterial vessels, and on atherosclerotic lesions in the aorta. Capture was more prominent in arterial vessels compared with venules. In venules, the incidence of capture increased with increasing vessel diameter and wall shear rate. Secondary capture required a minimum rolling leukocyte flux and contributed by ∼20–50% of total capture in all studied vessel types. In arteries, secondary capture induced formation of clusters and strings of rolling leukocytes. Function inhibition of L-selectin blocked secondary capture and thereby decreased the flux of rolling leukocytes in arterial vessels and in large (>45 μm in diameter), but not small (<45 μm), venules. These findings demonstrate the importance of leukocyte capture from the free flow in vivo. The different impact of blockage of secondary capture in venules of distinct diameter range, rolling flux, and wall shear rate provides explanations for the controversy regarding the role of L-selectin in various situations of leukocyte recruitment. What is more, secondary capture occurs on atherosclerotic lesions, a fact that provides the first evidence for roles of L-selectin in leukocyte accumulation in atherogenesis. PMID:11457895

  5. The relationship between oxidized lipoprotein(a and carotid atherosclerosis in asymptomatic subjects: A comparison with native lipoprotein(a

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    Taniguchi Nobuyuki

    2011-10-01

    Full Text Available Abstract Background Oxidized lipoprotein(a (oxLp(a can be a more potent marker of atherogenesis than native Lp(a, although Lp(a is considered to be a risk factor for atherosclerotic diseases. Limited clinical data are available regarding the significance of oxLp(a in atherosclerotic manifestations. This study aimed to investigate the association between the serum oxLp(a and carotid artery intima-media thickness (CIMT, in comparison to the serum Lp(a levels, among asymptomatic subjects. Methods The atheroscrerosis-related variables including Lp(a and oxLp(a were measured in 136 cardiovascular disease-free subjects (61 males and 75 females, mean age of 64 years. The serum oxLp(a level was quantified using a sandwich ELISA system. The CIMT level was ultrasonographically measured on bilateral carotid arteries. Results The median level of Lp(a was 120 μmol/L, oxLp(a was 0.06 nmol/L, and CIMT was 0.7 mm, respectively. A simple correlation test showed that the CIMT was significantly and positively correlated with age, systolic blood pressure and oxLp(a (r = 0.208, P Conclusions These results suggest that oxLp(a may be more closely associated with accelerated carotid atherosclerosis, in comparison to Lp(a, in this population. This finding can be important for obtaining a better understanding of the different atherogenic roles played by oxLp(a in comparison to Lp(a.

  6. Experimental Study of Yishou Tiaozhi Tablet(

    Institute of Scientific and Technical Information of China (English)

    ZHONG; Yi

    2001-01-01

    [1]XU SY. Screening method on lowering lipid drug and inhibiting arteriosclerosis drug. Pharmacological Experimental Methodology. Beijing: The People's Health Publishing House, 1985∶781-783.[2]LI YL. Assay of alkali hydrolytic decomposition method on serum HYP determination. Clinical Journal of Decimology 1988;6(2)∶69-71.[3]LI ZJ, HAN CS, WANG JX. Practical Radioimmunology. Beijing: The Scientific Technological Archive Publishing House, 1989∶198-221.[4]GAO YC. Effect of Yixing decoction on rats' serum lipid level in hyperlipidemia and its mechanism. Academic Journal of Traditional Chinese Medicine 1990;(5)∶53-56.[5]Manninen V, Tenkanen L. Lipid alteration and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988;260∶641-651.[6]HUANG JG, translated. The atherosclerous lipid marker. Fascicle of Cardiovascular Disease in Journal of Foreign Medicine 1987;14(1)∶4-9.[7]YANG RX. Lp(a) and atherosclerosis. Journal of Progression on Cardiovascular Disease 1994;15(4)∶221-223.[8]Colin J, Schwartz MD. A modern view of atherogenesis. Am J Cardio 1993;71∶9B-14B.[9]LIN XQ. Exploration on relationship between HYP and atherosclerosis in hyperlipidemia. Journal of Chinese Circulation 1993;8(3)∶160-163.[10].CHEN SH. Hyperlipidemia and platelet high response. Fascicle of Cardiovascular Disease in Journal of Foreign Medicine 1989;16(5)∶257-262.

  7. Stress and atherosclerotic cardiovascular disease.

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    Inoue, Nobutaka

    2014-01-01

    Recent major advances in medical science have introduced a wide variety of treatments against atherosclerosis-based cardiovascular diseases, which has led to a significant reduction in mortality associated with these diseases. However, atherosclerosis-based cardiovascular disease remains a leading cause of death. Furthermore, progress in medical science has demonstrated the pathogenesis of cardiovascular disease to be complicated, with a wide variety of underlying factors. Among these factors, stress is thought to be pivotal. Several types of stress are involved in the development of cardiovascular disease, including oxidative stress, mental stress, hemodynamic stress and social stress. Accumulating evidence indicates that traditional risk factors for atherosclerosis, including diabetes, hyperlipidemia, hypertension and smoking, induce oxidative stress in the vasculature. Oxidative stress is implicated in the pathogenesis of endothelial dysfunction, atherogenesis, hypertension and remodeling of blood vessels. Meanwhile, mental stress is a well-known major contributor to the development of cardiovascular disease. The cardiovascular system is constantly exposed to hemodynamic stress by the blood flow and/or pulsation, and hemodynamic stress exerts profound effects on the biology of vascular cells and cardiomyocytes. In addition, social stress, such as that due to a lack of social support, poverty or living alone, has a negative impact on the incidence of cardiovascular disease. Furthermore, there are interactions between mental, oxidative and hemodynamic stress. The production of reactive oxygen species is increased under high levels of mental stress in close association with oxidative stress. These stress responses and their interactions play central roles in the pathogenesis of atherosclerosis-based cardiovascular disease. Accordingly, the pathophysiological and clinical implications of stress are discussed in this article.

  8. PPAR Agonist-Induced Reduction of Mcp1 in Atherosclerotic Plaques of Obese, Insulin-Resistant Mice Depends on Adiponectin-Induced Irak3 Expression

    Science.gov (United States)

    Arnould, Thierry; Tsatsanis, Christos; Holvoet, Paul

    2013-01-01

    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. PMID:23620818

  9. Myeloid dendritic cells: Development, functions, and role in atherosclerotic inflammation.

    Science.gov (United States)

    Chistiakov, Dimitry A; Sobenin, Igor A; Orekhov, Alexander N; Bobryshev, Yuri V

    2015-06-01

    Myeloid dendritic cells (mDCs) comprise a heterogeneous population of professional antigen-presenting cells, which are responsible for capture, processing, and presentation of antigens on their surface to T cells. mDCs serve as a bridge linking adaptive and innate immune responses. To date, the development of DC lineage in bone marrow is better characterized in mice than in humans. DCs and macrophages share the common myeloid progenitor called macrophage-dendritic cell progenitor (MDP) that gives rise to monocytoid lineage and common DC progenitors (CDPs). CDP in turn gives rise to plasmacytoid DCs and predendritic cells (pre-mDCs) that are common precursor of myeloid CD11b+ and CD8α(+) DCs. The development and commitment of mDCs is regulated by several transcription and hematopoietic growth factors of which CCr7, Zbtb46, and Flt3 represent 'core' genes responsible for development and functional and phenotypic maintenance of mDCs. mDCs were shown to be involved in the pathogenesis of many autoimmune and inflammatory diseases including atherosclerosis. In atherogenesis, different subsets of mDCs could possess both proatherogenic (e.g. proinflammatory) and atheroprotective (e.g. anti-inflammatory and tolerogenic) activities. The proinflammatory role of mDCs is consisted in production of inflammatory molecules and priming proinflammatory subsets of effector T cells. In contrast, tolerogenic mDCs fight against inflammation through arrest of activity of proinflammatory T cells and macrophages and induction of immunosuppressive regulatory T cells. Microenvironmental conditions trigger differentiation of mDCs to acquire proinflammatory or regulatory properties.

  10. Human monocytes and macrophages express NADPH oxidase 5; a potential source of reactive oxygen species in atherosclerosis.

    Science.gov (United States)

    Manea, Adrian; Manea, Simona-Adriana; Gan, Ana Maria; Constantin, Alina; Fenyo, Ioana Madalina; Raicu, Monica; Muresian, Horia; Simionescu, Maya

    2015-05-22

    Monocytes (Mon) and Mon-derived macrophages (Mac) orchestrate important oxidative and inflammatory reactions in atherosclerosis by secreting reactive oxygen species (ROS) due, in large part, to the upregulated NADPH oxidases (Nox). The Nox enzymes have been extensively investigated in human Mon and Mac. However, the expression and functional significance of the Nox5 subtypes is not known. We aimed at elucidating whether Nox5 is expressed in human Mon and Mac, and examine its potential role in atherosclerosis. Human monocytic THP-1 cell line and CD14(+) Mon were employed to search for Nox5 expression. RT-PCR, Western blot, lucigenin-enhanced chemiluminescence and dihydroethidium assays were utilized to examine Nox5 in these cells. We found that Nox5 transcription variants and proteins are constitutively expressed in THP-1 cells and primary CD14(+) Mon. Silencing of Nox5 protein expression by siRNA reduced the Ca(2+)-dependent Nox activity and the formation of ROS in Mac induced by A23187, a selective Ca(2+) ionophore. Exposure of Mac to increasing concentrations of IFNγ (5-100 ng/ml) or oxidized LDL (5-100 μg/ml) resulted in a dose-dependent increase in Nox5 protein expression and elevation in intracellular Ca(2+) concentration. Immunohistochemical staining revealed that Nox5 is present in CD68(+) Mac-rich area within human carotid artery atherosclerotic plaques. To the best of our knowledge, this is the first evidence that Nox5 is constitutively expressed in human Mon. Induction of Nox5 expression in IFNγ- and oxidized LDL-exposed Mac and the presence of Nox5 in Mac-rich atheroma are indicative of the implication of Nox5 in atherogenesis.

  11. 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

  12. Paraoxsonase2 (PON2) and oxidative stress involvement in pomegranate juice protection against cigarette smoke-induced macrophage cholesterol accumulation.

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    Rom, Oren; Aviram, Michael

    2016-11-25

    Exposure to cigarette smoke (CS) promotes various stages of atherosclerosis development. Macrophages are the predominant cells in early atherogenesis, and the polyphenolic-rich pomegranate juice (PJ) is known for its protective role against macrophage atherogenicity. The aim of the current study was to examine the atherogenic effects of CS on macrophages, and to evaluate the protective effects of PJ against CS-induced macrophage atherogenicity. Murine J774A.1 macrophages were treated with CS-exposed medium in the absence or presence of PJ. Parameters of lipid peroxidation in CS-exposed medium were measured by the lipid peroxides and thiobarbituric acid reactive substances (TBARS) assays. Atherogenicity of macrophages incubated with increasing concentrations of CS-exposed medium was assessed by cytotoxicity, oxidative stress determined by generation of reactive oxygen species (ROS) using DCFH-DA, activity of the cellular anti-oxidant paraoxonase2 (PON2), macrophage accumulation of cholesterol and triglycerides, as well as through high density lipoprotein (HDL)-mediated cholesterol efflux from the cells. CS exposure resulted in significant and dose-dependent increases in lipid peroxides and TBARS medium levels (up to 3 and 8-fold, respectively). Incubation of macrophages with CS-exposed medium resulted in dose-dependent increases in macrophage damage/injury (up to 6-fold), intracellular ROS levels (up to 31%), PON2 activity (up to 2-fold), and macrophage cholesterol content (up to 24%). The latter might be explained by reduced HDL-mediated cholesterol efflux from CS-exposed macrophages (by 21%). PJ protected macrophages from CS-induced increases in intracellular ROS levels and cholesterol accumulation, as well as the attenuated efflux of cholesterol. These data indicate that CS stimulates macrophage oxidation and activates PON2 as a possible compensatory response to the oxidative burden. CS impairs HDL-mediated cholesterol efflux from macrophages leading to cellular

  13. Activin A Levels Are Associated With Abnormal Glucose Regulation in Patients With Myocardial Infarction

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    Andersen, Geir Ø.; Ueland, Thor; Knudsen, Eva C.; Scholz, Hanne; Yndestad, Arne; Sahraoui, Afaf; Smith, Camilla; Lekva, Tove; Otterdal, Kari; Halvorsen, Bente; Seljeflot, Ingebjørg; Aukrust, Pål

    2011-01-01

    OBJECTIVE On the basis of the role of activin A in inflammation, atherogenesis, and glucose homeostasis, we investigated whether activin A could be related to glucometabolic abnormalities in patients with acute myocardial infarction (MI). RESEARCH DESIGN AND METHODS Activin A measurement and oral glucose tolerance tests (OGTTs) were performed in patients (n = 115) with acute MI, without previously known diabetes, and repeated after 3 months. Release of activin A and potential anti-inflammatory effects of activin A were measured in human endothelial cells. Activin A effects on insulin secretion and inflammation were tested in human pancreatic islet cells. RESULTS 1) In patients with acute MI, serum levels of activin A were significantly higher in those with abnormal glucose regulation (AGR) compared with those with normal glucose regulation. Activin A levels were associated with the presence of AGR 3 months later (adjusted odds ratio 5.1 [95% CI 1.73–15.17], P = 0.003). 2) In endothelial cells, glucose enhanced the release of activin A, whereas activin A attenuated the release of interleukin (IL)-8 and enhanced the mRNA levels of the antioxidant metallothionein. 3) In islet cells, activin A attenuated the suppressive effect of inflammatory cytokines on insulin release, counteracted the ability of these inflammatory cytokines to induce mRNA expression of IL-8, and induced the expression of transforming growth factor-β. CONCLUSIONS We found a significant association between activin A and newly detected AGR in patients with acute MI. Our in vitro findings suggest that this association represents a counteracting mechanism to protect against inflammation, hyperglycemia, and oxidative stress. PMID:21464440

  14. Effects of insulin on physical factors: atherosclerosis in diabetes mellitus.

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    McMillan, D E

    1985-12-01

    Newton's laws of motion play a major role in blood flow. Inertia and conservation of momentum cause flow to separate at branches and curves in large blood vessels. Areas of separated flow in the arterial system are sites of atherogenesis. The place at which the separation ends, called the stagnation point, is the focus for plaque development. Pulsation of the arterial circulation causes the stagnation point to move downstream with each systole and upstream with each diastole. This movement generates forward and backward shearing force in the stagnation region as the separated flow migrates back and forth. Angular momentum, introduced into flowing blood with each heart beat and further enhanced by the asymmetry of origin of vessels branching from the aorta, generates a sidewise force component that is preserved during migration of the stagnation point. The sidewise force, added to the forward and backward shear stresses, creates an area of multidirectional shear stress under the migrating stagnation point that increases the permeability of the local endothelium. Blood is a complex fluid; it can generate greater shear stresses near the stagnation point than the simple fluids normally studied by fluid mechanicists. Blood is capable of retaining shear stress for short periods after it ceases to flow and extra work is required to establish its flow. In diabetes, reduced erythrocyte deformability further burdens flow onset. We are not yet able to establish whether the increase is only a few percent, or whether the burden is larger. Whatever its magnitude, diabetic modifications of the flow properties of blood, directly affect the size, location, and rate of development of atherosclerotic plaques.

  15. Smokeless tobacco, sport and the heart.

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    Chagué, Frédéric; Guenancia, Charles; Gudjoncik, Aurélie; Moreau, Daniel; Cottin, Yves; Zeller, Marianne

    2015-01-01

    Smokeless tobacco (snuff) is a finely ground or shredded tobacco that is sniffed through the nose or placed between the cheek and gum. Chewing tobacco is used by putting a wad of tobacco inside the cheek. Smokeless tobacco is widely used by young athletes to enhance performance because nicotine improves some aspects of physiology. However, smokeless tobacco has harmful health effects, including cardiovascular disorders, linked to nicotine physiological effects, mainly through catecholamine release. Nicotine decreases heart rate variability and the ventricular fibrillation threshold, and promotes the occurrence of various arrhythmias; it also impairs endothelial-dependent vasodilation and could therefore promote premature atherogenesis. At rest, heart rate, blood pressure, inotropism, cardiac output and myocardial oxygen consumption are increased by nicotine, leading to an imbalance between myocardial oxygen demand and supply. The same occurs at submaximal levels of exercise. These increases are accompanied by a rise in systemic resistances. At maximal exercise, heart rate, cardiac output and maximal oxygen uptake (V˙O2max) are unaffected by nicotine. Because endothelial dysfunction is promoted by nicotine, paradoxical coronary vasoconstriction may occur during exercise and recovery. Nicotine induces a decrease in muscular strength and impairs anaerobic performance. However, nicotine is used in sports as it diminishes anxiety, enhances concentration and agility, improves aerobic performance and favours weight control. Importantly, smokeless tobacco, similar to cigarette smoking, leads to nicotine dependence through dopaminergic pathways. Smokeless tobacco has harmful cardiovascular effects and is addictive: it fulfils all the criteria for inclusion in the World Anti-Doping Agency prohibited list as a doping product. Smokeless tobacco use in sporting activities must be discouraged.

  16. Vascular lipid accumulation, lipoprotein oxidation and macrophage lipid uptake in hypercholesterolemic zebrafish

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    Stoletov, Konstantin; Fang, Longhou; Choi, Soo-Ho; Hartvigsen, Karsten; Hansen, Lotte F.; Hall, Chris; Pattison, Jennifer; Juliano, Joseph; Miller, Elizabeth R.; Almazan, Felicidad; Crosier, Phil; Witztum, Joseph L.; Klemke, Richard L.; Miller, Yury I.

    2010-01-01

    Lipid accumulation in arteries induces vascular inflammation and atherosclerosis, the major cause of heart attack and stroke in humans. Extreme hyperlipidemia induced in mice and rabbits enables modeling many aspects of human atherosclerosis, but microscopic examination of plaques is possible only postmortem. Here we report that feeding adult zebrafish (Danio rerio) a high-cholesterol diet (HCD) resulted in hypercholesterolemia, remarkable lipoprotein oxidation and fatty streak formation in the arteries. Feeding an HCD supplemented with a fluorescent cholesteryl ester to optically transparent fli1:EGFP zebrafish larvae in which endothelial cells (EC) express GFP, and using confocal microscopy enabled monitoring vascular lipid accumulation and the EC layer disorganization and thickening in a live animal. The HCD feeding also increased leakage of a fluorescent dextran from the blood vessels. Administering ezetimibe significantly diminished the HCD-induced EC layer thickening and improved its barrier function. Feeding HCD to lyz:DsRed2 larvae in which macrophages and granulocytes express DsRed, resulted in the accumulation of fluorescent myeloid cells in the vascular wall. Using a fluorogenic substrate for phospholipase A2 (PLA2), we observed an increased vascular PLA2 activity in live HCD-fed larvae compared to control larvae. Furthermore, by transplanting genetically modified murine cells into HCD-fed larvae, we demonstrated that toll-like receptor-4 (TLR4) was required for efficient in vivo lipid uptake by macrophages. These results suggest that the novel zebrafish model is suitable for studying temporal characteristics of certain inflammatory processes of early atherogenesis and the in vivo function of vascular cells. PMID:19265037

  17. MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma

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    Wiesner, Philipp; Tafelmeier, Maria; Chittka, Dominik; Choi, Soo-Ho; Zhang, Li; Byun, Young Sup; Almazan, Felicidad; Yang, Xiaohong; Iqbal, Navaid; Chowdhury, Punam; Maisel, Alan; Witztum, Joseph L.; Handel, Tracy M.; Tsimikas, Sotirios; Miller, Yury I.

    2013-01-01

    Lipoprotein oxidation plays an important role in pathogenesis of atherosclerosis. Oxidized low density lipoprotein (OxLDL) induces profound inflammatory responses in vascular cells, such as production of monocyte chemoattractant protein-1 (MCP-1) [chemokine (C-C motif) ligand 2], a key chemokine in the initiation and progression of vascular inflammation. Here we demonstrate that OxLDL also binds MCP-1 and that the OxLDL-bound MCP-1 retains its ability to recruit monocytes. A human MCP-1 mutant in which basic amino acids Arg-18 and Lys-19 were replaced with Ala did not bind to OxLDL. The MCP-1 binding to OxLDL was inhibited by the monoclonal antibody E06, which binds oxidized phospholipids (OxPLs) in OxLDL. Because OxPLs are carried by lipoprotein(a) [Lp(a)] in human plasma, we tested to determine whether Lp(a) binds MCP-1. Recombinant wild-type but not mutant MCP-1 added to human plasma bound to Lp(a), and its binding was inhibited by E06. Lp(a) captured from human plasma contained MCP-1 and the Lp(a)-associated endogenous MCP-1 induced monocyte migration. These results demonstrate that OxLDL and Lp(a) bind MCP-1 in vitro and in vivo and that OxPLs are major determinants of the MCP-1 binding. The association of MCP-1 with OxLDL and Lp(a) may play a role in modulating monocyte trafficking during atherogenesis. PMID:23667177

  18. Early Stage of Hypertensive Retinopathy; Is It Really Important?

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    Murat KARAMAN

    2014-09-01

    Full Text Available OBJECTIVE: To investigate the relationship between early stage hypertensive retinopathy (HTRP and endothelial dysfunction (ED in atherogenesis. MATERIAL and METHODS: A total of 99 subjects consisting of 73 patients diagnosed with Essential Hypertension (HT and 26 healthy subjects were included to the study. Flow mediated dilatation (FMD was performed to detect ED. Asymmetric dimethylarginine-ADMA was measured as a marker of ED and the hsCRP and sTWEAK levels were measured for microvascular inflammation. All patients were screened for retinopathy. RESULTS: The mean blood pressure of the hypertensive patients and the control subjects was 140.1±13.7/86.1±10.7 and 107.12±10.0/65.38±10.2 respectively. HTRP was positive in 60.3% (n=44 and negative in 39.7% (n=29 of the patients with hypertension. There was grade 1 retinopathy in 52.1% and grade 2 retinopathy in 8.2% of hypertensive patients. The hsCRP, sTWEAK and ADMA levels were significantly higher in hypertensive patients than in the control group (respectively, p=0,011, p=0,001, p=0,001. FMD levels were lower in the hypertensive group, as expected. FMD levels were lower in the retinopathy group when the hypertensive group with and without retinopathy and the control group compared. hsCRP, sTWEAK and ADMA levels were significantly higher in subjects with retinopathy. hsCRP, sTWEAK and ADMA levels were also significantly higher in subjects with retinopathy (p=0.039, p=0.001, p=0.001. CONCLUSION: ED is thought to play a role in HT etiology and is also important in the development of HT complications. It would be appropriate to evaluate hypertensive patients more carefully and perform the necessary laboratory tests to detect ED so that the proper treatment can be started (ACEI, exercise, lifestyle changes.

  19. Correlation between serum adiponectin and clinical characteristics, biochemical parameters in Indian women with polycystic ovary syndrome

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    Ramanand, Sunita J.; Ramanand, Jaiprakash B.; Ghongane, Balasaheb B.; Patwardhan, Milind H.; Patwardhan, Varsha M.; Ghanghas, Ravi; Halasawadekar, Nimish R.; Patil, Praveenkumar

    2014-01-01

    Background: Polycystic ovary syndrome (PCOS) is a common disorder. PCOS women are at a high risk for insulin resistance and metabolic syndrome (MS). Adiponectin is positively related to insulin sensitivity. It has a preventive role in atherogenesis and MS. The present work was conducted to study the correlation between serum adiponectin levels and clinical characteristics and biochemical parameters in PCOS patients. Materials and Methods: A prospective study in 49 newly diagnosed (as per Rotterdam criteria) Indian PCOS women was conducted. PCOS women were clinically examined and investigated for biochemical parameters. Results: The mean serum adiponectin was 12 ± 9.4 μg/mL (range 0.47-45). Hypoadiponectinemia (serum adiponectin <4 μg/mL) was present in 22% patients. Age and adiponectin correlated significantly and inversely (r = −0.42, P = 0.027). Overweight/obese patients had lower mean adiponectin levels than normal weight (11.62 ± 9.5 vs 13.58 ± 9.5, P = 0.56). It was significantly lower in patients with acanthosis nigricans (AN) as compared with those without AN (8.4 ± 5.9 vs 15 ± 11, P = 0.038). Hirsute patients showed lower mean adiponectin levels than nonhirsute (10 ± 7.3 vs 13 ± 10, P = 0.57). A positive, insignificant correlation was observed between serum adiponectin and cholesterol, low-density lipoprotein, follicle stimulating hormone (FSH), thyroid stimulating hormone, levels. A negative insignificant correlation existed between serum adiponectin and luteinizing hormone (LH), LH: FSH ratio, prolactin, dehydroepiandrosterone, testosterone, triglyceride, high-density lipoprotein, fasting blood glucose, fasting insulin, and Homeostasis Model Assessment. Conclusion: Hypoadiponectinemia is present in one-fifth of women with PCOS. Adiponectin levels decrease as age advances. Low levels of adiponectin possibly contributes to the development of dermal manifestation (AN) of insulin resistance. PMID:24741521

  20. Dialysis water treated by reverse osmosis decreases the levels of C-reactive protein in uremic patients

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    Thomé F.S.

    2005-01-01

    Full Text Available Atherosclerosis is a major complication of chronic renal failure. Microinflammation is involved in atherogenesis and is associated with uremia and dialysis. The role of dialysate water contamination in inducing inflammation has been debated. Our aim was to study inflammatory markers in patients on chronic dialysis, before and 3 to 6 months after switching the water purification system from deionization to reverse osmosis. Patients had demographic, clinical and nutritional information collected and blood drawn for determination of albumin, ferritin, C-reactive protein (CRP, interleukin-6, and tumor necrosis factor-alpha in both situations. Acceptable levels of water purity were less than 200 colony-forming units of bacteria and less than 1 ng/ml of endotoxin. Sixteen patients died. They had higher median CRP (26.6 vs 11.2 mg/dl, P = 0.007 and lower median albumin levels (3.1 vs 3.9 g/l, P < 0.05 compared to the 31 survivors. Eight patients were excluded because of obvious inflammatory conditions. From the 23 remaining patients (mean age ± SD: 51.3 ± 13.9 years, 18 had a decrease in CRP after the water treatment system was changed. Overall, median CRP was lower with reverse osmosis than with deionization (13.2 vs 4.5 mg/l, P = 0.022, N = 23. There was no difference in albumin, cytokines, subjective global evaluation, or clinical and biochemical parameters. In conclusion, uremic patients presented a clinically significant reduction in CRP levels when dialysate water purification system switched from deionization to reverse osmosis. It is possible that better water treatments induce less inflammation and eventually less atherosclerosis in hemodialysis patients.

  1. Elevata espressione di hsp-60 di Chlamydophila pneumoniae su placche aterosclerotiche carotidee a prognosi infausta

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    Rosario Cultrera

    2007-06-01

    Full Text Available Some difficult microorganisms, including Chlamydophila pneumoniae, are associated with the atherosclerotic tissue damage.The aim of this study was to evaluate the employment of culture together molecular techniques in order to define the possible role of C. pneumoniae in the atherosclerotic tissue damage. Atheromatous carotid plaques (ACP were obtained by endoarterectomies from 10 patients with severe stenosis of the internal carotid artery. Each specimen was divided in three parts: a proximal tract to heart, without stenosis, a medial tract, corresponding to the atheromatous plaque, and a distal tract, above the plaque.Aliquots were employed to perform cultures for C. pneumoniae on Hep - 2 cell line in DMEM. DNA and total RNA were extracted from 50-70 mg. of tissue sample and from Hep - 2 106 cultures to investigate 16S rRNA, momp and hsp60 genes.The PCR and RT-PCR resulted negative for momp gene of C. pneumoniae in all samples. PCR and RT-PCR resulted positive for 16S rRNA or hsp60 genes of C. pneumoniae in the proximal portion of two ACPs with hemorrhagic evolution in two patients, one of which complicated with a retinal tromboembolic outcome. Molecular analyses on C. pneumoniae growing from the cultures are in progress.The DNA and RNA amplification of different portions from ACP seems to be useful to evidence the effective localization of C. pneumoniae in the atheromatous arterial tissue. The highly gene expression of C. pneumoniae hsp60 in a patient with acute hemorrhagic evolution of the carotid plaque may suggest that C. pneumoniae might partecipate in the atherogenesis and induce atherosclerosis complications by inflammatory pathways (activation of cytokines, endothelial factors and matrix-degrading metalloproteinases.

  2. Regulations of the key mediators in inflammation and atherosclerosis by Aspirin in human macrophages

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    Zhang Li

    2010-02-01

    Full Text Available Abstract Although its role to prevent secondary cardiovascular complications has been well established, how acetyl salicylic acid (ASA, aspirin regulates certain key molecules in the atherogenesis is still not known. Considering the role of matrix metalloproteinase-9 (MMP-9 to destabilize the atherosclerotic plaques, the roles of the scavenger receptor class BI (SR-BI and ATP-binding cassette transporter A1 (ABCA1 to promote cholesterol efflux in the foam cells at the plaques, and the role of NF-κB in the overall inflammation related to the atherosclerosis, we addressed whether these molecules are all related to a common mechanism that may be regulated by acetyl salicylic acid. We investigated the effect of ASA to regulate the expressions and activities of these molecules in THP-1 macrophages. Our results showed that ASA inhibited MMP-9 mRNA expression, and caused the decrease in the MMP-9 activities from the cell culture supernatants. In addition, it inhibited the nuclear translocation of NF-κB p65 subunit, thus the activity of this inflammatory molecule. On the contrary, acetyl salicylic acid induced the expressions of ABCA1 and SR-BI, two molecules known to reduce the progression of atherosclerosis, at both mRNA and protein levels. It also stimulated the cholesterol efflux out of macrophages. These data suggest that acetyl salicylic acid may alleviate symptoms of atherosclerosis by two potential mechanisms: maintaining the plaque stability via inhibiting activities of inflammatory molecules MMP-9 and NF-κB, and increasing the cholesterol efflux through inducing expressions of ABCA1 and SR-BI.

  3. Omega-3 fatty acids, inflammation and angiogenesis: basic mechanisms behind the cardioprotective effects of fish and fish oils.

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    Massaro, M; Scoditti, E; Carluccio, M A; Campana, M C; De Caterina, R

    2010-02-25

    Atherosclerosis is now widely accepted to be an inflammatory disease, characterized by degenerative as well as proliferative changes and extracellular accumulation of lipid and cholesterol, in which an ongoing inflammatory reaction plays an important role both in initiation and progression/destabilization, converting a chronic process into an acute disorder. Neovascularization has also been recognized as an important process for the progression/destabilization of atherosclerotic plaques. In fact, vulnerable atherosclerotic plaques prone to rupture are characterized by an enlarged necrotic core, containing an increased number of vasa vasorum, apoptotic macrophages, and more frequent intraplaque haemorrhage. Various functional roles have been assigned to intimal microvessels, however the relationship between the process of angiogenesis and its causal association with the progression and complications of atherosclerosis are still challenging and controversial. In the past 30 years, the dietary intake of omega-3 (n-3) polyunsaturated fatty acids--mainly derived from fish--has emerged as an important way to modify cardiovascular risk through beneficial effects on all stages of atherosclerosis, including plaque angiogenesis. This review specifically focuses on the modulating effects of n-3 fatty acids on molecular events involved in early and late atherogenesis, including effects on endothelial expression of adhesion molecules, as well as pro-inflammatory and pro-angiogenic enzymes. By accumulating in endothelial membrane phospholipids, omega-3 fatty acids have been shown to decrease the transcriptional activation of several genes through an attenuation of activation of the nuclear factor-kappaB system of transcription factors. This occurs secondary to decreased generation of intracellular reactive oxygen species. This series of investigations configures a clear example of nutrigenomics--i.e., how nutrients may affect gene expression, ultimately affecting a wide spectrum

  4. Prevention of Atherosclerosis Progression by 9-cis-β-Carotene Rich Alga Dunaliella in apoE-Deficient Mice

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    Ayelet Harari

    2013-01-01

    Full Text Available Introduction. β-Carotene-rich diet has been shown to be inversely associated with the risk of coronary heart disease. However, clinical trials using synthetic all-trans-β-carotene failed to demonstrate a beneficial effect. We therefore sought to study the effect of natural source of β-carotene, the alga Dunaliella, containing both all-trans and 9-cis-β-carotene on atherosclerosis. In a previous study we showed that 9-cis-β-carotene-rich powder of the alga Dunaliella inhibits early atherogenesis in low-density lipoprotein receptor knockout mice. Aims. The aims of the current work were to study whether diet enriched with Dunaliella powder would inhibit the progression of established atherosclerosis in old male apoE-deficient mice and to compare the effect of Dunaliella on lipid profile and atherosclerosis in a low-versus high-fat diet fed mice. Methods. In the first experiment, young mice (12 weeks old were allocated into 3 groups: (1 low-fat diet; (2 low-fat diet + Dunaliella powder (8%; (3 low-fat diet + β-carotene-deficient Dunaliella. In the second experiment, old mice (7 months old with established atherosclerotic lesions were allocated into 4 groups: (1 low-fat diet; (2 low-fat diet + Dunaliella; (3 high fat-diet; (4 high-fat diet + Dunaliella. Results. In young mice fed a low-fat diet, a trend toward lower atherosclerotic lesion area in the aortic sinus was found in the Dunaliella group compared with the control group. In old mice with established atherosclerotic lesion, Dunaliella inhibited significantly plasma cholesterol elevation and atherosclerosis progression in mice fed a high-fat diet. Conclusion. The results of this study suggest that a diet containing natural carotenoids, rich in 9-cis-β-carotene, has the potential to inhibit atherosclerosis progression, particularly in high-fat diet regime.

  5. 9-cis β-Carotene Increased Cholesterol Efflux to HDL in Macrophages

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    Sapir Bechor

    2016-07-01

    Full Text Available Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-β-carotene (9-cis-βc is a precursor for 9-cis-retinoic-acid (9-cis-RA, which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-βc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with βc from the alga Dunaliella led to βc accumulation in peritoneal macrophages. 9-cis-βc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from βc in RAW264.7 macrophages. Furthermore, 9-cis-βc, as well as all-trans-βc, significantly increased cholesterol efflux to high-density lipoprotein (HDL by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-βc augmented cholesterol efflux from macrophages ex vivo. 9-cis-βc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-βc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of βc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.

  6. The inhibition of macrophage foam cell formation by 9-cis β-carotene is driven by BCMO1 activity.

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    Noa Zolberg Relevy

    Full Text Available Atherosclerosis is a major cause of morbidity and mortality in developed societies, and begins when activated endothelial cells recruit monocytes and T-cells from the bloodstream into the arterial wall. Macrophages that accumulate cholesterol and other fatty materials are transformed into foam cells. Several epidemiological studies have demonstrated that a diet rich in carotenoids is associated with a reduced risk of heart disease; while previous work in our laboratory has shown that the 9-cis β-carotene rich alga Dunaliella inhibits atherogenesis in mice. The effect of 9-cis β-carotene on macrophage foam cell formation has not yet been investigated. In the present work, we sought to study whether the 9-cis β-carotene isomer, isolated from the alga Dunaliella, can inhibit macrophage foam cell formation upon its conversion to retinoids. The 9-cis β-carotene and Dunaliella lipid extract inhibited foam cell formation in the RAW264.7 cell line, similar to 9-cis retinoic acid. Furthermore, dietary enrichment with the algal powder in mice resulted in carotenoid accumulation in the peritoneal macrophages and in the inhibition of foam cell formation ex-vivo and in-vivo. We also found that the β-carotene cleavage enzyme β-carotene 15,15'-monooxygenase (BCMO1 is expressed and active in macrophages. Finally, 9-cis β-carotene, as well as the Dunaliella extract, activated the nuclear receptor RXR in hepa1-6 cells. These results indicate that dietary carotenoids, such as 9-cis β-carotene, accumulate in macrophages and can be locally cleaved by endogenous BCMO1 to form 9-cis retinoic acid and other retinoids. Subsequently, these retinoids activate the nuclear receptor RXR that, along with additional nuclear receptors, can affect various metabolic pathways, including those involved in foam cell formation and atherosclerosis.

  7. 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.

  8. Controlled type II diabetes mellitus has no major influence on platelet micro-RNA expression. Results from micro-array profiling in a cohort of 60 patients.

    Science.gov (United States)

    Stratz, Christian; Nührenberg, Thomas; Fiebich, Bernd L; Amann, Michael; Kumar, Asit; Binder, Harald; Hoffmann, Isabell; Valina, Christian; Hochholzer, Willibald; Trenk, Dietmar; Neumann, Franz-Josef

    2014-05-05

    Diabetes mellitus as a major contributor to cardiovascular disease burden induces dysfunctional platelets. Platelets contain abundant miRNAs, which are linked to inflammatory responses and, thus, may play a role in atherogenesis. While diabetes mellitus affects plasma miRNAs, no data exist on platelet miRNA profiles in this disease. Therefore, this study sought to explore the miRNA profile of platelets in patients with diabetes mellitus that is unrelated to the presence or absence of coronary artery disease (CAD). Platelet miRNA profiles were assessed in stable diabetic and non-diabetic patients (each n=30); 15 patients in each group had CAD. Platelet miRNA was isolated from leucocyte-depleted platelet-rich plasma, and miRNA profiling was performed using LNA micro-array technology (miRBase18.0, containing 1,917 human miRNAs). Effects of diabetes mellitus were explored by univariate statistical tests for each miRNA, adjusted for potential confounders, and by developing a multivariable signature; evaluated by resampling techniques. Platelets in non-diabetic patients demonstrated miRNA expression profiles comparable to previous data. The miRNA profiles of platelets in diabetics were similar. Statistical analysis unveiled three miRNAs (miR-377-5p, miR-628-3p, miR-3137) with high reselection probabilities in resampling techniques, corresponding to signatures with modest discriminatory performance. Functional annotation of predicted targets for these miRNAs pointed towards an influence of diabetes mellitus on mRNA processing. We did not find major differences in platelet miRNA profiles between diabetics and non-diabetics. Minor differences pertained to miRNAs associated with mRNA processing. Thus, described differences in plasma miRNAs between diabetic and non-diabetic patients cannot be explained by plain changes in platelet miRNA profile.

  9. TLR/MyD88 and liver X receptor alpha signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis.

    Science.gov (United States)

    Naiki, Yoshikazu; Sorrentino, Rosalinda; Wong, Michelle H; Michelsen, Kathrin S; Shimada, Kenichi; Chen, Shuang; Yilmaz, Atilla; Slepenkin, Anatoly; Schröder, Nicolas W J; Crother, Timothy R; Bulut, Yonca; Doherty, Terence M; Bradley, Michelle; Shaposhnik, Zory; Peterson, Ellena M; Tontonoz, Peter; Shah, Prediman K; Arditi, Moshe

    2008-11-15

    Experimental and clinical studies link Chlamydia pneumoniae infection to atherogenesis and atherothrombotic events, but the underlying mechanisms are unclear. We tested the hypothesis that C. pneumoniae-induced acceleration of atherosclerosis in apolipoprotein E (ApoE)(-/-) mice is reciprocally modulated by activation of TLR-mediated innate immune and liver X receptor alpha (LXRalpha) signaling pathways. We infected ApoE(-/-) mice and ApoE(-/-) mice that also lacked TLR2, TLR4, MyD88, or LXRalpha intranasally with C. pneumoniae followed by feeding of a high fat diet for 4 mo. Mock-infected littermates served as controls. Atherosclerosis was assessed in aortic sinuses and in en face preparation of whole aorta. The numbers of activated dendritic cells (DCs) within plaques and the serum levels of cholesterol and proinflammatory cytokines were also measured. C. pneumoniae infection markedly accelerated atherosclerosis in ApoE-deficient mice that was associated with increased numbers of activated DCs in aortic sinus plaques and higher circulating levels of MCP-1, IL-12p40, IL-6, and TNF-alpha. In contrast, C. pneumoniae infection had only a minimal effect on atherosclerosis, accumulation of activated DCs in the sinus plaques, or circulating cytokine increases in ApoE(-/-) mice that were also deficient in TLR2, TLR4, or MyD88. However, C. pneumoniae-induced acceleration of atherosclerosis in ApoE(-/-) mice was further enhanced in ApoE(-/-)LXRalpha(-/-) double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-alpha. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRalpha appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection.

  10. IL-17A is proatherogenic in high-fat diet-induced and Chlamydia pneumoniae infection-accelerated atherosclerosis in mice.

    Science.gov (United States)

    Chen, Shuang; Shimada, Kenichi; Zhang, Wenxuan; Huang, Ganghua; Crother, Timothy R; Arditi, Moshe

    2010-11-01

    The role of IL-17 in atherogenesis remains controversial. We previously reported that the TLR/MyD88 signaling pathway plays an important role in high-fat diet as well as Chlamydophila pneumoniae infection-mediated acceleration of atherosclerosis in apolipoprotein E-deficient mice. In this study, we investigated the role of the IL-17A in high-fat diet (HFD)- and C. pneumoniae-induced acceleration of atherosclerosis. The aortic sinus plaque and aortic lesion size and lipid composition as well as macrophage accumulation in the lesions were significantly diminished in IL-17A(-/-) mice fed an HFD compared with wild-type (WT) C57BL/6 control mice. As expected, C. pneumoniae infection led to a significant increase in size and lipid content of the atherosclerotic lesions in WT mice. However, IL-17A(-/-) mice developed significantly less acceleration of lesion size following C. pneumoniae infection compared with WT control despite similar levels of blood cholesterol levels. Furthermore, C. pneumoniae infection in WT but not in IL-17A(-/-) mice was associated with significant increases in serum concentrations of IL-12p40, CCL2, IFN-γ, and numbers of macrophages in their plaques. Additionally, in vitro studies suggest that IL-17A activates vascular endothelial cells, which secrete cytokines that in turn enhance foam cell formation in macrophages. Taken together, our data suggest that IL-17A is proatherogenic and that it plays an important role in both diet-induced atherosclerotic lesion development, and C. pneumoniae infection-mediated acceleration of atherosclerotic lesions in the presence of HFD.

  11. Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and -independent signaling and is reciprocally modulated by liver X receptor activation.

    Science.gov (United States)

    Chen, Shuang; Sorrentino, Rosalinda; Shimada, Kenichi; Bulut, Yonca; Doherty, Terence M; Crother, Timothy R; Arditi, Moshe

    2008-11-15

    Chlamydia pneumoniae is detected by macrophages and other APCs via TLRs and can exacerbate developing atherosclerotic lesions, but how that occurs is not known. Liver X receptors (LXRs) centrally control reverse cholesterol transport, but also negatively modulate TLR-mediated inflammatory pathways. We isolated peritoneal macrophages from wild-type, TLR2, TLR3, TLR4, TLR2/4, MyD88, TRIF, MyD88/TRIF, and IFN regulatory factor 3 (IRF3) KO mice, treated them with live or UV-killed C. pneumoniae in the presence or absence of oxidized LDL, then measured foam cell formation. In some experiments, the synthetic LXR agonist GW3965 was added to macrophages infected with C. pneumoniae in the presence of oxidized LDL. Both live and UV-killed C. pneumoniae induced IRF3 activation and promoted foam cell formation in wild-type macrophages, whereas the genetic absence of TLR2, TLR4, MyD88, TRIF, or IRF3, but not TLR3, significantly reduced foam cell formation. C. pneumoniae-induced foam cell formation was significantly reduced by the LXR agonist GW3965, which in turn inhibited C. pneumoniae-induced IRF3 activation, suggesting a bidirectional cross-talk. We conclude that C. pneumoniae facilitates foam cell formation via activation of both MyD88-dependent and MyD88-independent (i.e., TRIF-dependent and IRF3-dependent) pathways downstream of TLR2 and TLR4 signaling and that TLR3 is not involved in this process. This mechanism could at least partly explain why infection with C. pneumoniae accelerates the development of atherosclerotic plaque and lends support to the proposal that LXR agonists might prove clinically useful in suppressing atherogenesis.

  12. Variations in mass transfer to single endothelial cells.

    Science.gov (United States)

    Van Doormaal, Mark A; Zhang, Ji; Wada, Shigeo; Shaw, James E; Won, Doyon; Cybulsky, Myron I; Yip, Chris M; Ethier, C Ross

    2009-06-01

    Mass transfer between flowing blood and arterial mural cells (including vascular endothelial cells) may play an important role in atherogenesis. Endothelial cells are known to have an apical surface topography that is not flat, and hence mass transfer patterns to individual endothelial cells are likely affected by the local cellular topography. The purpose of this paper is to investigate the relationship between vascular endothelial cell surface topography and cellular level mass transfer. Confluent porcine endothelial monolayers were cultured under both shear and static conditions and atomic force microscopy was used to measure endothelial cell topography. Using finite element methods and the measured cell topography, flow and concentration fields were calculated for a typical, small, blood-borne solute. A relative Sherwood number was defined as the difference between the computed Sherwood number and that predicted by the Leveque solution for mass transfer over a flat surface: this eliminates the effects of axial location on mass transfer efficiency. The average intracellular relative Sherwood number range was found to be dependent on cell height and not dependent on cell elongation due to shear stress in culture. The mass flux to individual cells reached a maximum at the highest point on the endothelial cell surface, typically corresponding to the nucleus of the cell. Therefore, for small receptor-mediated solutes, increased solute uptake efficiency can be achieved by concentrating receptors near the nucleus. The main conclusion of the work is that although the rate of mass transfer varies greatly over an individual cell, the average mass transfer rate to a cell is close to that predicted for a flat cell. In comparison to other hemodynamic factors, the topography of endothelial cells therefore seems to have little effect on mass transfer rates and is likely physiologically insignificant.

  13. Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists.

    Directory of Open Access Journals (Sweden)

    Michael Gurven

    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

  14. Unique cellular events occurring during the initial interaction of macrophages with matrix-retained or methylated aggregated low density lipoprotein (LDL). Prolonged cell-surface contact during which ldl-cholesteryl ester hydrolysis exceeds ldl protein degradation.

    Science.gov (United States)

    Buton, X; Mamdouh, Z; Ghosh, R; Du, H; Kuriakose, G; Beatini, N; Grabowski, G A; Maxfield, F R; Tabas, I

    1999-11-05

    A critical event in atherogenesis is the interaction of arterial wall macrophages with subendothelial lipoproteins. Although most studies have investigated this interaction by incubating cultured macrophages with monomeric lipoproteins dissolved in media, arterial wall macrophages encounter lipoproteins that are mostly bound to subendothelial extracellular matrix, and these lipoproteins are often aggregated or fused. Herein, we utilize a specialized cell-culture system to study the initial interaction of macrophages with aggregated low density lipoprotein (LDL) bound to extracellular matrix. The aggregated LDL remains extracellular for a relatively prolonged period of time and becomes lodged in invaginations in the surface of the macrophages. As expected, the degradation of the protein moiety of the LDL was very slow. Remarkably, however, hydrolysis of the cholesteryl ester (CE) moiety of the LDL was 3-7-fold higher than that of the protein moiety, in stark contrast to the situation with receptor-mediated endocytosis of acetyl-LDL. Similar results were obtained using another experimental system in which the degradation of aggregated LDL protein was delayed by LDL methylation rather than by retention on matrix. Additional experiments indicated the following properties of this interaction: (a) LDL-CE hydrolysis is catalyzed by lysosomal acid lipase; (b) neither scavenger receptors nor the LDL receptor appear necessary for the excess LDL-CE hydrolysis; and (c) LDL-CE hydrolysis in this system is resistant to cellular potassium depletion, which further distinguishes this process from receptor-mediated endocytosis. In summary, experimental systems specifically designed to mimic the in vivo interaction of arterial wall macrophages with subendothelial lipoproteins have demonstrated an initial period of prolonged cell-surface contact in which CE hydrolysis exceeds protein degradation.

  15. 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.

  16. Differential effects of statins on endogenous H2S formation in perivascular adipose tissue.

    Science.gov (United States)

    Wójcicka, Grażyna; Jamroz-Wiśniewska, Anna; Atanasova, Pepa; Chaldakov, George N; Chylińska-Kula, Beata; Bełtowski, Jerzy

    2011-01-01

    Hydrogen sulfide (H(2)S) is a new gasotransmitter synthesized enzymatically from l-cysteine in cytosol and is oxidized in mitochondria. In the cardiovascular system, H(2)S regulates vascular tone, inhibits atherogenesis, and protects against myocardial ischemia-reperfusion injury. We examined the effect of statins on vascular H(2)S production. Male Wistar rats received pravastatin (40mg/kg/day) or atorvastatin (20mg/kg/day) for 3 weeks and then H(2)S formation was measured in aortic media, periaortic adipose tissue (PAAT) and the liver. Only atorvastatin increased H(2)S production in PAAT whereas both statins stimulated its formation in the liver. Neither statin affected H(2)S production in aortic media. H(2)S formation in post-mitochondrial supernatant was higher than in mitochondria-containing supernatant and was not influenced by statins in any tissue. In addition, oxidation of exogenous H(2)S in isolated liver mitochondria was slower in statin-treated than in control rats. These data indicate that statins increase net H(2)S production by inhibiting its mitochondrial oxidation. Statins had no effect on the activity of H(2)S-metabolizing enzyme, sulfide:quinone oxidoreductase, measured at saturating coenzyme Q concentration. Both statins reduced CoQ(9) concentration in plasma and liver, but only atorvastatin decreased CoQ(9) in PAAT. Atorvastatin attenuated phenylephrine-induced contraction of PAAT+ but not of PAAT- aortic rings. Effects of atorvastatin on net H(2)S production, mitochondrial H(2)S oxidation and aortic contractility were abolished by supplementation of exogenous CoQ(9). In conclusion, lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H(2)S production in perivascular adipose tissue by inhibiting its mitochondrial oxidation. This effect is mediated by statin-induced CoQ(9) deficiency and results in the augmentation of anticontractile effect of perivascular adipose tissue.

  17. Mechanisms of endothelium and internal organs dysfunction associated with exposure to cobalt chloride (experimental study

    Directory of Open Access Journals (Sweden)

    L.V. Gigolaeva

    2016-09-01

    Full Text Available Cobalt administration in the human body is a risk factor for developing pulmonary and cardiovascular health problems. In this paper we report the results of functional studies and biochemical mechanisms of endothelial dysfunction and pathology of internal organs in cobalt intoxication in experiment. System-organ nature of the activation of oxidative processes is identified according to the increase of MDA secondary product in erythrocytes and homogenates of internal organs as well as the participation of AOC imbalance in the development of lipid peroxidation, the peculiarities of the violations of NO release endothelial function and participation in this process of L-arginine and an analogue of endogenous inhibitor of expression eNOS -L–NC - arginine methyl ester (L-NAME or L-nitro-arginine-methilester with cobalt intoxication in conditions of activation of oxidative processes. Chronic cobalt intoxication in rats leads to the activation of oxidative processes, thus there is inhibition of superoxide dismutase activity and the concentration of catalase and ceruloplasmin increased. Cholesterol metabolism is disturbed, as well as impaired nitric oxide production and its bioavailability, which is accompanied by the change of the microcirculatory hemodynamics of the visceral organs. The evaluation of the internal organs’ functional state according to the activity of the Na+,K+-ATPase in homogenates is performed, as well as due to the activity of organ-specific and excretory enzymes in blood serum on the background of cobalt toxicity. The role of changes of cholesterol metabolism is established – as a risk factor of atherogenesis in violation of the bioavailability of nitric oxide. For the pathogenetic correction of violations we applied the method using the endogenous antioxidant coenzyme Q10 and regulators of the expression eNOS L-arginine, L-NAME and their combination with coenzyme Q10.

  18. A novel in vitro model for the study of plaque development in atherosclerosis.

    Science.gov (United States)

    Dorweiler, Bernhard; Torzewski, Michael; Dahm, Manfred; Ochsenhirt, Viola; Lehr, Hans-Anton; Lackner, Karl J; Vahl, Christian-Friedrich

    2006-01-01

    For the study of atherogenesis in vitro, coculture systems have been devised, in which two or more cell types can be cultured in close contact to each other. Herein, we describe a novel in vitro model that aims at the simulation of the morphology of a normal muscular artery allowing for the study of the initial events in atherosclerosis. Using a modified fibrin gel as a scaffold for the coculture of endothelial cells (ECs) and smooth muscle cells (SMCs), we generated an autologous in vitro model with a multilayer growth of SMCs (intima-like structure) covered by an endothelium. The production of extracellular matrix (ECM) could be visualized histologically and verified by (i) ascorbic-acid dependent secretion of procollagen I into the supernatant and (ii) deposition of collagens I and III as well as laminin in the gel as assessed by immunohistochemistry. By BrdU-incorporation and Ki67 expression, the SMCs exhibited minimal proliferative activity, even when the culture period was extended to 6 weeks. Lipoprotein insudation was investigated under simulated hypo-, normo- and hypercholesterolemic conditions through addition of 0.5, 1 or 2 mg/mL LDL to the medium with subsequent time and dose dependent insudation of LDL. When human monocytes were added to the culture medium, infiltration and foam cell formation of macrophages and SMCs as well as expression of interleukin-8 (IL-8) was demonstrated. The in vitro model of the human vascular wall described herein appears to be suitable for the study of pivotal events in atherosclerotic plaque development. The applicability for long-term culture, the ability to study cell-matrix interactions and the opportunities for histomorphological and immunohistochemical examinations represent additional advantages of this model.

  19. Induction of cell-rich and lipid-rich plaques in a transfilter coculture system with human vascular cells.

    Science.gov (United States)

    Axel, D I; Brehm, B R; Wolburg-Buchholz, K; Betz, E L; Köveker, G; Karsch, K R

    1996-01-01

    Cell-to-cell interactions are mainly involved in the control of the proliferation, migration, differentiation and function of different cell types in a wide range of tissues. In the arterial vessel wall, human arterial endothelial cells (haEC) and smooth muscle cells (haSMC) coexist in close contact with each other. In atherogenesis, haSMC can migrate from the media to the subintimal space to form fibromuscular and atheromatous plaques. In the present study, a transfilter coculture system is described, in which the interface between haSMC and confluent or proliferative haEC can be studied in detail. Cells were cocultured on the opposite sides of a porous filter which separates both cell types like the internal elastic lamina in vivo. In cocultures containing proliferative haEC, haSMC growth was significantly stimulated (33.4 +/- 5.7 cells/section, p cocultures containing confluent haEC (15.6 +/- 2.9 cells/section). If confluent haEC were injured mechanically, haSMC growth increased highly significantly (71.3 +/- 16.8 cells/section, p monocytes to cocultures with arterial media explants and haEC resulted in the formation of lipid-rich, low-cellular structures. After 28 days, characteristic in vitro plaque growth was induced; the plaque contained a lipid core with predominantly necrotic cells, extracellular lipid accumulations, atypically shaped lipid-loaded haSMC and macrophages, similar to in vivo foam cells, as well as an increased amount of extracellular matrix (collagen I, III and IV). These areas were surrounded by typical fibromuscular caps consisting of smooth muscle alpha-actin-positive haSMC. Finally, the formation of capillaries by haEC could also be observed within these structures.

  20. Correlation between serum adiponectin and clinical characteristics, biochemical parameters in Indian women with polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Sunita J Ramanand

    2014-01-01

    Full Text Available Background: Polycystic ovary syndrome (PCOS is a common disorder. PCOS women are at a high risk for insulin resistance and metabolic syndrome (MS. Adiponectin is positively related to insulin sensitivity. It has a preventive role in atherogenesis and MS. The present work was conducted to study the correlation between serum adiponectin levels and clinical characteristics and biochemical parameters in PCOS patients. Materials and Methods: A prospective study in 49 newly diagnosed (as per Rotterdam criteria Indian PCOS women was conducted. PCOS women were clinically examined and investigated for biochemical parameters. Results : The mean serum adiponectin was 12 ± 9.4 μg/mL (range 0.47-45. Hypoadiponectinemia (serum adiponectin <4 μg/mL was present in 22% patients. Age and adiponectin correlated significantly and inversely (r = −0.42, P = 0.027. Overweight/obese patients had lower mean adiponectin levels than normal weight (11.62 ± 9.5 vs 13.58 ± 9.5, P = 0.56. It was significantly lower in patients with acanthosis nigricans (AN as compared with those without AN (8.4 ± 5.9 vs 15 ± 11, P = 0.038. Hirsute patients showed lower mean adiponectin levels than nonhirsute (10 ± 7.3 vs 13 ± 10, P = 0.57. A positive, insignificant correlation was observed between serum adiponectin and cholesterol, low-density lipoprotein, follicle stimulating hormone (FSH, thyroid stimulating hormone, levels. A negative insignificant correlation existed between serum adiponectin and luteinizing hormone (LH, LH: FSH ratio, prolactin, dehydroepiandrosterone, testosterone, triglyceride, high-density lipoprotein, fasting blood glucose, fasting insulin, and Homeostasis Model Assessment. Conclusion: Hypoadiponectinemia is present in one-fifth of women with PCOS. Adiponectin levels decrease as age advances. Low levels of adiponectin possibly contributes to the development of dermal manifestation (AN of insulin resistance.

  1. Vitamin E and cardiovascular disease.

    Science.gov (United States)

    Saremi, Adonis; Arora, Rohit

    2010-01-01

    The objective of this article is to review the role of vitamin E in cardiovascular disease. We begin by describing the general characteristics and metabolism of vitamin E and the pathogenesis of atherosclerosis as it relates to oxidation. We also discuss key in vitro studies, animal studies, observational studies, and clinical trials regarding the potentially cardioprotective effect of vitamin E. Lastly, we outline the current recommendations regarding vitamin E in the prevention and treatment of cardiovascular disease as stated by the American Heart Association. Vitamin E is a fat-soluble antioxidant vitamin and alpha-tocopherol is its most naturally abundant and active form. Oxidation is a key step in atherogenesis. Oxidized low-density lipoprotein stimulates endothelial cells to produce inflammatory markers, is involved in foam cell formation, has cytotoxic effects on endothelial cells, inhibits the motility of tissue macrophages, and inhibits nitric oxide-induced vasodilatation. Vitamin E has been shown to increase oxidative resistance in vitro and prevent atherosclerotic plaque formation in mouse models. Consumption of foods rich in vitamin E has been associated with lower risk of coronary heart disease in middle-aged to older men and women. Clinical studies at large have not demonstrated a benefit of vitamin E in the primary and secondary prevention of cardiovascular disease. Vitamin E supplementation might be associated with an increase in total mortality, heart failure, and hemorrhagic stroke. The American Heart Association does not support the use of vitamin E supplements to prevent cardiovascular disease, but does recommend the consumption of foods abundant in antioxidant vitamins and other nutrients.

  2. Cacao polyphenols influence the regulation of apolipoprotein in HepG2 and Caco2 cells.

    Science.gov (United States)

    Yasuda, Akiko; Natsume, Midori; Osakabe, Naomi; Kawahata, Keiko; Koga, Jinichiro

    2011-02-23

    Cocoa powder is rich in polyphenols, such as catechins and procyanidins, and has been shown to inhibit low-density lipoprotein (LDL) oxidation and atherogenesis in a variety of models. Human studies have also shown daily intake of cocoa increases plasma high-density lipoprotein (HDL) and decreases LDL levels. However, the mechanisms responsible for these effects of cocoa on cholesterol metabolism have yet to be fully elucidated. The present study investigated the effects of cacao polyphenols on the production of apolipoproteins A1 and B in human hepatoma HepG2 and intestinal Caco2 cell lines. The cultured HepG2 cells or Caco2 cells were incubated for 24 h in the presence of cacao polyphenols such as (-)-epicatechin, (+)-catechin, procyanidin B2, procyanidin C1, and cinnamtannin A2. The concentration of apolipoproteins in the cell culture media was quantified using an enzyme-linked immunoassay, and the mRNA expression was quantified by RT-PCR. Cacao polyphenols increased apolipoprotein A1 protein levels and mRNA expression, even though apolipoprotein B protein and the mRNA expression were slightly decreased in both HepG2 cells and Caco2 cells. In addition, cacao polyphenols increased sterol regulatory element binding proteins (SREBPs) and activated LDL receptors in HepG2 cells. These results suggest that cacao polyphenols may increase the production of mature form SREBPs and LDL receptor activity, thereby increasing ApoA1 and decreasing ApoB levels. These results elucidate a novel mechanism by which HDL cholesterol levels become elevated with daily cocoa intake.

  3. Antioxidant activity of tea polyphenols in vivo: evidence from animal studies.

    Science.gov (United States)

    Frei, Balz; Higdon, Jane V

    2003-10-01

    Tea is particularly rich in polyphenols, including catechins, theaflavins and thearubigins, which are thought to contribute to the health benefits of tea. Tea polyphenols act as antioxidants in vitro by scavenging reactive oxygen and nitrogen species and chelating redox-active transition metal ions. They may also function indirectly as antioxidants through 1) inhibition of the redox-sensitive transcription factors, nuclear factor-kappaB and activator protein-1; 2) inhibition of "pro-oxidant" enzymes, such as inducible nitric oxide synthase, lipoxygenases, cyclooxygenases and xanthine oxidase; and 3) induction of phase II and antioxidant enzymes, such as glutathione S-transferases and superoxide dismutases. The fact that catechins are rapidly and extensively metabolized emphasizes the importance of demonstrating their antioxidant activity in vivo. Animal studies offer a unique opportunity to assess the contribution of the antioxidant properties of tea and tea polyphenols to the physiological effects of tea administration in different models of oxidative stress. Most promising are the consistent findings in animal models of skin, lung, colon, liver and pancreatic cancer that tea and tea polyphenol administration inhibit carcinogen-induced increases in the oxidized DNA base, 8-hydroxy-2'-deoxyguanosine. In animal models of atherosclerosis, green and black tea administration has resulted in modest improvements in the resistance of lipoproteins to ex vivo oxidation, although limited data suggest that green tea or green tea catechins inhibit atherogenesis. To determine whether tea polyphenols act as effective antioxidants in vivo, future studies in animals and humans should employ sensitive and specific biomarkers of oxidative damage to lipids, proteins and DNA.

  4. Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages.

    Science.gov (United States)

    Ayaori, Makoto; Yakushiji, Emi; Ogura, Masatsune; Nakaya, Kazuhiro; Hisada, Tetsuya; Uto-Kondo, Harumi; Takiguchi, Shunichi; Terao, Yoshio; Sasaki, Makoto; Komatsu, Tomohiro; Iizuka, Maki; Yogo, Makiko; Uehara, Yoshinari; Kagechika, Hiroyuki; Nakanishi, Tsuyoshi; Ikewaki, Katsunori

    2012-04-01

    ABC transporter G1 (ABCG1) plays a pivotal role in HDL-mediated cholesterol efflux and atherogenesis. We investigated whether, and how, retinoic acid receptors (RARs) regulate ABCG1 expression in macrophages. All-trans retinoic acid (ATRA), an RAR ligand, increased ABCG1 protein levels and apoA-I/HDL-mediated cholesterol efflux from the macrophages. Both ATRA and other RAR agonists, TTNPB and Am580, increased major transcripts driven by promoter B upstream of exon 5, though minor transcripts driven by promoter A upstream of exon 1 were only increased by ATRA. The stimulatory effects of ATRA on ABCG1 expression were completely abolished in the presence of RAR/RXR antagonists but were only partially canceled in the presence of an LXR antagonist. Adenovirus with overexpressed oxysterol sulfotransferase abolished the LXR pathway, as previously reported, and ATRA-responsiveness in ABCA1/ABCG1 expressions were respectively attenuated by 38 and 22% compared to the control virus. Promoter assays revealed that ABCG1 levels were regulated more by promoter B than promoter A, and ATRA activated promoter B in a liver X receptor-responsive element (LXRE)-dependent manner. Further, LXRE-B in intron 7, but not LXRE-A in intron 5, enhanced ATRA responsiveness under overexpression of all RAR isoforms-RARα/β/γ. In contrast, the activation of promoter B by TTNPB depended on LXRE-B and RARα, but not on RARβ/γ. Finally, chromatin immunoprecipitation and gel-shift assays revealed a specific and direct repeat 4-dependent binding of RARα to LXRE-B. In conclusion, RAR ligands increase ABCA1/G1 expression and apoA-I/HDL-mediated cholesterol efflux from macrophages, and modulate ABCG1 promoter activity via LXRE-dependent mechanisms.

  5. An experimental evaluation of the anti-atherogenic potential of the plant, Piper betle, and its active constitutent, eugenol, in rats fed an atherogenic diet.

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    Venkadeswaran, Karuppasamy; Thomas, Philip A; Geraldine, Pitchairaj

    2016-05-01

    Hypercholesterolemia is a major risk factor for systemic atherosclerosis and subsequent cardiovascular disease. Lipoperoxidation-mediated oxidative damage is believed to contribute strongly to the progression of atherogenesis. In the current investigation, putative anti-atherogenic and antioxidative properties of an ethanolic extract of Piper betle and of its active constituent, eugenol, were sought in an experimental animal model of chronic hypercholesterolemia. Atherogenic diet-fed rats that received either Piper betle extract orally (500mg/kg b.wt) or eugenol orally (5mg/kg b.wt) for 15days (commencing 30days after the atherogenic diet had been started) exhibited the following variations in different parameters, when compared to atherogenic diet-fed rats that received only saline: (1) significantly lower mean levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and very low density lipoprotein cholesterol in both serum and hepatic tissue samples; (2) lower mean serum levels of aspartate amino-transferase, alanine amino-transferase, alkaline phosphatase, lactate dehydrogenase and lipid-metabolizing enzymes (lipoprotein lipase, 3-hydroxy-3-methyl-glutaryl-CoA reductase; (3) significantly lower mean levels of enzymatic antioxidants (catalase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase) and non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) and significantly higher mean levels of malondialdehyde in haemolysate and hepatic tissue samples. Histopathological findings suggested a protective effect of the Piper betle extract and a more pronounced protective effect of eugenol on the hepatic and aortic tissues of atherogenic diet-fed (presumed atherosclerotic) rats. These results strongly suggest that the Piper betle extract and its active constituent, eugenol, exhibit anti-atherogenic effects which may be due to their anti-oxidative properties.

  6. Cocaine-induced renal infarction: report of a case and review of the literature

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    Nosrati Saeid M

    2005-09-01

    Full Text Available Abstract Background Cocaine abuse has been known to have detrimental effects on the cardiovascular system. Its toxicity has been associated with myocardial ischemia, cerebrovascular accidents and mesenteric ischemia. The pathophysiology of cocaine-related renal injury is multifactorial and involves renal hemodynamic changes, alterations in glomerular matrix synthesis, degradation and oxidative stress, and possibly induction of renal atherogenesis. Renal infarction as a result of cocaine exposure, however, is rarely reported in the literature. Case presentation A 48 year-old male presented with a four-day history of severe right flank pain following cocaine use. On presentation, he was tachycardic, febrile and had severe right costovertebral angle tenderness. He had significant proteinuria, leukocytosis and elevated serum creatinine and lactate dehydrogenase. Radiographic imaging studies as well as other screening tests for thromboembolic events, hypercoagulability states, collagen vascular diseases and lipid disorders were suggestive of Cocaine-Induced Renal Infarction (CIRI by exclusion. Conclusion In a patient with a history of cocaine abuse presenting with fevers and flank pain suggestive of urinary tract infection or nephrolithiasis, cocaine-induced renal infarction must be considered in the differential diagnosis. In this article, we discuss the prior reported cases of CIRI and thoroughly review the literature available on this disorder. This is important for several reasons. First, it will allow us to discuss and elaborate on the mechanism of renal injury caused by cocaine. In addition, this review will demonstrate the importance of considering the diagnosis of CIRI in a patient with documented cocaine use and an atypical presentation of acute renal injury. Finally, we will emphasize the need for a consensus on optimal treatment of this disease, for which therapy is not yet standardized.

  7. Line-scanning particle image velocimetry: an optical approach for quantifying a wide range of blood flow speeds in live animals.

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    Tyson N Kim

    Full Text Available BACKGROUND: The ability to measure blood velocities is critical for studying vascular development, physiology, and pathology. A key challenge is to quantify a wide range of blood velocities in vessels deep within living specimens with concurrent diffraction-limited resolution imaging of vascular cells. Two-photon laser scanning microscopy (TPLSM has shown tremendous promise in analyzing blood velocities hundreds of micrometers deep in animals with cellular resolution. However, current analysis of TPLSM-based data is limited to the lower range of blood velocities and is not adequate to study faster velocities in many normal or disease conditions. METHODOLOGY/PRINCIPAL FINDINGS: We developed line-scanning particle image velocimetry (LS-PIV, which used TPLSM data to quantify peak blood velocities up to 84 mm/s in live mice harboring brain arteriovenous malformation, a disease characterized by high flow. With this method, we were able to accurately detect the elevated blood velocities and exaggerated pulsatility along the abnormal vascular network in these animals. LS-PIV robustly analyzed noisy data from vessels as deep as 850 µm below the brain surface. In addition to analyzing in vivo data, we validated the accuracy of LS-PIV up to 800 mm/s using simulations with known velocity and noise parameters. CONCLUSIONS/SIGNIFICANCE: To our knowledge, these blood velocity measurements are the fastest recorded with TPLSM. Partnered with transgenic mice carrying cell-specific fluorescent reporters, LS-PIV will also enable the direct in vivo correlation of cellular, biochemical, and hemodynamic parameters in high flow vascular development and diseases such as atherogenesis, arteriogenesis, and vascular anomalies.

  8. Serum Amyloid A Receptor Blockade and Incorporation into High-Density Lipoprotein Modulates Its Pro-Inflammatory and Pro-Thrombotic Activities on Vascular Endothelial Cells

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    Belal Chami

    2015-05-01

    Full Text Available The acute phase protein serum amyloid A (SAA, a marker of inflammation, induces expression of pro-inflammatory and pro-thrombotic mediators including ICAM-1, VCAM-1, IL-6, IL-8, MCP-1 and tissue factor (TF in both monocytes/macrophages and endothelial cells, and induces endothelial dysfunction—a precursor to atherosclerosis. In this study, we determined the effect of pharmacological inhibition of known SAA receptors on pro-inflammatory and pro-thrombotic activities of SAA in human carotid artery endothelial cells (HCtAEC. HCtAEC were pre-treated with inhibitors of formyl peptide receptor-like-1 (FPRL-1, WRW4; receptor for advanced glycation-endproducts (RAGE, (endogenous secretory RAGE; esRAGE and toll-like receptors-2/4 (TLR2/4 (OxPapC, before stimulation by added SAA. Inhibitor activity was also compared to high-density lipoprotein (HDL, a known inhibitor of SAA-induced effects on endothelial cells. SAA significantly increased gene expression of TF, NFκB and TNF and protein levels of TF and VEGF in HCtAEC. These effects were inhibited to variable extents by WRW4, esRAGE and OxPapC either alone or in combination, suggesting involvement of endothelial cell SAA receptors in pro-atherogenic gene expression. In contrast, HDL consistently showed the greatest inhibitory action, and often abrogated SAA-mediated responses. Increasing HDL levels relative to circulating free SAA may prevent SAA-mediated endothelial dysfunction and ameliorate atherogenesis.

  9. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review

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    Sarah Mousavi

    2015-01-01

    Full Text Available Background. Heparin, used clinically as an anticoagulant, also has anti-inflammatory properties. The purpose of this systematic review was to provide a comprehensive review regarding the efficacy and safety of heparin and its derivatives as anti-inflammatory agents. Methods. We searched the following databases up to March 2012: Pub Med, Scopus, Web of Science, Ovid, Elsevier, and Google Scholar using combination of Mesh terms. Randomized Clinical Trials (RCTs and trials with quasi-experimental design in clinical setting published in English were included. Quality assessments of RCTs were performed using Jadad score and Consolidated Standards of Reporting Trials (CONSORT checklist. Results. A total of 280 relevant studies were reviewed and 57 studies met the inclusion criteria. Among them 48 studies were RCTs. About 65% of articles had score of 3 and higher according to Jadad score. Twelve studies had a quality score > 40% according to CONSORT items. Asthma (n=7, inflammatory bowel disease (n=5, cardiopulmonary bypass (n=8, and cataract surgery (n=6 were the most studied disease condition. Forty studies use unfractionated heparin (UFH for intervention; the remaining studies use low molecular weight heparin (LMWH. Conclusion. Despite the conflicting results, heparin seems to be a safe and effective anti-inflammatory agent; although it is shown that heparin can decrease the level of inflammatory biomarkers and improves patient conditions, still more data from larger rigorously designed studies are needed to support use of heparin as an anti-inflammatory agent in clinical setting. However, because of the association between inflammation, atherogenesis, thrombogenesis, and cell proliferation, heparin and related compounds with pleiotropic effects may have greater therapeutic efficacy than compounds acting against a single target.

  10. Receptor for Advanced Glycation End Products (RAGE) Deficiency Attenuates the Development of Atherosclerosis in Diabetes

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    Soro-Paavonen, Aino; Watson, Anna M.D.; Li, Jiaze; Paavonen, Karri; Koitka, Audrey; Calkin, Anna C.; Barit, David; Coughlan, Melinda T.; Drew, Brian G.; Lancaster, Graeme I.; Thomas, Merlin; Forbes, Josephine M.; Nawroth, Peter P.; Bierhaus, Angelika; Cooper, Mark E.; Jandeleit-Dahm, Karin A.

    2008-01-01

    OBJECTIVE—Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE−/− model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS—ApoE−/− and RAGE−/−/apoE−/− double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS—Although diabetic apoE−/− mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE−/−/apoE−/− mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE−/− mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE−/− mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE−/−/apoE−/− mice. CONCLUSIONS—This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications. PMID:18511846

  11. Toll-Like Receptor induced CD11b and L-selectin response in patients with coronary artery disease.

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    Ellen H A M Elsenberg

    Full Text Available Toll-Like Receptor (TLR -2 and -4 expression and TLR-induced cytokine response of inflammatory cells are related to atherogenesis and atherosclerotic plaque progression. We examined whether immediate TLR induced changes in CD11b and L-selectin (CD62L expression are able to discriminate the presence and severity of atherosclerotic disease by exploring single dose whole blood TLR stimulation and detailed dose-response curves. Blood samples were obtained from 125 coronary artery disease (CAD patients and 28 controls. CD11b and L-selectin expression on CD14+ monocytes was measured after whole blood stimulation with multiple concentrations of the TLR4 ligand LPS (0.01-10 ng/ml and the TLR2 ligand P3C (0.5-500 ng/ml. Subsequently, dose-response curves were created and the following parameters were calculated: hillslope, EC50, area under the curve (AUC and delta. These parameters provide information about the maximum response following activation, as well as the minimum trigger required to induce activation and the intensity of the response. CAD patients showed a significantly higher L-selectin, but not CD11b response to TLR ligation than controls after single dose stimulations as well as significant differences in the hillslope and EC50 of the dose-response curves. Within the CAD patient group, dose-response curves of L-selectin showed significant differences in the presence of hypertension, dyslipidemia, coronary occlusion and degree of stenosis, whereas CD11b expression had the strongest discriminating power after single dose stimulation. In conclusion, single dose stimulations and dose-response curves of CD11b and L-selectin expression after TLR stimulation provide diverse but limited information about atherosclerotic disease severity in stable angina patients. However, both single dose stimulation and dose-response curves of LPS-induced L-selectin expression can discriminate between controls and CAD patients.

  12. Retinol binding protein 4 concentrations relate to enhanced atherosclerosis in obese patients with rheumatoid arthritis.

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    Patrick H Dessein

    Full Text Available BACKGROUND: Retinol binding protein 4 (RBP enhances metabolic risk and atherogenesis. Whether RBP4 contributes to cardiovascular risk in rheumatoid arthritis (RA is unknown. METHODS: We assessed RBP4 concentrations and those of endothelial activation molecules including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 by ELISA, and the common carotid artery intima-media thickness (cIMT and carotid artery plaque by ultrasound in 217 (112 black and 105 white patients with RA. Relationships were identified in potential confounder and mediator adjusted mixed regression models. RESULTS: RBP4 concentrations were associated with systolic and mean blood pressure, and those of glucose and E-selectin (partial R = -0.207 (p = 0.003, -0.195 (p = 0.006, -0.155 (p = 0.03 and -0.191 (p = 0.007, respectively in all patients; these RBP4-cardiovascular risk relations were mostly reproduced in patients with but not without adverse traditional or non-traditional cardiovascular risk profiles. RBP4 concentrations were not associated with atherosclerosis in all patients, but related independently to cIMT (partial R = 0.297, p = 0.03 and plaque (OR (95%CI = 2.95 (1.31-6.68, p = 0.008 in those with generalized obesity, as well as with plaque in those with abdominal obesity (OR (95%CI  = 1.95 (1.12-3.42, p = 0.01. CONCLUSION: In the present study, RBP4 concentrations were inversely associated with metabolic risk and endothelial activation in RA. This requires further investigation. RBP4 concentrations were related to enhanced atherosclerosis in patients with generalized or/and abdominal obesity.

  13. S100A8 and S100A9: DAMPs at the Crossroads between Innate Immunity, Traditional Risk Factors, and Cardiovascular Disease

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    Alexandru Schiopu

    2013-01-01

    Full Text Available Amplification of innate immune responses by endogenous danger-associated molecular patterns (DAMPs promotes inflammation. The involvement of S100A8 and S100A9, DAMPs belonging to the S100 calgranulin family, in the pathogenesis of cardiovascular disease is attracting an increasing amount of interest. S100A8 and S100A9 (also termed MRP8 and MRP14 preferentially form the S100A8/A9 heterodimer (MRP8/14 or calprotectin and are constitutively expressed in myeloid cells. The levels of circulating S100A8/A9 in humans strongly correlate to blood neutrophil counts and are increased by traditional cardiovascular risk factors such as smoking, obesity, hyperglycemia, and dyslipidemia. S100A8/A9 is an endogenous ligand of toll-like receptor 4 (TLR4 and of the receptor for advanced glycation end products (RAGE and has been shown to promote atherogenesis in mice. In humans, S100A8/A9 correlates with the extent of coronary and carotid atherosclerosis and with a vulnerable plaque phenotype. S100A8/A9 is locally released following myocardial infarction and amplifies the inflammatory responses associated with myocardial ischemia/reperfusion injury. Elevated plasma levels of S100A8/A9 are associated with increased risk of future coronary events in healthy individuals and in myocardial infarction survivors. Thus, S100A8/A9 might represent a useful biomarker and therapeutic target in cardiovascular disease. Importantly, S100A8/A9 blockers have been developed and are approved for clinical testing.

  14. Differential effects of drug interventions and dietary lifestyle in developing type 2 diabetes and complications: a systems biology analysis in LDLr-/- mice.

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    Marijana Radonjic

    Full Text Available Excess caloric intake leads to metabolic overload and is associated with development of type 2 diabetes (T2DM. Current disease management concentrates on risk factors of the disease such as blood glucose, however with limited success. We hypothesize that normalizing blood glucose levels by itself is insufficient to reduce the development of T2DM and complications, and that removal of the metabolic overload with dietary interventions may be more efficacious. We explored the efficacy and systems effects of pharmaceutical interventions versus dietary lifestyle intervention (DLI in developing T2DM and complications. To mimic the situation in humans, high fat diet (HFD-fed LDLr-/- mice with already established disease phenotype were treated with ten different drugs mixed into HFD or subjected to DLI (switch to low-fat chow, for 7 weeks. Interventions were compared to untreated reference mice kept on HFD or chow only. Although most of the drugs improved HFD-induced hyperglycemia, drugs only partially affected other risk factors and also had limited effect on disease progression towards microalbuminuria, hepatosteatosis and atherosclerosis. By contrast, DLI normalized T2DM risk factors, fully reversed hepatosteatosis and microalbuminuria, and tended to attenuate atherogenesis. The comprehensive beneficial effect of DLI was reflected by normalized metabolite profiles in plasma and liver. Analysis of disease pathways in liver confirmed reversion of the metabolic distortions with DLI. This study demonstrates that the pathogenesis of T2DM towards complications is reversible with DLI and highlights the differential effects of current pharmacotherapies and their limitation to resolve the disease.

  15. Lipid minor constituents in wines. A biochemical approach in the French paradox

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    E Fragopoulou

    2009-03-01

    Full Text Available E Fragopoulou1, C A Demopoulos2, S Antonopoulou11Department of Science of Nutrition-Dietetics, Harokopio University, Athens, Greece; 2Faculty of Chemistry, National and Kapodistrian University of Athens, Athens, GreeceAbstract: The “French paradox” is the observation that the French suffer a relatively low incidence of coronary heart disease, despite having a diet relatively rich in saturated fats. Several theories have been proposed in order to explain this phenomenon and several debates arose. One of them attributed this phenomenon to the regular and moderate consumption of wine in France. More specific, it is thought that the existence of bioactive compounds in wine could have an effect on the cardiovascular system, preventing or delaying atherosclerosis. The mechanisms mediating these beneficial effects include: low-density lipoprotein oxidation; endothelium function; smooth muscle cells proliferation; platelet aggregation and angiogenesis. Several mediators participate in these pathophysiological mechanisms, among them are plateletactivating factor (PAF and oxidized phospholipids that play a crucial and essential role in the initiation and the progression of atherogenesis. In this review, apart from the already known and well characterized biological effects of wine bioactive compounds, the co-existence of compounds that could modulate the production and the actions of PAF is highlighted. The existence of bioactive compounds in wine that could reduce PAF production and inhibit its actions may offer a new insight into the well  known French paradox and expand the already reported mechanisms by including the inhibition of PAF actions.Keywords: wine, bioactive compounds, lipids, platelet-activating factor, atherosclerosis

  16. TNFα signals via p66(Shc to induce E-Selectin, promote leukocyte transmigration and enhance permeability in human endothelial cells.

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    Luigi Laviola

    Full Text Available Endothelial cells participate in inflammatory events leading to atherogenesis by regulating endothelial cell permeability via the expression of VE-Cadherin and β-catenin and leukocyte recruitment via the expression of E-Selectins and other adhesion molecules. The protein p66(Shc acts as a sensor/inducer of oxidative stress and may promote vascular dysfunction. The objective of this study was to investigate the role of p66(Shc in tumor necrosis factor TNFα-induced E-Selectin expression and function in human umbilical vein endothelial cells (HUVEC. Exposure of HUVEC to 50 ng/ml TNFα resulted in increased leukocyte transmigration through the endothelial monolayer and E-Selectin expression, in association with augmented phosphorylation of both p66(Shc on Ser(36 and the stress kinase c-Jun NH2-terminal protein kinase (JNK-1/2, and higher intracellular reactive oxygen species (ROS levels. Overexpression of p66(Shc in HUVEC resulted in enhanced p66(Shc phosphorylation on Ser(36, increased ROS and E-Selectin levels, and amplified endothelial cell permeability and leukocyte transmigration through the HUVEC monolayer. Conversely, overexpression of a phosphorylation-defective p66(Shc protein, in which Ser(36 was replaced by Ala, did not augment ROS and E-Selectin levels, nor modify cell permeability or leukocyte transmigration beyond those found in wild-type cells. Moreover, siRNA-mediated silencing of p66(Shc resulted in marked reduction of E-Selectin expression and leukocyte transmigration. In conclusion, p66(Shc acts as a novel intermediate in the TNFα pathway mediating endothelial dysfunction, and its action requires JNK-dependent phosphorylation of p66(Shc on Ser(36.

  17. Pathophysiological role and clinical significance of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) bound to LDL and HDL.

    Science.gov (United States)

    Tellis, Constantinos C; Tselepis, Alexandros D

    2014-01-01

    Lipoprotein-associated phospholipase A2 (Lp-PLA2), also named as platelet-activating factor (PAF)-acetylhydrolase, exhibits a Ca2+-independent phospholipase A2 activity and catalyzes the hydrolysis of the ester bond at the sn-2 position of PAF and oxidized phospholipids (oxPL). These phospholipids are formed under oxidative and inflammatory conditions, and may play important roles in atherogenesis. The vast majority of plasma Lp-PLA2 mass binds to low-density lipoprotein (LDL) while a smaller amount is associated with high-density lipoprotein (HDL). Lp-PLA2 is also bound to lipoprotein (a) [Lp(a)], very low-density lipoprotein (VLDL) and remnant lipoproteins. Several lines of evidence suggest that the role of plasma Lp-PLA2 in atherosclerosis may depend on the type of lipoprotein particle with which this enzyme is associated. Data from large Caucasian population studies have supported plasma Lp-PLA2 (primarily LDL-associated Lp-PLA2) as a cardiovascular risk marker independent of, and additive to, traditional risk factors. On the contrary, the HDL-associated Lp-PLA2 may express antiatherogenic activities and is also independently associated with lower risk for cardiac death. The present review presents data on the biochemical and enzymatic properties of Lp-PLA2 as well as its structural characteristics that determine the association with LDL and HDL. We also critically discuss the possible pathophysiological and clinical significance of the Lp- PLA2 distribution between LDL and HDL in human plasma, in view of the results of prospective epidemiologic studies on the association of Lp-PLA2 with future cardiovascular events as well the recent studies that evaluate the possible effectiveness of specific Lp-PLA2 inhibitors in reducing residual cardiovascular risk.

  18. Paradoxical effect of a pequi oil-rich diet on the development of atherosclerosis: balance between antioxidant and hyperlipidemic properties

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. SERUM AMYLASE: AN EARLY MARKER OF RENAL DAMAGE IN HYPERTENSION

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    Rangaswamy

    2014-08-01

    Full Text Available : INTRODUCTION: Hypertension is one of the risk factors for cardiovascular disease and causes progressive damage to kidney in a long term process. Hypertension impairs glomerular function and also leads to subclinical atherogenesis, there is a excretion of low molecular weight compounds like albumin and amylase in urine. This study was conducted to analyze the changes in amylase levels in hypertension. MATERIAL AND METHODS: This is a hospital based study. The patients attending the medicine department were selected for the study. 60 subjects were selected based on history and clinical examination consisting of 30 hypertensive patients and 30 normotensive subjects in the age group 35-60 years. Blood samples collected in vacutainers were analyzed in the clinical biochemistry laboratory. Serum samples were analyzed for total protein, albumin and amylase. RESULT: The study showed a statistically significant change in the levels of serum albumin and amylase. The level of serum albumin was 3.71 ± 0.22 g/dl in cases while it was 4.14 ± 0.20 g/dl in controls. The serum amylase levels were 99.79 ±13.63 U/L in cases while it was 137.76 ± 16.86 U/L in the control. The p-value was 0.0001 which was statistically significant. CONCLUSION: The initial damage to glomerulus can be detected by the alteration in serum amylase values in hypertension. Thus serum amylase can be considered as an early marker for detecting the renal damage in hypertension

  20. Microarray analysis of ox-LDL (oxidized low-density lipoprotein)-regulated genes in human coronary artery smooth muscle cells.

    Science.gov (United States)

    Minta, Joe; Jungwon Yun, James; St Bernard, Rosanne

    2010-01-01

    Recent studies suggest that circulating LDL (low-density lipoproteins) play a central role in the pathogenesis of atherosclerosis, and the oxidized form (ox-LDL) is highly atherogenic. Deposits of ox-LDL have been found in atherosclerotic plaques, and ox-LDL has been shown to promote monocyte recruitment, foam cell formation and the transition of quiescent and contractile vascular SMCs (smooth muscle cells) to the migratory and proliferative phenotype. SMC phenotype transition and hyperplasia are the pivotal events in the pathogenesis of atherosclerosis. To comprehend the complex molecular mechanisms involved in ox-LDL-mediated SMC phenotype transition, we have compared the differential gene expression profiles of cultured quiescent human coronary artery SMCs with cells induced with ox-LDL for 3 and 21 h using Affymetrix HG-133UA cDNA microarray chips. Assignment of the regulated genes into functional groups indicated that several genes involved in metabolism, membrane transport, cell-cell interactions, signal transduction, transcription, translation, cell migration, proliferation and apoptosis were differentially expressed. Our data suggests that the interaction of ox-LDL with its cognate receptors on SMCs modulates the induction of several growth factors and cytokines, which activate a variety of intracellular signalling mechanisms (including PI3K, MAPK, Jak/STAT, sphingosine, Rho kinase pathways) that contribute to SMC transition from the quiescent and contractile phenotype to the proliferative and migratory phenotype. Our study has also identified several genes (including CDC27, cyclin A1, cyclin G2, glypican 1, MINOR, p15 and apolipoprotein) not previously implicated in ox-LDL-induced SMC phenotype transition and substantially extends the list of potential candidate genes involved in atherogenesis.

  1. Amyloid beta deposition and phosphorylated tau accumulation are key features in aged choroidal vessels in the complement factor H knock out model of retinal degeneration.

    Science.gov (United States)

    Aboelnour, Asmaa; Kam, Jaimie Hoh; Elnasharty, M A; Sayed-Ahmed, Ahmed; Jeffery, Glen

    2016-06-01

    Extra-cellular deposition including amyloid beta (Aβ) is a feature of retinal ageing. It has been documented for Bruch's membrane (BM) where Aβ is elevated in complement factor H knockout mice (Cfh(-/-)) proposed as a model for age related macular degeneration. However, arterial deposition in choroidal vessels prior to perfusion across BM has not been examined. Aβ is associated with tau phosphorylation and these are linked in blood vessels in Alzheimers Disease where they can drive perivascular pathology. Here we ask if Aβ, tau and phosphorylated tau are features of ageing in choroidal vessels in 12 month C57 BL/6 and Cfh(-/-) mice, using immune staining and Western blot analysis. Greater levels of Aβ and phosphorylated tau are found in choroidal vessels in Cfh(-/-) mice. Western blot revealed a 40% increase in Aβ in Cfh(-/-) over C57 BL/6 mice. Aβ deposits coat around 55% of the luminal wall in Cfh(-/-) compared to only about 40% in C57 BL/6. Total tau was similar in both groups, but phosphorylated tau increased by >100% in Cfh(-/-) compared to C57 BL/6 and covered >75% of the luminal wall compared to 50% in C57 BL/6. Hence, phosphorylated tau is a marked choroidal feature in this mouse model. Aβ deposition was clumped in Cfh(-/-) mice and likely to influence blood flow dynamics. Disturbed flow is associated with atherogenesis and may be related to the accumulation of membrane attack complex recently identified between choroidal vessels in those at high risk of macular degeneration due to complement factor H polymorphisms.

  2. Involvement of insulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: a review.

    Science.gov (United States)

    Stragier, Bart; De Bundel, Dimitri; Sarre, Sophie; Smolders, Ilse; Vauquelin, Georges; Dupont, Alain; Michotte, Yvette; Vanderheyden, Patrick

    2008-09-01

    For decades, angiotensin (Ang) II was considered as the end product and the only bioactive peptide of the renin-angiotensin system (RAS). However, later studies revealed biological activity for other Ang fragments. Amongst those, Ang IV has drawn a lot of attention since it exerts a wide range of central and peripheral effects including the ability to enhance learning and memory recall, anticonvulsant and anti-epileptogenic properties, protection against cerebral ischemia, activity at the vascular level and an involvement in atherogenesis. Some of these effects are AT(1) receptor dependent but others most likely result from the binding of Ang IV to insulin-regulated aminopeptidase (IRAP) although the exact mechanism(s) of action that mediate the Ang IV-induced effects following this binding are until now not fully known. Nevertheless, three hypotheses have been put forward: since Ang IV is an inhibitor of the catalytic activity of IRAP, its in vivo effects might result from a build-up of IRAP's neuropeptide substrates. Second, IRAP is co-localized with the glucose transporter GLUT4 in several tissue types and therefore, Ang IV might interact with the uptake of glucose. A final and more intriguing hypothesis ascribes a receptor function to IRAP and hence an agonist role to Ang IV. Taken together, it is clear that further work is required to clarify the mechanism of action of Ang IV. On the other hand, a wide range of studies have made it clear that IRAP might become an important target for drug development against different pathologies such as Alzheimer's disease, epilepsy and ischemia.

  3. Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a.

    Science.gov (United States)

    O'Toole, Timothy E; Abplanalp, Wesley; Li, Xiaohong; Cooper, Nigel; Conklin, Daniel J; Haberzettl, Petra; Bhatnagar, Aruni

    2014-08-01

    Acrolein is a major reactive component of vehicle exhaust, and cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation, and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high-throughput technology, we found that treatment of cultured human umbilical vein endothelial cells with acrolein led to a significant (>1.5-fold) upregulation of 12, and downregulation of 15, miRNAs. Among the miRNAs upregulated were members of the let-7 family and this upregulation was associated with decreased expression of their protein targets, β3 integrin, Cdc34, and K-Ras. Exposure to acrolein attenuated β3 integrin-dependent migration and reduced Akt phosphorylation in response to insulin. These effects of acrolein on endothelial cell migration and insulin signaling were reversed by expression of a let-7a inhibitor. Also, inhalation exposure of mice to acrolein (1 ppm x 6 h/day x 4 days) upregulated let-7a and led to a decrease in insulin-stimulated Akt phosphorylation in the aorta. These results suggest that acrolein exposure has broad effects on endothelial miRNA repertoire and that attenuation of endothelial cell migration and insulin signaling by acrolein is mediated in part by the upregulation of let-7a. This mechanism may be a significant feature of vascular injury caused by inflammation, oxidized lipids, and exposure to environmental pollutants.

  4. KR-31543 reduces the production of proinflammatory molecules in human endothelial cells and monocytes and attenuates atherosclerosis in mouse model.

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    Choi, Jae-Hoon; Yoo, Ji-Young; Kim, Sun-Ok; Yoo, Sung-Eun; Oh, Goo Taeg

    2012-12-31

    KR-31543, (2S, 3R, 4S)-6-amino-4-[N-(4-chlorophenyl)- N-(2-methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro- 2-dimethyoxymethyl-3-hydroxy-2-methyl-2H-1-benz opyran is a new neuroprotective agent for ischemiareperfusion damage. It has also been reported that KR-31543 has protective effects on lipid peroxidation and H₂O₂-induced reactive oxygen species production. In this study, we investigated the anti-inflammatory and anti-atherogenic properties of KR-31543. We observed that KR-31543 treatment reduced the production of MCP-1, IL-8, and VCAM-1 in HUVECs, and of MCP-1 and IL-6 in THP-1 human monocytes. We also examined the effect of KR-31543 on monocytes migration in vitro. KR-31543 treatment effectively reduced the migration of THP-1 human monocytes to the HUVEC monolayer in a dose-dependent manner. We next examined the effects of this compound on atherogenesis in LDL receptor deficient (Ldlr ⁻/⁻) mice. After 10 weeks of western diet, the formation of atherosclerotic lesion in aorta was reduced in the KR-31543-treated group compared to the control group. The accumulation of macrophages in lesion was also reduced in KR-31543 treated group. However, the plasma levels of total cholesterol, HDL, LDL, and triglyceride were not affected by KR-31543 treatment. Taken together, these results show that KR-31543 has anti-inflammatory properties on human monocytes and endothelial cells, and inhibits fatty streak lesion formation in mouse model of atherosclerosis, suggesting the potential of KR-31543 for the treatment for atherosclerosis.

  5. Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the arginase inhibitor L-norvaline

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    Ruffieux Jean

    2009-03-01

    Full Text Available Abstract Background Pharmacological inhibition of endothelial arginase-II has been shown to improve endothelial nitric oxide synthase (eNOS function and reduce atherogenesis in animal models. We investigated whether the endothelial arginase II is involved in inflammatory responses in endothelial cells. Methods Human endothelial cells were isolated from umbilical veins and stimulated with TNFα (10 ng/ml for 4 hours. Endothelial expression of the inflammatory molecules i.e. vascular cell adhesion molecule-1 (VCAM-1, intercellular adhesion molecule-1 (ICAM-1, and E-selectin were assessed by immunoblotting. Results The induction of the expression of endothelial VCAM-1, ICAM-1 and E-selectin by TNFα was concentration-dependently reduced by incubation of the endothelial cells with the arginase inhibitor L-norvaline. However, inhibition of arginase by another arginase inhibitor S-(2-boronoethyl-L-cysteine (BEC had no effects. To confirm the role of arginase-II (the prominent isoform expressed in HUVECs in the inflammatory responses, adenoviral mediated siRNA silencing of arginase-II knocked down the arginase II protein level, but did not inhibit the up-regulation of the adhesion molecules. Moreover, the inhibitory effect of L-norvaline was not reversed by the NOS inhibitor L-NAME and L-norvaline did not interfere with TNFα-induced activation of NF-κB, JNK, p38mapk, while it inhibited p70s6k (S6K1 activity. Silencing S6K1 prevented up-regulation of E-selectin, but not that of VCAM-1 or ICAM-1 induced by TNFα. Conclusion The arginase inhibitor L-norvaline exhibits anti-inflammatory effects independently of inhibition of arginase in human endothelial cells. The anti-inflammatory properties of L-norvaline are partially attributable to its ability to inhibit S6K1.

  6. Review of the evidence for the clinical utility of lipoprotein-associated phospholipase A2 as a cardiovascular risk marker.

    Science.gov (United States)

    Corson, Marshall A; Jones, Peter H; Davidson, Michael H

    2008-06-16

    A substantial body of peer-reviewed studies has been published validating the role of inflammation in atherogenesis and supporting lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) as a cardiovascular risk marker independent of and additive to traditional risk factors. As with elevated high-sensitivity C-reactive protein, an elevated Lp-PLA(2) level approximately doubles the risk for primary and secondary cardiovascular events. Interestingly, when both inflammatory markers are increased together, they provide an even greater predictive capability to help identify very-high-risk individuals who would benefit most from aggressive lipid-lowering therapy. High levels of Lp-PLA(2) are present in inflamed, rupture-prone plaques, and it appears that Lp-PLA(2) is released from these plaques into the circulation. Over 25 prospective epidemiologic studies have demonstrated the association of elevated Lp-PLA(2) levels with future coronary events and stroke-11 of 12 prospective studies have shown a statistically significant association between elevated Lp-PLA(2) and primary coronary or cardiovascular events, 12 of 13 have shown a statistically significant association with recurrent coronary or cardiovascular events, and 6 studies have shown a positive association with stroke. Lp-PLA(2) should be viewed today as an important cardiovascular risk marker whose utility is as an adjunct to the major risk factors to adjust absolute risk status and thereby modify low-density lipoprotein cholesterol goals. The low biologic fluctuation and high vascular specificity of Lp-PLA(2) makes it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA(2) marker serially. Ultimately, Lp-PLA(2) may also be classified as a risk factor, but this should not detract from its utility today as a risk marker.

  7. The Effect of EDTA and Garlic Extract Combination on Plasma Lipids, Lipoporteins, and Fatty Streaks in Cholesterol Fed Male Rabbit Aorta

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    M R Sharifi

    2004-12-01

    Full Text Available Background: Garlic extract is used in treatment of hypercholesterolemia, although its efficacy isn’t exactly clear. There is a little information about mechanism of garlic effect on plasma lipids. By intervention of garlic in atherogenesis process it has been shown that it has a protective effect against cardiovascular disease. On the other hand, it has been shown that EDTA (Ethylene Diamin Tetra Acetic Acid improves blood flow and decreases the vascular atherosclerotic symptoms. Methods: The objective of this study was to evaluate the effect of EDTA and garlic extract with together on plasma concentration of cholesterol, Triglyceride, LDL, and HDL, and formation of fatty streaks through the phenomena called “chelation therapy” in male Rabbit aorta. 32 male Rabbits were used and divided to 4 groups as group 1: cholesterol – rich diet (CRD + EDTA + Garlic Extract (GE, group 2: CRD + EDTA, Group 3: CRD + GE, Group 4: CRD (control group. The animals were under food and drug diet for 5 weeks. Blood samples of Rabbits were taken before and after the test and then plasma cholesterol, triglyceride, LDL and HDL were measured. Finally, abdominal aorta was studied and pathologically evaluated. Results: The experiments showed the significant decrease of mean cholesterol in case groups and mean triglyceride in the groups which have received EDTA + GE and EDTA. Our results showed that mean LDL and LDL/HDL Ratio in case groups have been decreased in comparison to control group. In addition, there was a significant increase in mean HDL in the group which has received EDTA + GE. Conclusion: In this study it was shown that the using of fresh garlic and EDTA with together has a reductive effect on cholesterol, Triglyceride, and LDL concentration and also has an increasing effect on HDL concentration. But it seems that concomitant using of these tow substances with together strengthen the effect of each one, and it produces a great reduction of the blood

  8. Adipokine Imbalance in the Pericardial Cavity of Cardiac and Vascular Disease Patients.

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    Atlanta G I M Elie

    Full Text Available Obesity and especially hypertrophy of epicardial adipose tissue accelerate coronary atherogenesis. We aimed at comparing levels of inflammatory and atherogenic hormones from adipose tissue in the pericardial fluid and circulation of cardiovascular disease patients.Venous plasma (P and pericardial fluid (PF were obtained from elective cardiothoracic surgery patients (n = 37. Concentrations of leptin, adipocyte fatty acid-binding protein (A-FABP and adiponectin (APN were determined by enzyme-linked immunosorbent assays (ELISA. The median concentration of leptin in PF (4.3 (interquartile range: 2.8-9.1 μg/L was comparable to that in P (5.9 (2.2-11 μg/L and these were significantly correlated to most of the same patient characteristics. The concentration of A-FABP was markedly higher (73 (28-124 versus 8.4 (5.2-14 μg/L and that of APN was markedly lower (2.8 (1.7-4.2 versus 13 (7.2-19 mg/L in PF compared to P. APN in PF was unlike in P not significantly related to age, body mass index, plasma triglycerides or coronary artery disease. PF levels of APN, but not A-FABP, were related to the size of paracardial adipocytes. PF levels of APN and A-FABP were not related to the immunoreactivity of paracardial adipocytes for these proteins.In cardiac and vascular disease patients, PF is enriched in A-FABP and poor in APN. This adipokine microenvironment is more likely determined by the heart than by the circulation or paracardial adipose tissue.

  9. Both common and specialty mushrooms inhibit adhesion molecule expression and in vitro binding of monocytes to human aortic endothelial cells in a pro-inflammatory environment

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    Martin Keith R

    2010-07-01

    Full Text Available Abstract Background Cardiovascular disease (CVD is a leading cause of mortality in the United States as well as globally. Epidemiological studies show that regular fruit and vegetable consumption reduces CVD risk, in part, due to antioxidant activity and immunomodulation since oxidative stress and inflammation are features of atherogenesis. Accumulating evidence also shows that dietary fungi, viz., mushrooms, can protect against chronic disease by altering inflammatory environments such as those associated with CVD although most research has focused on specialty mushrooms. In this study, we tested the ability of both common and specialty mushrooms to inhibit cellular processes associated with CVD. Methods Human aortic endothelial cells (HAEC were incubated overnight with control media with dimethylsulfoxide (DMSO vehicle (1% v/v or containing DMSO extracts of whole dehydrated mushrooms (0.1 mg/mL, which included Agaricus bisporus (white button and crimini, Lentinula edodes (shiitake, Pleurotus ostreatus (oyster, and Grifola frondosa (maitake. Monolayers were subsequently washed and incubated with medium alone or containing the pro-inflammatory cytokine IL-1β (5 ng/mL for 6 h to upregulate pro-atherosclerotic adhesion molecules (AM. AM expression was assayed by ELISA and binding of U937 human monocytes pre-loaded with fluorescent dye was determined. Results White button mushrooms consistently reduced (p Conclusion These data provide evidence that dietary mushrooms can inhibit cellular processes such as adhesion molecule expression and ultimate binding of monocytes to the endothelium under pro-inflammatory conditions, which are associated with CVD. As a result, these findings support the notion that dietary mushrooms can be protective against CVD.

  10. Erythropoietin and a nonerythropoietic peptide analog promote aortic endothelial cell repair under hypoxic conditions: role of nitric oxide

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    Heikal L

    2016-08-01

    Full Text Available Lamia Heikal,1 Pietro Ghezzi,1 Manuela Mengozzi,1 Blanka Stelmaszczuk,2 Martin Feelisch,2 Gordon AA Ferns1 1Brighton and Sussex Medical School, Falmer, Brighton, 2Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton, UK Abstract: The cytoprotective effects of erythropoietin (EPO and an EPO-related nonerythropoietic analog, pyroglutamate helix B surface peptide (pHBSP, were investigated in an in vitro model of bovine aortic endothelial cell injury under normoxic (21% O2 and hypoxic (1% O2 conditions. The potential molecular mechanisms of these effects were also explored. Using a model of endothelial injury (the scratch assay, we found that, under hypoxic conditions, EPO and pHBSP enhanced scratch closure by promoting cell migration and proliferation, but did not show any effect under normoxic conditions. Furthermore, EPO protected bovine aortic endothelial cells from staurosporine-induced apoptosis under hypoxic conditions. The priming effect of hypoxia was associated with stabilization of hypoxia inducible factor-1α, EPO receptor upregulation, and decreased Ser-1177 phosphorylation of endothelial nitric oxide synthase (NOS; the effect of hypoxia on the latter was rescued by EPO. Hypoxia was associated with a reduction in nitric oxide (NO production as assessed by its oxidation products, nitrite and nitrate, consistent with the oxygen requirement for endogenous production of NO by endothelial NOS. However, while EPO did not affect NO formation in normoxia, it markedly increased NO production, in a manner sensitive to NOS inhibition, under hypoxic conditions. These data are consistent with the notion that the tissue-protective actions of EPO-related cytokines in pathophysiological settings associated with poor oxygenation are mediated by NO. These findings may be particularly relevant to atherogenesis and postangioplasty restenosis. Keywords

  11. G-protein coupled receptor 30 (GPR30: a novel regulator of endothelial inflammation.

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    Subhadeep Chakrabarti

    Full Text Available Estrogen, the female sex hormone, is known to exert anti-inflammatory and anti-atherogenic effects. Traditionally, estrogen effects were believed to be largely mediated through the classical estrogen receptors (ERs. However, there is increasing evidence that G-protein coupled receptor 30 (GPR30, a novel estrogen receptor, can mediate many estrogenic effects on the vasculature. Despite this, the localization and functional significance of GPR30 in the human vascular endothelium remains poorly understood. Given this background, we examined the subcellular location and potential anti-inflammatory roles of GPR30 using human umbilical vein endothelial cells as a model system. Inflammatory changes were induced by treatment with tumor necrosis factor (TNF, a pro-inflammatory cytokine involved in atherogenesis and many other inflammatory conditions. We found that GPR30 was located predominantly in the endothelial cell nuclei. Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1. This effect was completely abolished by the selective GPR30 antagonist G-15, suggesting that it was indeed mediated in a GPR30 dependent manner. Interestingly, estrogen alone had no effects on TNF-treated endothelium. Concomitant activation of the classical ERs blocked the anti-inflammatory effects of G-1, indicating opposing effects of GPR30 and the classical ERs. Our findings demonstrate that endothelial GPR30 is a novel regulator of the inflammatory response which could be a potential therapeutic target against atherosclerosis and other inflammatory diseases.

  12. Endothelial dysfunction is associated with carotid plaque: a cross-sectional study from the population based Northern Manhattan Study

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    Boden-Albala Bernadette

    2006-08-01

    Full Text Available Abstract Background Impaired vascular function occurs early in atherogenesis. Brachial flow mediated dilatation (FMD is a non-invasive measure of vascular function and may be an important marker of preclinical atherosclerosis. Data on the association between FMD and carotid plaque in multi-ethnic populations are limited. The objective of this study was to determine whether endothelial dysfunction is independently associated with carotid plaque in a community of northern Manhattan. Methods In the population-based Northern Manhattan Study (NOMAS, high-resolution B-mode ultrasound images of the brachial and carotid arteries were obtained in 643 stroke-free subjects (mean age 66 years; 55% women; 65% Caribbean-Hispanic, 17% African-American, 16% Caucasian. Brachial FMD was measured during reactive hyperemia. Maximum carotid plaque thickness (MCPT was measured at the peak plaque prominence. Results The mean brachial FMD was 5.78 ± 3.83 %. Carotid plaque was present in 339 (53% subjects. The mean MCPT was 1.68 ± 0.82 mm, and the 75th percentile was 2.0 mm. Reduced FMD was significantly associated with increased MCPT. After adjusting for demographics, vascular risk factors, and education, each percent of FMD decrease was associated with a significant 0.02 mm increase in MCPT (p = 0.028. In a dichotomous adjusted model, blunted FMD was associated with an increased risk of MCPT ≥ 2.0 mm (OR, 1.11 for every 1% decrease in FMD; 95% CI, 1.03–1.19. Conclusion Decreased brachial FMD is independently associated with carotid plaque. Non-invasive evaluation of endothelial dysfunction may be a useful marker of preclinical atherosclerosis and help to individualize cardiovascular risk assessment beyond traditional risk factors.

  13. 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.

  14. 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.

  15. 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.

  16. Experimental Study of Yishou Tiaozhi Tablet(益寿调脂片) on Inhibiting Hyperlipemia and Atherosclerosis

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To observe the effect of Yishou Tiaozhi tablet(YSTZT) on lipid metabolism and aortic intimal atherosclerotic plaque coverage in rabbit model of experimental hyperlipemia and atherosclerosis.Methods: Thirty-two rabbits were randomly divided into four groups, Group A, B, C and D, 8 in each group. Forage with cholesterol and lipid plus 1.59 g/kg of YSTZT was fed to Group A every day;for Group B, 22.54 mg/kg gypenoside tablet was added to forage with cholesterol and lipid; for Group C, hyperlipid forage was given and for Group D, only ordinary forage was given. Biochemical parameters were measured and pathomorphological examinations were carried out 6 weeks later.Results: (1) YSTZT obviously lowered the levels of serum total cholesterol(TC), triglyceride(TG), atherosclerotic index(AI), apoprotein(ApoB), lipoprotein [Lp(a)], oxygen-low density lipoprotein cholesterol(ox-LDL), hydroxyproline(HYP), plasma Ca2+, thromboxane B2(TXB2), and increased the levels of serum high-density lipoprotein cholesterol(HDL-C), apoprotein A1(Apo A1), ApoA1 /ApoB, plasma 6-keto-PGF1α (P<0.01). (2) Pathomorphological examination showed that in Group A aortic intimal atherosclerotic plaque area and arterial intima thickness were obviously reduced, smooth muscle cell hyperplasia and elastic fibers were not seen.Conclusion: YSTZT can inhibit experimental hyperlipemia and atherogenesis. It is an ideal and effective medicine in preventing and treating hyperlipemia and atherosclerosis.

  17. Acrolein increases macrophage atherogenicity in association with gut microbiota remodeling in atherosclerotic mice: protective role for the polyphenol-rich pomegranate juice.

    Science.gov (United States)

    Rom, Oren; Korach-Rechtman, Hila; Hayek, Tony; Danin-Poleg, Yael; Bar, Haim; Kashi, Yechezkel; Aviram, Michael

    2016-09-30

    The unsaturated aldehyde acrolein is pro-atherogenic, and the polyphenol-rich pomegranate juice (PJ), known for its anti-oxidative/anti-atherogenic properties, inhibits macrophage foam cell formation, the hallmark feature of early atherosclerosis. This study aimed to investigate two unexplored areas of acrolein atherogenicity: macrophage lipid metabolism and the gut microbiota composition. The protective effects of PJ against acrolein atherogenicity were also evaluated. Atherosclerotic apolipoprotein E-deficient (apoE(-/-)) mice that were fed acrolein (3 mg/kg/day) for 1 month showed significant increases in serum and aortic cholesterol, triglycerides, and lipid peroxides. In peritoneal macrophages isolated from the mice and in J774A.1 cultured macrophages, acrolein exposure increased intracellular oxidative stress and stimulated cholesterol and triglyceride accumulation via enhanced rates of their biosynthesis and over-expression of key regulators of cellular lipid biosynthesis: sterol regulatory element-binding proteins (SREBPs), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), and diacylglycerol acyltransferase1 (DGAT1). Acrolein-fed mice demonstrated a major shift in the gut microbiota composition, including a significant phylum-level change in increased Firmicutes and decreased Bacteroidetes. At the family level, acrolein significantly increased the prevalence of Ruminococcaceae and Lachnospiraceae of which the Coprococcus genus was significantly and positively correlated with serum, aortic and macrophage lipid levels and peroxidation. The pro-atherogenic effects of acrolein on serum, aortas, macrophages, and the gut microbiota were substantially abolished by PJ. In conclusion, these findings provide novel mechanisms by which acrolein increases macrophage lipid accumulation and alters the gut microbiota composition in association with enhanced atherogenesis. Moreover, PJ was found as an effective strategy against acrolein atherogenicity.

  18. Supplementation with linoleic acid-rich soybean oil stimulates macrophage foam cell formation via increased oxidative stress and diacylglycerol acyltransferase1-mediated triglyceride biosynthesis.

    Science.gov (United States)

    Rom, Oren; Jeries, Helana; Hayek, Tony; Aviram, Michael

    2017-01-02

    During the last decades there has been a staggering rise in human consumption of soybean oil (SO) and its major polyunsaturated fatty acid linoleic acid (LA). The role of SO or LA in cardiovascular diseases is highly controversial, and their impact on macrophage foam cell formation, the hallmark of early atherogenesis, is unclear. To investigate the effects of high SO or LA intake on macrophage lipid metabolism and the related mechanisms of action, C57BL/6 mice were orally supplemented with increasing levels of SO-based emulsion or equivalent levels of purified LA for 1 month, followed by analyses of lipid accumulation and peroxidation in aortas, serum and in peritoneal macrophages (MPM) of the mice. Lipid peroxidation and triglyceride mass in aortas from SO or LA supplemented mice were dose-dependently and significantly increased. In MPM from SO or LA supplemented mice, lipid peroxides were significantly increased and a marked accumulation of cellular triglycerides was found in accordance with enhanced triglyceride biosynthesis rate and overexpression of diacylglycerol acyltransferase1 (DGAT1), the key enzyme in triglyceride biosynthesis. In cultured J774A.1 macrophages treated with SO or LA, triglyceride accumulated via increased oxidative stress and a p38 mitogen-activated protein kinase (MAPK)-mediated overexpression of DGAT1. Accordingly, anti-oxidants (pomegranate polyphenols), inhibition of p38 MAPK (by SB202190) or DGAT1 (by oleanolic acid), all significantly attenuated SO or LA-induced macrophage triglyceride accumulation. These findings reveal novel mechanisms by which supplementation with SO or LA stimulate macrophage foam cell formation, suggesting a pro-atherogenic role for overconsumption of SO or LA. © 2016 BioFactors, 43(1):100-116, 2017.

  19. Inhibition of tumor necrosis factor-alpha-induced interleukin-6 expression by telmisartan through cross-talk of peroxisome proliferator-activated receptor-gamma with nuclear factor kappaB and CCAAT/enhancer-binding protein-beta.

    Science.gov (United States)

    Tian, Qingping; Miyazaki, Ryohei; Ichiki, Toshihiro; Imayama, Ikuyo; Inanaga, Keita; Ohtsubo, Hideki; Yano, Kotaro; Takeda, Kotaro; Sunagawa, Kenji

    2009-05-01

    Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-gamma. Although peroxisome proliferator-activated receptor-gamma activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor-alpha (TNF-alpha). Telmisartan decreased TNF-alpha-induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor-gamma antagonist, peroxisome proliferator-activated receptor-gamma may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-alpha. Deletion analysis suggested that the DNA segment between -150 bp and -27 bp of the IL-6 gene promoter that contains nuclear factor kappaB and CCAAT/enhancer-binding protein-beta sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-alpha-induced nuclear factor kappaB- and CCAAT/enhancer-binding protein-beta-dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-alpha-infused mice and IL-6 production from rat aorta stimulated with TNF-alpha ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-alpha in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-alpha and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change.

  20. Antibodies Against β2-Glycoprotein I Complexed With an Oxidised Lipoprotein Relate to Intima Thickening of Carotid Arteries in Primary Antiphospholipid Syndrome

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    P. R. J. Ames

    2006-01-01

    Full Text Available To explore whether antibodies against β2-glycoprotein I (β2GPI complexed to 7-ketocholesteryl-9-carboxynonanoate (oxLig-1 and to oxidised low-density lipoproteins (oxLDL relate to paraoxonase activity (PONa and/or intima media thickness (IMT of carotid arteries in primary antiphospholipid syndrome (PAPS. As many as 29 thrombotic patients with PAPS, 10 subjects with idiopathic antiphospholipid antibodies (aPL without thrombosis, 17 thrombotic patients with inherited thrombophilia and 23 healthy controls were investigated. The following were measured in all participants: β2GPI−oxLDL complexes, IgG anti-β2GPI−oxLig-1, IgG anti-β2GPI−oxLDL antibodies (ELISA, PONa, (para-nitrophenol method, IMT of common carotid (CC artery, carotid bifurcation (B, internal carotid (IC by high resolution sonography. β2GPI−oxLDL complex was highest in the control group (p < 0.01, whereas, IgG anti-β2GPI−oxLig1 and IgG anti-β2GPI−oxLDL were highest in PAPS (p < 0.0001. In healthy controls, β2GPI−oxLDL complexes positively correlated to IMT of the IC (p = 0.007 and negatively to PONa after correction for age (p < 0.03. PONa inversely correlated with age (p = 0.008. In PAPS, IgG anti-2GPI−oxLig-1 independently predicted PONa (p = 0.02 and IMT of B (p = 0.003, CC, (p = 0.03 and of IC (p = 0.04. In PAPS, PONa inversely correlated to the IMT of B, CC and IC (p = 0.01, 0.02 and 0.003, respectively. IgG anti-2GPI−oxLig-1 may be involved in PAPS related atherogenesis via decreased PON activity.

  1. Early vascular alterations in SLE and RA patients--a step towards understanding the associated cardiovascular risk.

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    Maria José Santos

    Full Text Available Accelerated atherosclerosis represents a major problem in both systemic lupus erythematosus (SLE and rheumatoid arthritis (RA patients, and endothelial damage is a key feature of atherogenesis. We aimed to assess early endothelial changes in SLE and RA female patients (127 SLE and 107 RA without previous CV events. Biomarkers of endothelial cell activation (intercellular adhesion molecule-1 (sICAM-1, vascular cell adhesion molecule-1 (sVCAM-1, thrombomodulin (TM, and tissue factor (TF were measured and endothelial function was assessed using peripheral artery tonometry. Reactive hyperemia index (RHI, an indicator of microvascular reactivity, and augmentation index (AIx, a measure of arterial stiffness, were obtained. In addition, traditional CV risk factors, disease activity and medication were determined. Women with SLE displayed higher sICAM-1 and TM and lower TF levels than women with RA (p = 0.001, p<0.001 and p<0.001, respectively. These differences remained significant after controlling for CV risk factors and medication. Serum levels of vascular biomarkers were increased in active disease and a moderate correlation was observed between sVCAM-1 levels and lupus disease activity (rho = 0.246 and between TF levels and RA disease activity (rho = 0.301. Although RHI was similar across the groups, AIx was higher in lupus as compared to RA (p = 0.04. Also in active SLE, a trend towards poorer vasodilation was observed (p = 0.06. In conclusion, women with SLE and RA present with distinct patterns of endothelial cell activation biomarkers not explained by differences in traditional CV risk factors. Early vascular alterations are more pronounced in SLE which is in line with the higher CV risk of these patients.

  2. Rosiglitazone reverses endothelial dysfunction but not remodeling of femoral artery in Zucker diabetic fatty rats

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    Onyia Jude E

    2010-05-01

    Full Text Available Abstract Objectives Endothelial dysfunction precedes atherogenesis and clinical complications in type 2 diabetes. The vascular dysfunction in Zucker diabetic fatty (ZDF rats was evaluated at different ages along with the effect of treatment with rosiglitazone (Rosi on endothelial function and mechanical remodeling. Methods The Rosi treatment was given to ZDF rats for 3 weeks. The endothelium-dependent vasodilation and α-adrenoceptor-dependent vasoconstriction of femoral arteries were studied using an ex-vivo isovolumic myograph. The biomechanical passive property of the arteries was studied in Ca2+-free condition. The expressions of endothelial nitric oxide synthase (eNOS, α-adrenoceptor, matrix metalloproteinase 9 (MMP9, and elastase were evaluated. Results Endothelium-dependent vasorelaxation of the femoral artery was blunted at low doses in ZDF rats at 11 weeks of age and attenuated at all doses in ZDF rats at 19 weeks of age. The expression of eNOS was consistent with the endothelium-dependent vasorelaxation. The α-adrenoceptor was activated and the mechanical elastic modulus was increased in ZDF rats at 19 weeks of age. The expressions of α-adrenoceptor, MMP9, and elastase were up regulated in ZDF rats at 19 weeks of age. Rosi treatment for 3 weeks restored endothelium-dependent vasorelaxation and the expression of eNOS and the adrenoceptor activation at the doses below 10-6 mole/L in ZDF rats at 19 weeks of age. Rosi treatment for 3 weeks did not, however, improve the mechanical properties of blood vessel, the expressions of α-adrenoceptor, MMP9, and elastase in ZDF rats. Conclusion The endothelial dysfunction and mechanical remodeling are observed as early as 19 weeks of age in ZDF rat. Rosi treatment for 3 weeks improves endothelial function but not mechanical properties.

  3. [Pathobiological determinants of atherosclerosis in youths: data from a macromorphometric and histomorphometric investigation of the aorta and coronary arteries].

    Science.gov (United States)

    Lesauskaite, Vaiva; Stalioraityte, Elena; Tanganelli, Piero; Epistolato, Maria Carmela

    2004-01-01

    We present a review of data from epidemiological and morphological studies carried out in Kaunas of atherosclerosis in youths. Since 1985, Kaunas has been a Collaborating Center involved with the World Health Organization and International Society and Federation of Cardiology studying the pathobiological determinants of atherosclerosis in youth. During the pilot study (1985-1987), we estimated the prevalence and extent of atherosclerotic lesions in the aorta and coronary arteries correlated to various risk factors in Kaunas residents aged 5 to 44 years. Within the framework of this international study, we compared histomorphometric characteristics of arteries collected from trauma victims aged 5 to 34 years in Budapest (Hungary), Heidelberg (Germany), Kaunas (Lithuania), Yaounde (Cameroon), and Mexico City (Mexico). These data revealed that males from countries with a high mortality from ischemic heart disease (Hungary, Lithuania, Germany) tended to have thicker intima in the thoracic and abdominal aorta and left anterior descending coronary artery than did males from countries with low mortality from ischemic heart disease (Mexico, Cameroon). We detected an increased mean intimal thickness of the abdominal aorta in male smokers aged 25-34 years. Males with hypertension aged 15-24 and 25-34 years had a thicker intima in the aorta and left anterior descending coronary artery than normotensive males. The morphological and epidemiological studies of atherosclerosis in youths carried out in Kaunas demonstrated that aortic and coronary atherosclerotic lesions appeared as early as childhood and advanced until the lesions become clinically apparent in adulthood. Histomorphometric findings support the postulate that increased intimal thickness can be considered a structural determinant of atherogenesis. These data draw attention to the means for the primary prevention of atherosclerosis in youth.

  4. Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages

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    Stavri, Simona; Trusca, Violeta G.; Simionescu, Maya; Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro

    2015-05-29

    The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5–10 mM). Low doses of metformin (1–3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated that LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5′-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory state