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Sample records for prevent endothelial dysfunction

  1. Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats.

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    Serizawa, Kenichi; Yogo, Kenji; Tashiro, Yoshihito; Takeda, Satoshi; Kawasaki, Ryohei; Aizawa, Ken; Endo, Koichi

    2016-02-01

    Postmenopausal women have high incidence of cardiovascular events as estrogen deficiency can cause endothelial dysfunction. Vitamin D is reported to be beneficial on endothelial function, but it remains controversial whether vitamin D is effective for endothelial dysfunction under the treatment for osteoporosis in postmenopausal women. The aim of this study was to evaluate the endothelial protective effect of eldecalcitol (ELD) in ovariectomized (OVX) rats. ELD (20  ng/kg) was orally administrated five times a week for 4 weeks from 1 day after surgery. After that, flow-mediated dilation (FMD) as an indicator of endothelial function was measured by high-resolution ultrasound in the femoral artery of living rats. ELD ameliorated the reduction of FMD in OVX rats. ELD inhibited the increase in NOX4, nitrotyrosine, and p65 and the decrease in dimer/monomer ratio of nitric oxide synthase in OVX rat femoral arteries. ELD also prevented the decrease in peroxisome proliferator-activated receptor gamma (PPARγ) in femoral arteries and cultured endothelial cells. Although PPARγ is known to inhibit osteoblastogenesis, ELD understandably increased bone mineral density of OVX rats without increase in PPARγ in bone marrow. These results suggest that ELD prevented the deterioration of endothelial function under condition of preventing bone loss in OVX rats. This endothelial protective effect of ELD might be exerted through improvement of endothelial nitric oxide synthase uncoupling, which is mediated by an antioxidative effect through normalization of vascular PPARγ/NF-κB signaling. © 2016 Society for Endocrinology.

  2. Endothelial dysfunction

    OpenAIRE

    Yaylalı, Yalın Tolga; Küçükaslan, Mete

    2011-01-01

    Endothelium is a multi-functional cluster of cells within the vascular system consisting of a single layer ofsquamous epithelium. Physiologically, endothelium performs various arrangement and protection functions.However, when these functions are disturbed toward derangement, endothelium also mediates pathologicalfunctions with negative effects on the body. Endothelial dysfunction is mediated by several mediators (nitricoxide, endothelins, prostaglandins, angiotensin 2, etc). Endothelial dysf...

  3. Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction.

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    Koudelka, Adolf; Ambrozova, Gabriela; Klinke, Anna; Fidlerova, Tana; Martiskova, Hana; Kuchta, Radek; Rudolph, Tanja K; Kadlec, Jaroslav; Kuchtova, Zdenka; Woodcock, Steven R; Freeman, Bruce A; Kubala, Lukas; Pekarova, Michaela

    2016-12-01

    Pulmonary hypertension (PH) represents a serious health complication accompanied with hypoxic conditions, elevated levels of asymmetric dimethylarginine (ADMA), and overall dysfunction of pulmonary vascular endothelium. Since the prevention strategies for treatment of PH remain largely unknown, our study aimed to explore the effect of nitro-oleic acid (OA-NO 2 ), an exemplary nitro-fatty acid (NO 2 -FA), in human pulmonary artery endothelial cells (HPAEC) under the influence of hypoxia or ADMA. HPAEC were treated with OA-NO 2 in the absence or presence of hypoxia and ADMA. The production of nitric oxide (NO) and interleukin-6 (IL-6) was monitored using the Griess method and ELISA, respectively. The expression or activation of different proteins (signal transducer and activator of transcription 3, STAT3; hypoxia inducible factor 1α, HIF-1α; endothelial nitric oxide synthase, eNOS; intercellular adhesion molecule-1, ICAM-1) was assessed by the Western blot technique. We discovered that OA-NO 2 prevents development of endothelial dysfunction induced by either hypoxia or ADMA. OA-NO 2 preserves normal cellular functions in HPAEC by increasing NO production and eNOS expression. Additionally, OA-NO 2 inhibits IL-6 production as well as ICAM-1 expression, elevated by hypoxia and ADMA. Importantly, the effect of OA-NO 2 is accompanied by prevention of STAT3 activation and HIF-1α stabilization. In summary, OA-NO 2 eliminates the manifestation of hypoxia- and ADMA-mediated endothelial dysfunction in HPAEC via the STAT3/HIF-1α cascade. Importantly, our study is bringing a new perspective on molecular mechanisms of NO 2 -FAs action in pulmonary endothelial dysfunction, which represents a causal link in progression of PH. Graphical Abstract ᅟ.

  4. Nicorandil prevents sirolimus-induced production of reactive oxygen species, endothelial dysfunction, and thrombus formation

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    Ken Aizawa

    2015-03-01

    Full Text Available Sirolimus (SRL is widely used to prevent restenosis after percutaneous coronary intervention. However, its beneficial effect is hampered by complications of thrombosis. Several studies imply that reactive oxygen species (ROS play a critical role in endothelial dysfunction and thrombus formation. The present study investigated the protective effect of nicorandil (NIC, an anti-angina agent, on SRL-associated thrombosis. In human coronary artery endothelial cells (HCAECs, SRL stimulated ROS production, which was prevented by co-treatment with NIC. The preventive effect of NIC on ROS was abolished by 5-hydroxydecanoate but not by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. NIC also inhibited SRL-induced up-regulation of NADPH oxidase subunit p22phox mRNA. Co-treatment with NIC and SRL significantly up-regulated superoxide dismutase 2. NIC treatment significantly improved SRL-induced decrease in viability of HCAECs. The functional relevance of the preventive effects of NIC on SRL-induced ROS production and impairment of endothelial viability was investigated in a mouse model of thrombosis. Pretreatment with NIC inhibited the SRL-induced acceleration of FeCl3-initiated thrombus formation and ROS production in the testicular arteries of mice. In conclusion, NIC prevented SRL-induced thrombus formation, presumably due to the reduction of ROS and to endothelial protection. The therapeutic efficacy of NIC could represent an additional option in the prevention of SRL-related thrombosis.

  5. Probiotics (VSL#3 prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.

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    Sherzad K Rashid

    Full Text Available AIMS: Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO and endothelium-dependent hyperpolarization (EDH has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL was evaluated. METHODS: Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹ for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry. RESULTS: Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS. In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels. CONCLUSIONS: These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.

  6. Tongxinluo Prevents Endothelial Dysfunction Induced by Homocysteine Thiolactone In Vivo via Suppression of Oxidative Stress

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    Yi Zhang

    2015-01-01

    Full Text Available Aim. To explore whether Chinese traditional medicine, tongxinluo (TXL, exerts beneficial effects on endothelial dysfunction induced by homocysteine thiolactone (HTL and to investigate the potential mechanisms. Methods and Results. Incubation of cultured human umbilical vein endothelial cells with HTL (1 mM for 24 hours significantly reduced cell viabilities assayed by MTT, and enhanced productions of reactive oxygen species. Pretreatment of cells with TXL (100, 200, and 400 μg/mL for 1 hour reversed these effects induced by HTL. Further, coincubation with GW9662 (0.01, 0.1 mM abolished the protective effects of TXL on HTL-treated cells. In ex vivo experiments, exposure of isolated aortic rings from rats to HTL (1 mM for 1 hour dramatically impaired acetylcholine-induced endothelium-dependent relaxation, reduced SOD activity, and increased malondialdehyde content in aortic tissues. Preincubation of aortic rings with TXL (100, 200, and 400 μg/mL normalized the disorders induced by HTL. Importantly, all effects induced by TXL were reversed by GW9662. In vivo analysis indicated that the administration of TXL (1.0 g/kg/d remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats fed with HTL (50 mg/kg/d for 8 weeks. Conclusions. TXL improves endothelial functions in rats fed with HTL, which is related to PPARγ-dependent suppression of oxidative stress.

  7. Polyphenol-enriched diet prevents coronary endothelial dysfunction by activating the Akt/eNOS pathway.

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    Vilahur, Gemma; Padró, Teresa; Casaní, Laura; Mendieta, Guiomar; López, José A; Streitenberger, Sergio; Badimon, Lina

    2015-03-01

    The Mediterranean diet, rich in polyphenols, has shown to be cardioprotective. However the mechanisms involved remain unknown. We investigated whether supplementation with a pomegranate extract rich in polyphenols renders beneficial effects on coronary function in a clinically relevant experimental model and characterized the underlying mechanisms. Pigs were fed a 10-day normocholesterolemic or hypercholesterolemic diet. Half of the animals were given a supplement of 625 mg/day of a pomegranate extract (Pomanox; 200 mg punicalagins/day). Coronary responses to escalating doses of vasoactive drugs (acetylcholine, calcium ionophore, and sodium nitroprusside) and L-NG-monomethylarginine (endothelial nitric oxide-synthase inhibitor) were measured using flow Doppler. Akt/endothelial nitric oxide-synthase axis activation, monocyte chemoattractant protein-1 expression, oxidative deoxyribonucleic acid damage in the coronary artery, and lipoprotein resistance to oxidation were evaluated. In dyslipidemic animals, Pomanox supplementation prevented diet-induced impairment of endothelial relaxation, reaching vasodilatory values comparable to normocholesterolemic animals upon stimulation with acetylcholine and/or calcium ionophore. These beneficial effects were associated with vascular Akt/endothelial nitric oxide-synthase activation and lower monocyte chemoattractant protein-1 expression. Pomanox supplementation reduced systemic oxidative stress (higher high-density lipoprotein-antioxidant capacity and higher low-density lipoprotein resistance to oxidation) and coronary deoxyribonucleic acid damage. Normocholesterolemic animals elicited similar drug-related vasodilation regardless of Pomanox supplementation. All animals displayed a similar vasodilatory response to sodium nitroprusside and L-NG-monomethylarginine blunted all vasorelaxation responses except for sodium nitroprusside. Pomanox supplementation hinders hyperlipemia-induced coronary endothelial dysfunction by activating

  8. Aldolase B knockdown prevents high glucose-induced methylglyoxal overproduction and cellular dysfunction in endothelial cells.

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    Jianghai Liu

    Full Text Available We used cultured endothelial cells as a model to examine whether up-regulation of aldolase B and enhanced methylglyoxal (MG formation play an important role in high glucose-induced overproduction of advanced glycosylation endproducts (AGEs, oxidative stress and cellular dysfunction. High glucose (25 mM incubation up-regulated mRNA levels of aldose reductase (an enzyme converting glucose to fructose and aldolase B (a key enzyme that catalyzes MG formation from fructose and enhanced MG formation in human umbilical vein endothelial cells (HUVECs and HUVEC-derived EA. hy926 cells. High glucose-increased MG production in EA. hy926 cells was completely prevented by siRNA knockdown of aldolase B, but unaffected by siRNA knockdown of aldolase A, an enzyme responsible for MG formation during glycolysis. In addition, inhibition of cytochrome P450 2E1 or semicarbazide-sensitive amine oxidase which produces MG during the metabolism of lipid and proteins, respectively, did not alter MG production. Both high glucose (25 mM and MG (30, 100 µM increased the formation of N(ε-carboxyethyl-lysine (CEL, a MG-induced AGE, oxidative stress (determined by the generation of oxidized DCF, H(2O(2, protein carbonyls and 8-oxo-dG, O-GlcNAc modification (product of the hexosamine pathway, membrane protein kinase C activity and nuclear translocation of NF-κB in EA. hy926 cells. However, the above metabolic and signaling alterations induced by high glucose were completely prevented by knockdown of aldolase B and partially by application of aminoguanidine (a MG scavenger or alagebrium (an AGEs breaker. In conclusion, efficient inhibition of aldolase B can prevent high glucose-induced overproduction of MG and related cellular dysfunction in endothelial cells.

  9. Obesity, inflammation and endothelial dysfunction.

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    Iantorno, M; Campia, U; Di Daniele, N; Nistico, S; Forleo, G B; Cardillo, C; Tesauro, M

    2014-01-01

    Cardiovascular disease is the leading cause of morbidity and mortality in obese individuals. Obesity dramatically increases the risk of development of metabolic and cardiovascular disease. This risk appears to originate from disruption in adipose tissue function leading to a chronic inflammatory state and to dysregulation of the endocrine and paracrine actions of adipocyte-derived factors. These, in turn, impair vascular homeostasis and lead to endothelial dysfunction. An altered endothelial cell phenotype and endothelial dysfunction are common among all obesity-related complications. A crucial aspect of endothelial dysfunction is reduced nitric oxide (NO) bioavailability. A systemic pro-inflammatory state in combination with hyperglycemia, insulin resistance, oxidative stress and activation of the renin angiotensin system are systemic disturbances in obese individuals that contribute independently and synergistically to decreasing NO bioavailability. On the other hand, pro-inflammatory cytokines are locally produced by perivascular fat and act through a paracrine mechanism to independently contribute to endothelial dysfunction and smooth muscle cell dysfunction and to the pathogenesis of vascular disease in obese individuals. The promising discovery that obesity-induced vascular dysfunction is, at least in part, reversible, with weight loss strategies and drugs that promote vascular health, has not been sufficiently proved to prevent the cardiovascular complication of obesity on a large scale. In this review we discuss the pathophysiological mechanisms underlying inflammation and vascular damage in obese patients.

  10. A Fermented Whole Grain Prevents Lipopolysaccharides-Induced Dysfunction in Human Endothelial Progenitor Cells

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    Laura Giusti

    2017-01-01

    Full Text Available Endogenous and exogenous signals derived by the gut microbiota such as lipopolysaccharides (LPS orchestrate inflammatory responses contributing to development of the endothelial dysfunction associated with atherosclerosis in obesity, metabolic syndrome, and diabetes. Endothelial progenitor cells (EPCs, bone marrow derived stem cells, promote recovery of damaged endothelium playing a pivotal role in cardiovascular repair. Since healthy nutrition improves EPCs functions, we evaluated the effect of a fermented grain, Lisosan G (LG, on early EPCs exposed to LPS. The potential protective effect of LG against LPS-induced alterations was evaluated as cell viability, adhesiveness, ROS production, gene expression, and NF-kB signaling pathway activation. Our results showed that LPS treatment did not affect EPCs viability and adhesiveness but induced endothelial alterations via activation of NF-kB signaling. LG protects EPCs from inflammation as well as from LPS-induced oxidative and endoplasmic reticulum (ER stress reducing ROS levels, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defense. Moreover, LG pretreatment prevented NF-kB translocation from the cytoplasm into the nucleus caused by LPS exposure. In human EPCs, LPS increases ROS and upregulates proinflammatory tone, proapoptotic factors, and antioxidants. LG protects EPCs exposed to LPS reducing ROS, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defenses possibly by inhibiting NF-κB nuclear translocation.

  11. The prevention of endothelial dysfunction through endothelial cell apoptosis inhibition in a hypercholesterolemic rabbit model: the effect of L-arginine supplementation

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    Haghjooyjavanmard Shaghayegh

    2008-08-01

    Full Text Available Abstract Background The impact of L-arginine on atherogenesis and its ability to prevent endothelial dysfunction have been studied extensively during the past years. L-arginine is a substance for nitric oxide synthesis which involves in apoptosis. Hypercholesterolemia promotes endothelial dysfunction, and it is hypothesized that L-arginine prevents endothelial dysfunction through endothelial cells apoptosis inhibition. To test this hypothesis, thirty rabbits were assigned into two groups. The control group received 1% cholesterol diet for 4 weeks, and the L-arginine group received same diets plus 3% L-arginine in drinking water. Results No significant differences were observed in cholesterol level between two groups, but the nitrite concentration in L-arginine group was significantly higher than other group (control group: 11.8 ± 1; L-arginine group: 14.7 ± 0.5 μmol/l; (p p p Conclusion The inhibition of endothelial cells apoptosis by L-arginine restores endothelial function in a model of hypercholesterolemia.

  12. Swimming training prevents coronary endothelial dysfunction in ovariectomized spontaneously hypertensive rats

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    E.R.G. Claudio

    Full Text Available Estrogen deficiency and hypertension are considered major risk factors for the development of coronary heart disease. On the other hand, exercise training is considered an effective form to prevent and treat cardiovascular diseases. However, the effects of swimming training (SW on coronary vascular reactivity in female ovariectomized hypertensive rats are not known. We aimed to evaluate the effects of SW on endothelium-dependent coronary vasodilation in ovariectomized hypertensive rats. Three-month old spontaneously hypertensive rats (SHR, n=50 were divided into four groups: sham (SH, sham plus swimming training (SSW, ovariectomized (OVX, and ovariectomized plus swimming training (OSW. The SW protocol (5 times/week, 60 min/day was conducted for 8 weeks. The vasodilatory response was measured in isolated hearts in the absence and presence of a nitric oxide synthase inhibitor (L-NAME, 100 µM. Cardiac oxidative stress was evaluated in situ by dihydroethidium fluorescence, while the expression of antioxidant enzymes (SOD-2 and catalase and their activities were assessed by western blotting and spectrophotometry, respectively. Vasodilation in SHR was significantly reduced by OVX, even in the presence of L-NAME, in conjunction with an increased oxidative stress. These effects were prevented by SW, and were associated with a decrease in oxidative stress. Superoxide dismutase 2 (SOD-2 and catalase expression increased only in the OSW group. However, no significant difference was found in the activity of these enzymes. In conclusion, SW prevented the endothelial dysfunction in the coronary bed of ovariectomized SHR associated with an increase in the expression of antioxidant enzymes, and therefore may prevent coronary heart disease in hypertensive postmenopausal women.

  13. Endothelial dysfunction in diabetes mellitus

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    Hadi AR Hadi

    2008-01-01

    Full Text Available Hadi AR Hadi, Jassim Al SuwaidiDepartment of Cardiology and Cardiovascular Surgery, Hamad General Hospital – Hamad Medical Corporation, Doha, State of Qatar; Department of Cardioscience, Sheikh Khalifa Medical City, Abu Dhabi, UAEAbstract: Diabetes mellitus is associated with an increased risk of cardiovascular disease, even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggest that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Microalbuminuria is now considered to be an atherosclerotic risk factor and predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain

  14. Roselle supplementation prevents nicotine-induced vascular endothelial dysfunction and remodelling in rats.

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    Si, Lislivia Yiang-Nee; Kamisah, Yusof; Ramalingam, Anand; Lim, Yi Cheng; Budin, Siti Balkis; Zainalabidin, Satirah

    2017-07-01

    Vascular endothelial dysfunction (VED) plays an important role in the initiation of cardiovascular diseases. Roselle, enriched with antioxidants, demonstrates high potential in alleviating hypertension. This study was undertaken to investigate the effects of roselle supplementation of VED and remodelling in a rodent model with prolonged nicotine administration. Male Sprague-Dawley rats (n = 6 per group) were administered with 0.6 mg/kg nicotine for 28 days to induce VED. The rats were given either aqueous roselle (100 mg/kg) or normal saline orally 30 min prior to nicotine injection daily. One additional group of rats served as control. Thoracic aorta was isolated from rats to measure vascular reactivity, vascular remodelling and oxidative stress. Roselle significantly lowered aortic sensitivity to phenylephrine-induced vasoconstriction (Endo-(+) C max = 234.5 ± 3.9%, Endo-(-) C max = 247.6 ± 5.2%) compared with untreated nicotine group (Endo-(+) C max = 264.5 ± 6.9%, Endo-(-) C max = 276.5 ± 6.8%). Roselle also improved aortic response to endothelium-dependent vasodilator, acetylcholine (Endo-(+) R max = 73.2 ± 2.1%, Endo-(-) R max = 26.2 ± 0.8%) compared to nicotine group (Endo-(+) R max = 57.8 ± 1.7%, Endo-(-) R max = 20.9 ± 0.8%). In addition, roselle prevented an increase in intimal media thickness and elastic lamellae proliferation to preserve vascular architecture. Moreover, we also observed a significantly lowered degree of oxidative stress in parallel with increased antioxidant enzymes in aortic tissues of the roselle-treated group. This study demonstrated that roselle prevents VED and remodelling, and as such it has high nutraceutical value as supplement to prevent cardiovascular diseases.

  15. Do Coffee Polyphenols Have a Preventive Action on Metabolic Syndrome Associated Endothelial Dysfunctions? An Assessment of the Current Evidence

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    Yamagata, Kazuo

    2018-01-01

    Epidemiologic studies from several countries have found that mortality rates associated with the metabolic syndrome are inversely associated with coffee consumption. Metabolic syndrome can lead to arteriosclerosis by endothelial dysfunction, and increases the risk for myocardial and cerebral infarction. Accordingly, it is important to understand the possible protective effects of coffee against components of the metabolic syndrome, including vascular endothelial function impairment, obesity and diabetes. Coffee contains many components, including caffeine, chlorogenic acid, diterpenes and trigonelline. Studies have found that coffee polyphenols, such as chlorogenic acids, have many health-promoting properties, such as antioxidant, anti-inflammatory, anti-cancer, anti-diabetes, and antihypertensive properties. Chlorogenic acids may exert protective effects against metabolic syndrome risk through their antioxidant properties, in particular toward vascular endothelial cells, in which nitric oxide production may be enhanced, by promoting endothelial nitric oxide synthase expression. These effects indicate that coffee components may support the maintenance of normal endothelial function and play an important role in the prevention of metabolic syndrome. However, results related to coffee consumption and the metabolic syndrome are heterogeneous among studies, and the mechanisms of its functions and corresponding molecular targets remain largely elusive. This review describes the results of studies exploring the putative effects of coffee components, especially in protecting vascular endothelial function and preventing metabolic syndrome. PMID:29401716

  16. Do Coffee Polyphenols Have a Preventive Action on Metabolic Syndrome Associated Endothelial Dysfunctions? An Assessment of the Current Evidence

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    Kazuo Yamagata

    2018-02-01

    Full Text Available Epidemiologic studies from several countries have found that mortality rates associated with the metabolic syndrome are inversely associated with coffee consumption. Metabolic syndrome can lead to arteriosclerosis by endothelial dysfunction, and increases the risk for myocardial and cerebral infarction. Accordingly, it is important to understand the possible protective effects of coffee against components of the metabolic syndrome, including vascular endothelial function impairment, obesity and diabetes. Coffee contains many components, including caffeine, chlorogenic acid, diterpenes and trigonelline. Studies have found that coffee polyphenols, such as chlorogenic acids, have many health-promoting properties, such as antioxidant, anti-inflammatory, anti-cancer, anti-diabetes, and antihypertensive properties. Chlorogenic acids may exert protective effects against metabolic syndrome risk through their antioxidant properties, in particular toward vascular endothelial cells, in which nitric oxide production may be enhanced, by promoting endothelial nitric oxide synthase expression. These effects indicate that coffee components may support the maintenance of normal endothelial function and play an important role in the prevention of metabolic syndrome. However, results related to coffee consumption and the metabolic syndrome are heterogeneous among studies, and the mechanisms of its functions and corresponding molecular targets remain largely elusive. This review describes the results of studies exploring the putative effects of coffee components, especially in protecting vascular endothelial function and preventing metabolic syndrome.

  17. Do Coffee Polyphenols Have a Preventive Action on Metabolic Syndrome Associated Endothelial Dysfunctions? An Assessment of the Current Evidence.

    Science.gov (United States)

    Yamagata, Kazuo

    2018-02-04

    Epidemiologic studies from several countries have found that mortality rates associated with the metabolic syndrome are inversely associated with coffee consumption. Metabolic syndrome can lead to arteriosclerosis by endothelial dysfunction, and increases the risk for myocardial and cerebral infarction. Accordingly, it is important to understand the possible protective effects of coffee against components of the metabolic syndrome, including vascular endothelial function impairment, obesity and diabetes. Coffee contains many components, including caffeine, chlorogenic acid, diterpenes and trigonelline. Studies have found that coffee polyphenols, such as chlorogenic acids, have many health-promoting properties, such as antioxidant, anti-inflammatory, anti-cancer, anti-diabetes, and antihypertensive properties. Chlorogenic acids may exert protective effects against metabolic syndrome risk through their antioxidant properties, in particular toward vascular endothelial cells, in which nitric oxide production may be enhanced, by promoting endothelial nitric oxide synthase expression. These effects indicate that coffee components may support the maintenance of normal endothelial function and play an important role in the prevention of metabolic syndrome. However, results related to coffee consumption and the metabolic syndrome are heterogeneous among studies, and the mechanisms of its functions and corresponding molecular targets remain largely elusive. This review describes the results of studies exploring the putative effects of coffee components, especially in protecting vascular endothelial function and preventing metabolic syndrome.

  18. Montelukast prevents vascular endothelial dysfunction from internal combustion exhaust inhalation during exercise.

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    Rundell, Kenneth W; Steigerwald, Michelle D; Fisk, Michelle Z

    2010-08-01

    Associations between high particulate matter (PM) pollution and increased morbidity and mortality from coronary heart disease have been identified. This study assessed leukotriene (LT) participation in PM-induced vascular endothelial dysfunction. Ten healthy males exercised 4 times for 30 min in both high PM (550,286 +/- 42,004 particles x cm(-3)) and low PM (4571 +/- 1922 particles x cm(-3)) after ingesting placebo (PL) or 10 mg montelukast (MK; half-life 3-6 h), a leukotriene receptor antagonist. Brachial artery flow-mediated dilation (FMD) was measured pre- and 30 min, 4 h, 24 h post-exercise. No basal brachial artery vascoconstriction was evident from high PM exercise. High PM blunted FMD, whereas high PM MK, low PM PL, and low PM MK demonstrated normal FMD (p < .003). Change in FMD (pre- to post-exercise) for high PM PL was different than for high PM MK, low PM PL, and low PM MK at 30 min post-exercise (p < .007). At 4 h, high PM MK FMD blunting increased (p = .1). At 24 h, high PM FMD blunting persisted (p < .05); no difference was observed between high PM PL or MK treatment, but was different that low PM PL/MK treatments (p < .05). MK blocked high PM post-exercise FMD blunting and maintained normal response, suggesting that leukotrienes are involved in PM-initiated vascular endothelial dysfunction.

  19. Lidocaine Prevents Oxidative Stress-Induced Endothelial Dysfunction of the Systemic Artery in Rats With Intermittent Periodontal Inflammation.

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    Saito, Takumi; Yamamoto, Yasuhiro; Feng, Guo-Gang; Kazaoka, Yoshiaki; Fujiwara, Yoshihiro; Kinoshita, Hiroyuki

    2017-06-01

    Periodontal inflammation causes endothelial dysfunction of the systemic artery. However, it is unknown whether the use of local anesthetics during painful dental procedures alleviates periodontal inflammation and systemic endothelial function. This study was designed to examine whether the gingival or systemic injection of lidocaine prevents oxidative stress-induced endothelial dysfunction of the systemic artery in rats with intermittent periodontal inflammation caused by lipopolysaccharides (LPS). Some rats received 1500 µg LPS injections to the gingiva during a week interval from the age of 8 to 11 weeks (LPS group). Lidocaine (3 mg/kg), LPS + lidocaine (3 mg/kg), LPS + lidocaine (1.5 mg/kg), and LPS + lidocaine (3 mg/kg, IP) groups simultaneously received gingival 1.5 or 3 mg/kg or IP 3 mg/kg injection of lidocaine on the same schedule as the gingival LPS. Isolated aortas or mandibles were subjected to the evaluation of histopathologic change, isometric force recording, reactive oxygen species, and Western immunoblotting. Mean blood pressure and heart rate did not differ among the control, LPS, LPS + lidocaine (3 mg/kg), and lidocaine (3 mg/kg) groups. LPS application reduced acetylcholine (ACh, 10 to 10 mol/L)-induced relaxation (29% difference at ACh 3 × 10 mol/L, P = .01), which was restored by catalase. Gingival lidocaine (1.5 and 3 mg/kg) dose dependently prevented the endothelial dysfunction caused by LPS application (24.5%-31.1% difference at ACh 3 × 10 mol/L, P = .006 or .001, respectively). Similar to the gingival application, the IP injection of lidocaine (3 mg/kg) restored the ACh-induced dilation of isolated aortas from rats with the LPS application (27.5% difference at ACh 3 × 10 mol/L, P lidocaine (3 mg/kg), or the combination. The LPS induced a 4-fold increase in the protein expression of tumor necrosis factor-α in the periodontal tissue (P lidocaine (3 mg/kg) coadministration partly reduced the levels. Lidocaine application also decreased

  20. Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction.

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    Reis, Patricia A; Alexandre, Pedro C B; D'Avila, Joana C; Siqueira, Luciana D; Antunes, Barbara; Estato, Vanessa; Tibiriça, Eduardo V; Verdonk, Franck; Sharshar, Tarek; Chrétien, Fabrice; Castro-Faria-Neto, Hugo C; Bozza, Fernando A

    2017-02-01

    Acute brain dysfunction is a frequent condition in sepsis patients and is associated with increased mortality and long-term neurocognitive consequences. Impaired memory and executive function are common findings in sepsis survivors. Although neuroinflammation and blood-brain barrier dysfunction have been associated with acute brain dysfunction and its consequences, no specific treatments are available that prevent cognitive impairment after sepsis. Experimental sepsis was induced in Swiss Webster mice by intraperitoneal injection of cecal material (5mg/kg, 500μL). Control groups (n=5/group each experiment) received 500μL of saline. Support therapy recover (saline 0.9%, 1mL and imipenem 30mg/kg) were applied (6, 24 and 48h post injection, n=5-10/group, each experiment), together or not with additive orally treatment with statins (atorvastatin/simvastatin 20mg/kg b.w.). Survival rate was monitored at 6, 24 and 48h. In a setting of experiments, animals were euthanized at 6 and 24h after induction for biochemical, immunohistochemistry and intravital analysis. Statins did not prevented mortality in septic mice, however survivors presented lower clinical score. At another setting of experiments, after 15days, mice survivors from fecal supernatant peritoneal sepsis presented cognitive dysfunction for contextual hippocampal and aversive amygdala-dependent memories, which was prevented by atorvastatin/simvastatin treatment. Systemic and brain tissue levels of proinflammatory cytokines/chemokines and activation of microglial were lower in septic mice treated with statins. Brain lipid peroxidation and myeloperoxidase levels were also reduced by statins treatment. Intravital examination of the brain vessels of septic animals revealed decreased functional capillary density and increased rolling and adhesion of leukocytes, and blood flow impairment, which were reversed by treatment with statins. In addition, treatment with statins restored the cholinergic vasodilator response

  1. Taurine supplementation reduces blood pressure and prevents endothelial dysfunction and oxidative stress in post-weaning protein-restricted rats.

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    Maia, Aline R; Batista, Thiago M; Victorio, Jamaira A; Clerici, Stefano P; Delbin, Maria A; Carneiro, Everardo M; Davel, Ana P

    2014-01-01

    Taurine is a sulfur-containing amino acid that exerts protective effects on vascular function and structure in several models of cardiovascular diseases through its antioxidant and anti-inflammatory properties. Early protein malnutrition reprograms the cardiovascular system and is linked to hypertension in adulthood. This study assessed the effects of taurine supplementation in vascular alterations induced by protein restriction in post-weaning rats. Weaned male Wistar rats were fed normal- (12%, NP) or low-protein (6%, LP) diets for 90 days. Half of the NP and LP rats concomitantly received 2.5% taurine supplementation in the drinking water (NPT and LPT, respectively). LP rats showed elevated systolic, diastolic and mean arterial blood pressure versus NP rats; taurine supplementation partially prevented this increase. There was a reduced relaxation response to acetylcholine in isolated thoracic aortic rings from the LP group that was reversed by superoxide dismutase (SOD) or apocynin incubation. Protein expression of p47phox NADPH oxidase subunit was enhanced, whereas extracellular (EC)-SOD and endothelial nitric oxide synthase phosphorylation at Ser 1177 (p-eNOS) were reduced in aortas from LP rats. Furthermore, ROS production was enhanced while acetylcholine-induced NO release was reduced in aortas from the LP group. Taurine supplementation improved the relaxation response to acetylcholine and eNOS-derived NO production, increased EC-SOD and p-eNOS protein expression, as well as reduced ROS generation and p47phox expression in the aortas from LPT rats. LP rats showed an increased aortic wall/lumen ratio and taurine prevented this remodeling through a reduction in wall media thickness. Our data indicate a protective role of taurine supplementation on the high blood pressure, endothelial dysfunction and vascular remodeling induced by post-weaning protein restriction. The beneficial vascular effect of taurine was associated with restoration of vascular redox

  2. Taurine supplementation reduces blood pressure and prevents endothelial dysfunction and oxidative stress in post-weaning protein-restricted rats.

    Directory of Open Access Journals (Sweden)

    Aline R Maia

    Full Text Available INTRODUCTION: Taurine is a sulfur-containing amino acid that exerts protective effects on vascular function and structure in several models of cardiovascular diseases through its antioxidant and anti-inflammatory properties. Early protein malnutrition reprograms the cardiovascular system and is linked to hypertension in adulthood. This study assessed the effects of taurine supplementation in vascular alterations induced by protein restriction in post-weaning rats. METHODS AND RESULTS: Weaned male Wistar rats were fed normal- (12%, NP or low-protein (6%, LP diets for 90 days. Half of the NP and LP rats concomitantly received 2.5% taurine supplementation in the drinking water (NPT and LPT, respectively. LP rats showed elevated systolic, diastolic and mean arterial blood pressure versus NP rats; taurine supplementation partially prevented this increase. There was a reduced relaxation response to acetylcholine in isolated thoracic aortic rings from the LP group that was reversed by superoxide dismutase (SOD or apocynin incubation. Protein expression of p47phox NADPH oxidase subunit was enhanced, whereas extracellular (EC-SOD and endothelial nitric oxide synthase phosphorylation at Ser 1177 (p-eNOS were reduced in aortas from LP rats. Furthermore, ROS production was enhanced while acetylcholine-induced NO release was reduced in aortas from the LP group. Taurine supplementation improved the relaxation response to acetylcholine and eNOS-derived NO production, increased EC-SOD and p-eNOS protein expression, as well as reduced ROS generation and p47phox expression in the aortas from LPT rats. LP rats showed an increased aortic wall/lumen ratio and taurine prevented this remodeling through a reduction in wall media thickness. CONCLUSION: Our data indicate a protective role of taurine supplementation on the high blood pressure, endothelial dysfunction and vascular remodeling induced by post-weaning protein restriction. The beneficial vascular effect of

  3. Aging compounds western diet-associated large artery endothelial dysfunction in mice: prevention by voluntary aerobic exercise.

    Science.gov (United States)

    Lesniewski, Lisa A; Zigler, Melanie L; Durrant, Jessica R; Nowlan, Molly J; Folian, Brian J; Donato, Anthony J; Seals, Douglas R

    2013-11-01

    We tested the hypothesis that aging will exacerbate the negative vascular consequences of exposure to a common physiological stressor, i.e., consumption of a "western" (high fat/high sucrose) diet (WD), by inducing superoxide-associated reductions in nitric oxide (NO) bioavailability, and that this would be prevented by voluntary aerobic exercise. Incremental stiffness and endothelium-dependent dilation (EDD) were measured in the carotid arteries of young (5.4±0.3 mo, N=20) and old (30.4±0.2 mo, N=19) male B6D2F1 mice fed normal chow (NC: 17% fat, 0% sucrose) or a western diet (40% fat, 19% sucrose) and housed in either standard cages or cages equipped with running wheels for 10-14 weeks. Incremental stiffness was higher in old NC (P<0.05) and both young (P<0.01) and old (P<0.01) WD fed mice compared with young NC mice, but WD did not further increase stiffness in the old mice. In cage control mice, maximal EDD was 17% lower in both NC fed old mice and young WD fed mice (P<0.05). Consumption of WD by old mice led to a further 20% reduction in maximal EDD (P<0.05). Incremental stiffness was 28% lower and maximal EDD was 38% greater in old WD fed mice with access to running wheels vs. old WD fed control mice (P<0.05) and not different from young NC fed controls. Wheel running also tended to improve maximal EDD (+9%, P=0.11), but not incremental stiffness in young WD fed mice. Ex vivo treatment with the superoxide scavenger TEMPOL and NO inhibitor l-NAME abolished these respective effects of age, WD and voluntary running on EDD. Ingestion of a WD induces similar degrees of endothelial dysfunction in old and young adult B6D2F1 mice, and these effects are mediated by a superoxide-dependent impairment of NO bioavailability. However, the combination of old age and WD, a common occurrence in our aging society, results in a marked, additive reduction in endothelial function. Importantly, regular voluntary aerobic exercise reduces arterial stiffness and protects against

  4. Endothelial dysfunction: a comprehensive appraisal

    Directory of Open Access Journals (Sweden)

    Vilariño Jorge O

    2006-02-01

    Full Text Available Abstract The endothelium is a thin monocelular layer that covers all the inner surface of the blood vessels, separating the circulating blood from the tissues. It is not an inactive organ, quite the opposite. It works as a receptor-efector organ and responds to each physical or chemical stimulus with the release of the correct substance with which it may maintain vasomotor balance and vascular-tissue homeostasis. It has the property of producing, independently, both agonistic and antagonistic substances that help to keep homeostasis and its function is not only autocrine, but also paracrine and endocrine. In this way it modulates the vascular smooth muscle cells producing relaxation or contraction, and therefore vasodilatation or vasoconstriction. The endothelium regulating homeostasis by controlling the production of prothrombotic and antithrombotic components, and fibrynolitics and antifibrynolitics. Also intervenes in cell proliferation and migration, in leukocyte adhesion and activation and in immunological and inflammatory processes. Cardiovascular risk factors cause oxidative stress that alters the endothelial cells capacity and leads to the so called endothelial "dysfunction" reducing its capacity to maintain homeostasis and leads to the development of pathological inflammatory processes and vascular disease. There are different techniques to evaluate the endothelium functional capacity, that depend on the amount of NO produced and the vasodilatation effect. The percentage of vasodilatation with respect to the basal value represents the endothelial functional capacity. Taking into account that shear stress is one of the most important stimulants for the synthesis and release of NO, the non-invasive technique most often used is the transient flow-modulate "endothelium-dependent" post-ischemic vasodilatation, performed on conductance arteries such as the brachial, radial or femoral arteries. This vasodilatation is compared with the

  5. Sildenafil inhibits superoxide formation and prevents endothelial dysfunction in a mouse model of secondhand smoke induced erectile dysfunction.

    Science.gov (United States)

    Bivalacqua, Trinity J; Sussan, Thomas E; Gebska, Melina A; Strong, Travis D; Berkowitz, Dan E; Biswal, Shyam; Burnett, Arthur L; Champion, Hunter C

    2009-02-01

    We determined the effect of passive secondhand cigarette smoke on 1) erectile function in vivo, 2) molecular mechanisms involved in penile vascular function, and 3) erectile function and penile molecular signaling in the presence of phosphodiesterase type 5 inhibitor therapy. Four groups of mice were used, including group 1--controls, group 2--mice exposed to 3 weeks of secondhand smoke (5 hours per day for 5 days per week), group 3--control plus sildenafil (100 mg/kg per day) and group 4--smoke exposed plus sildenafil (100 mg/kg per day). Cavernous nerve electrical stimulation and intracavernous injection of acetylcholine were done to assess erectile function. Constitutive and inducible nitric oxide synthase activity, reactive oxygen species generation, nitrotyrosine formation and superoxide anion levels were assessed. Decreased erectile responses to cavernous nerve electrical stimulation and impaired endothelium dependent erectile responses to ACh in mice exposed to secondhand smoke were observed. Superoxide anion was increased in endothelial and corporeal smooth muscle cells of smoking mouse penises. In mice exposed to secondhand smoke constitutive nitric oxide synthase activity was decreased, and inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation increased. Sildenafil therapy restored constitutive nitric oxide synthase activity in the penis of smoking mice, decreased inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation, and improved erectile responses to cavernous nerve electrical stimulation and acetylcholine. Short-term exposure to secondhand smoke impairs erectile function through excessive penile reactive oxygen species signaling and inducible nitric oxide synthase activity. Decreased penile constitutive nitric oxide synthase activity may be attributable to the decreased endothelial nitric oxide synthase activity resulting from increased oxidative

  6. EPA:DHA 6:1 prevents angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase- and COX-derived oxidative stress.

    Science.gov (United States)

    Niazi, Zahid Rasul; Silva, Grazielle C; Ribeiro, Thais Porto; León-González, Antonio J; Kassem, Mohamad; Mirajkar, Abdur; Alvi, Azhar; Abbas, Malak; Zgheel, Faraj; Schini-Kerth, Valérie B; Auger, Cyril

    2017-12-01

    Eicosapentaenoic acid:docosahexaenoic acid (EPA:DHA) 6:1, an omega-3 polyunsaturated fatty acid formulation, has been shown to induce a sustained formation of endothelial nitric oxide (NO) synthase-derived NO, a major vasoprotective factor. This study examined whether chronic intake of EPA:DHA 6:1 prevents hypertension and endothelial dysfunction induced by angiotensin II (Ang II) in rats. Male Wister rats received orally corn oil or EPA:DHA 6:1 (500 mg kg -1 per day) before chronic infusion of Ang II (0.4 mg kg -1 per day). Systolic blood pressure was determined by tail cuff sphingomanometry, vascular reactivity using a myograph, oxidative stress using dihydroethidium and protein expression by immunofluorescence and western blot analysis. Ang II-induced hypertension was associated with reduced acetylcholine-induced relaxations of secondary branch mesenteric artery rings affecting the endothelium-dependent hyperpolarization (EDH)- and the NO-mediated relaxations, both of which were improved by the NADPH oxidase inhibitor VAS-2870. The Ang II treatment induced also endothelium-dependent contractile responses (EDCFs), which were abolished by the cyclooxygenase (COX) inhibitor indomethacin. An increased level of vascular oxidative stress and expression of NADPH oxidase subunits (p47 phox and p22 phox ), COX-1 and COX-2, endothelial NO synthase and Ang II type 1 receptors were observed in the Ang II group, whereas SK Ca and connexin 37 were downregulated. Intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction by improving both the NO- and EDH-mediated relaxations, and by reducing EDCFs and the expression of target proteins. The present findings indicate that chronic intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction in rats, most likely by preventing NADPH oxidase- and COX-derived oxidative stress.

  7. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction.

    Science.gov (United States)

    Brownfoot, Fiona C; Hastie, Roxanne; Hannan, Natalie J; Cannon, Ping; Tuohey, Laura; Parry, Laura J; Senadheera, Sevvandi; Illanes, Sebastian E; Kaitu'u-Lino, Tu'uhevaha J; Tong, Stephen

    2016-03-01

    Preeclampsia is associated with placental ischemia/hypoxia and secretion of soluble fms-like tyrosine kinase 1 and soluble endoglin into the maternal circulation. This causes widespread endothelial dysfunction that manifests clinically as hypertension and multisystem organ injury. Recently, small molecule inhibitors of hypoxic inducible factor 1α have been found to reduce soluble fms-like tyrosine kinase 1 and soluble endoglin secretion. However, their safety profile in pregnancy is unknown. Metformin is safe in pregnancy and is also reported to inhibit hypoxic inducible factor 1α by reducing mitochondrial electron transport chain activity. The purposes of this study were to determine (1) the effects of metformin on placental soluble fms-like tyrosine kinase 1 and soluble endoglin secretion, (2) to investigate whether the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion are regulated through the mitochondrial electron transport chain, and (3) to examine its effects on endothelial dysfunction, maternal blood vessel vasodilation, and angiogenesis. We performed functional (in vitro and ex vivo) experiments using primary human tissues to examine the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from placenta, endothelial cells, and placental villous explants. We used succinate, mitochondrial complex II substrate, to examine whether the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion were mediated through the mitochondria. We also isolated mitochondria from preterm preeclamptic placentas and gestationally matched control subjects and measured mitochondrial electron transport chain activity using kinetic spectrophotometric assays. Endothelial cells or whole maternal vessels were incubated with metformin to determine whether it rescued endothelial dysfunction induced by either tumor necrosis factor-α (to endothelial cells) or placenta villous

  8. L-arginine is an effective medication for prevention of endothelial dysfunction, a predictor of anthracycline cardiotoxicity in patients with acute leukemia.

    Science.gov (United States)

    Skrypnyk, I; Maslova, G; Lymanets, T; Gusachenko, I

    2017-12-01

    To evaluate the effectiveness of L-arginine in the prevention of endothelial dysfunction, which may be a predictor of anthracycline-induced myocardial injury, in patients with acute leukemia (AL) on the background of anthracycline antibiotics low cumulative doses from 100 to 200 mg/m 2 . A total of 81 adult AL patients (38 males and 43 females with the age of 16-59 years) were studied. The patients were divided into two groups: group I (n = 34), AL patients treated with chemotherapy (CT) and L-arginine hydrochloride; group II (n = 47) - AL patients treated with CT only. Cardiac evaluation and endothelial function assessment were performed at baseline and after second CT. Electrocardiography (ECG) parameters, lipid peroxidation activity, antioxidant protection and NO system state were evaluated. The bioelectric activity abnormalities of the myocardium were observed in studied patients with low cardiac risk after induction CT. In case of L-arginine administration, only minimal daily ECG changes were recorded. A significant difference in the lipid peroxidation and antioxidant defense system activity in patients of groups I and II was determined. We noticed deepening of endothelial dysfunction on the background of cytostatic therapy with anthracycline antibiotics compared with baseline values in patients of group II. It was found that prophylactic L-arginine increases superoxide dismutase level and reduces the total NOS activity due to its inducible isoform. The leading factor of anthracycline-induced cardiotoxicity is the imbalance between free radical generation and their inactivation that leads to endothelial dysfunction development. L-arginine eliminates the prooxidant-antioxidant imbalance and improves the endothelial function.

  9. Doinseunggitang Ameliorates Endothelial Dysfunction in Diabetic Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Jung Joo Yoon

    2013-01-01

    Full Text Available Atherosclerosis, a chronic and progressive disease characterized by vascular inflammation, is a leading cause of death in diabetes patients. Doinseunggitang (DYSGT, traditional prescription, has been used for promoting blood circulation to remove blood stasis. The aim of this study was to investigate the beneficial effects of DYSGT on endothelial dysfunction in diabetic atherosclerosis animal model. Apolipoprotein E knockout (ApoE KO mice fed on a Western diet were treated with DYSGT (200 mg/kg/day. DYSGT significantly lowered blood glucose level and glucose tolerance as well as systolic blood pressure. Metabolic parameter showed that DYSGT markedly decreased triglyceride and LDL-cholesterol levels. In the thoracic aorta, the impairment of vasorelaxation response to acetylcholine and atherosclerotic lesion was attenuated by DYSGT. Furthermore, DYSGT restored the reduction of endothelial nitric oxide synthase (eNOS expression, leading to the inhibition of intracellular adhesion molecule-1 (ICAM-1 and endothelin-1 (ET-1 expression. In conclusion, DYSGT improved the development of diabetic atherosclerosis via attenuation of the endothelial dysfunction, possibly by inhibiting ET-1, cell adhesion molecules, and lesion formation. Therefore, these results suggest that Korean traditional prescription Doinseunggitang may be useful in the treatment and prevention of diabetic vascular complications.

  10. Polyphenol-Rich Blackcurrant Juice Prevents Endothelial Dysfunction in the Mesenteric Artery of Cirrhotic Rats with Portal Hypertension: Role of Oxidative Stress and the Angiotensin System.

    Science.gov (United States)

    Rashid, Sherzad; Idris-Khodja, Noureddine; Auger, Cyril; Kevers, Claire; Pincemail, Joël; Alhosin, Mahmoud; Boehm, Nelly; Oswald-Mammosser, Monique; Schini-Kerth, Valérie B

    2018-04-01

    Chronic liver diseases with portal hypertension are characterized by a progressive vasodilatation, endothelial dysfunction, and NADPH oxidase-derived vascular oxidative stress, which have been suggested to involve the angiotensin system. This study evaluated the possibility that oral intake of polyphenol-rich blackcurrant juice (PRBJ), a rich natural source of antioxidants, prevents endothelial dysfunction in a rat model of cirrhosis induced by chronic bile duct ligation (CBDL), and, if so, determined the underlying mechanism. Male Wistar rats received either control drinking water or water containing 60 mg/kg gallic acid equivalents of PRBJ for 3 weeks before undergoing surgery with CBDL or sham surgery. After 4 weeks, vascular reactivity was assessed in mesenteric artery rings using organ chambers. Both the acetylcholine-induced nitric oxide (NO)- and endothelium-dependent hyperpolarization (EDH)-mediated relaxations in mesenteric artery rings were significantly reduced in CBDL rats compared to sham rats. An increased level of oxidative stress and expression of NADPH oxidase subunits, COX-2, NOS, and of the vascular angiotensin system are observed in arterial sections in the CBDL group. Chronic intake of PRBJ prevented the CBDL-induced impaired EDH-mediated relaxation, oxidative stress, and expression of the different target proteins in the arterial wall. In addition, PRBJ prevented the CBDL-induced increase in the plasma level of proinflammatory cytokines (interleukin [IL]-1α, monocyte chemotactic protein 1, and tumor necrosis factor α) and the decrease of the anti-inflammatory cytokine, IL-4. Altogether, these observations indicate that regular ingestion of PRBJ prevents the CBDL-induced endothelial dysfunction in the mesenteric artery most likely by normalizing the level of vascular oxidative stress and the angiotensin system.

  11. [Endothelial dysfunction in hypertension--clinical implications].

    Science.gov (United States)

    Kosmala, Wojciech

    2002-04-01

    Endothelial cells produce both vasodilatating compounds as nitric oxide, prostacycline, endothelial derived hyperpolarising factor and counteracting substances known as endothelial derived contracting factors: endothelin, tromboxan A2, prostaglandin H2, free oxygen radicals. Natural balance between both groups affects blood perfusion of various tissues and constitutes important element in blood pressure control. More and more attention is paid to endothelial dysfunction in patogenesis of hypertension. In a number of studies endothelial dysfunction in hypertensive patients was found out as decreased release of nitric oxide or increased production of endothelin. Principle mechanism of impaired function of endothelium in hypertension seems to be decreased production and increased degradation of nitric oxide mainly due to free oxygen radicals. Favorable effects in improvement of endothelial function were achieved by using ACE inhibitors, AT1 receptor blockers and calcium channel antagonists.

  12. Nicorandil prevents endothelial dysfunction due to antioxidative effects via normalisation of NADPH oxidase and nitric oxide synthase in streptozotocin diabetic rats

    Directory of Open Access Journals (Sweden)

    Serizawa Ken-ichi

    2011-11-01

    Full Text Available Abstract Background Nicorandil, an anti-angina agent, reportedly improves outcomes even in angina patients with diabetes. However, the precise mechanism underlying the beneficial effect of nicorandil on diabetic patients has not been examined. We investigated the protective effect of nicorandil on endothelial function in diabetic rats because endothelial dysfunction is a major risk factor for cardiovascular disease in diabetes. Methods Male Sprague-Dawley rats (6 weeks old were intraperitoneally injected with streptozotocin (STZ, 40 mg/kg, once a day for 3 days to induce diabetes. Nicorandil (15 mg/kg/day and tempol (20 mg/kg/day, superoxide dismutase mimetic were administered in drinking water for one week, starting 3 weeks after STZ injection. Endothelial function was evaluated by measuring flow-mediated dilation (FMD in the femoral arteries of anaesthetised rats. Cultured human coronary artery endothelial cells (HCAECs were treated with high glucose (35.6 mM, 24 h and reactive oxygen species (ROS production with or without L-NAME (300 μM, apocynin (100 μM or nicorandil (100 μM was measured using fluorescent probes. Results Endothelial function as evaluated by FMD was significantly reduced in diabetic as compared with normal rats (diabetes, 9.7 ± 1.4%; normal, 19.5 ± 1.7%; n = 6-7. There was a 2.4-fold increase in p47phox expression, a subunit of NADPH oxidase, and a 1.8-fold increase in total eNOS expression in diabetic rat femoral arteries. Nicorandil and tempol significantly improved FMD in diabetic rats (nicorandil, 17.7 ± 2.6%; tempol, 13.3 ± 1.4%; n = 6. Nicorandil significantly inhibited the increased expressions of p47phox and total eNOS in diabetic rat femoral arteries. Furthermore, nicorandil significantly inhibited the decreased expression of GTP cyclohydrolase I and the decreased dimer/monomer ratio of eNOS. ROS production in HCAECs was increased by high-glucose treatment, which was prevented by L-NAME and nicorandil

  13. Endothelial Dysfunction in Idiopathic Sudden Sensorineural Hearing Loss: A Review

    Science.gov (United States)

    Quaranta, Nicola; De Ceglie, Vincenzo; D’Elia, Alessandra

    2016-01-01

    An endothelial dysfunction has been described in idiopathic sudden sensorineural hearing loss (ISSHL) patients. The purpose of our review was to: i) identify, evaluate and review recent research about cardiovascular risk factors involvement and signs of endothelial dysfunction in ISSHL; ii) implication of these discovering in clinical practice and future research. A Medline literature search was conducted to identify any study on the involvement of endothelial dysfunction in ISSHL, published in the English language in the last decade. The following MEDLINE search terms were used: sudden sensorineural hearing loss (SSHL) and endothelial dysfunction (text words). Additional studies were identified by hand searching the references of original articles and review articles. Studies were not excluded on the basis of the qualitative or quantitative definitions of SSHL, treatment regimens, or outcome measures. Data were extracted from included papers by a reviewer. Information on the patients, investigations, methods, interventions, and outcomes were systematically analyzed. Characteristics and results of all included studies were reviewed systematically. High levels of adhesion molecules, hyperhomocysteinemia and lower folate levels, unbalanced oxidative status, a lower value of flow-mediated dilatation of brachial artery and a reduced percentage of circulating endothelial progenitor cells in patients affected by ISSHL support the hypothesis that this syndrome should be considered as a microcirculation disorder based on endothelial dysfunction and drive clinicians to implement all the traditional strategies used for preventing cardiovascular events, to also reduce the likelihood of ISSHL occurrence. PMID:27588164

  14. Endothelial dysfunction after non-cardiac surgery

    DEFF Research Database (Denmark)

    Søndergaard, E S; Fonnes, S; Gögenur, I

    2015-01-01

    BACKGROUND: More than 50% of patients with increased troponin levels after non-cardiac surgery have an impaired endothelial function pre-operatively. Non-invasive markers of endothelial function have been developed for the assessment of endothelial dysfunction. The aim of this paper was to system......BACKGROUND: More than 50% of patients with increased troponin levels after non-cardiac surgery have an impaired endothelial function pre-operatively. Non-invasive markers of endothelial function have been developed for the assessment of endothelial dysfunction. The aim of this paper...... was to systematically review the literature to evaluate the association between non-cardiac surgery and non-invasive markers of endothelial function. METHODS: A systematic search was conducted in MEDLINE, EMBASE and Cochrane Library Database according to the PRISMA guidelines. Endothelial dysfunction was described only...... with non-invasive measurements done both pre- and post-operatively and published in English. All types of non-cardiac surgery and both men and women of all ages were included. RESULTS: We found 1722 eligible studies in our search, and of these, five studies fulfilled our inclusion and exclusion criteria...

  15. Dysfunctional Endothelial Progenitor Cells in Metabolic Syndrome

    Science.gov (United States)

    Devaraj, Sridevi; Jialal, Ishwarlal

    2012-01-01

    The metabolic syndrome (MetS) is highly prevalent and confers an increased risk of diabetes and cardiovascular disease. A key early event in atherosclerosis is endothelial dysfunction. Numerous groups have reported endothelial dysfunction in MetS. However, the measurement of endothelial function is far from optimum. There has been much interest recently in a subtype of progenitor cells, termed endothelial progenitor cells (EPCs), that can circulate, proliferate, and dfferentiate into mature endothelial cells. EPCs can be characterized by the assessment of surface markers, CD34 and vascular endothelial growth factor receptor-2, VEGFR-2 (KDR). The CD34+KDR+ phenotype has been demonstrated to be an independent predictor of cardiovascular outcomes. MetS patients without diabetes or cardiovascular diseases have decreased EPC number and functionality as evidenced by decreased numbers of colony forming units, decreased adhesion and migration, and decreased tubule formation. Strategies that have been shown to upregulate and enhance EPC number and functionality include statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and peroxisome-proliferator-activating-receptor gamma agonists. Mechanisms by which they affect EPC number and functionality need to be studied. Thus, EPC number and/or functionality could emerge as novel cellular biomarkers of endothelial dysfunction and cardiovascular disease risk in MetS. PMID:21941528

  16. Arginase Inhibitor in the Pharmacological Correction of Endothelial Dysfunction

    Directory of Open Access Journals (Sweden)

    Mihail V. Pokrovskiy

    2011-01-01

    Full Text Available This paper is about a way of correction of endothelial dysfunction with the inhibitor of arginase: L-norvaline. There is an imbalance between vasoconstriction and vasodilatation factors of endothelium on the basis of endothelial dysfunction. Among vasodilatation agents, nitrogen oxide plays the basic role. Amino acid L-arginine serves as a source of molecules of nitrogen oxide in an organism. Because of the high activity of arginase enzyme which catalyzes the hydrolysis of L-arginine into ornithine and urea, the bioavailability of nitrogen oxide decreases. The inhibitors of arginase suppress the activity of the given enzyme, raising and production of nitrogen oxide, preventing the development of endothelial dysfunction.

  17. Type 2 Diabetes: Endothelial dysfunction and Exercise

    OpenAIRE

    Hwang, Moon-Hyon; Kim, Sangho

    2014-01-01

    [Purpose] Vascular endothelial dysfunction is an early marker of atherosclerosis characterized by decreased nitric oxide bioavailability in the vascular endothelium and smooth muscle cells. Recently, some animal models and in vitro trials demonstrated that excessive superoxide production from mitochondria within vascular endothelial cells played a role in the pathogenesis of atherosclerosis in type 2 diabetes. This review provides a systematic assessment of the effectiveness of exercise to id...

  18. ENDOTHELIAL DYSFUNCTION IN ISCHEMIC HEART DISEASE

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    N. E. Zakirova

    2008-01-01

    Full Text Available Aim. To assess the role of endothelial vasodilating, vasoconstrictive and adhesive dysfunction in the development of angina pectoris (AP in patients with ischemic heart disease (IHD.Material and methods. 83 patients with IHD were included in the study. 30 patients had AP of functional class (FC-II, 27 patients - FC-III and 26 patients - FC-IV. The control group consisted of 25 healthy persons. Bicycle ergometry, daily ECG monitoring and echocardiography were used for verification of IHD. Endothelial vasodilating function was assessed by endothelium-dependent (EDVD and endothelium-independent vasodilatation (EIDVD of brachial artery. Vasoconstrictive function was assessed by the level of endothelin (ET-1. Endothelial adhesive function was evaluated by plasma concentration of intracellular adhesion molecules – JCAM-1, VCAM-1 and Е-selectin.Results. Normal EDVD and EIDVD were observed in patients with AP of FC-II. The more severe FC of AP the more prominent endothelial vasodilating dysfunction was revealed as well as the higher levels of ET-1 and intracellular adhesion molecules. Patients with AP of FC-IV had hyperexpression of JCAM-1, VCAM-1, Е-selectin and ET-1 and low levels of EDVD and EIDVD.Conclusion. Progression of IHD related with growing endothelial vasodilating, vasoconstrictive and adhesive dysfunction.

  19. Combined aliskiren and L-arginine treatment has antihypertensive effects and prevents vascular endothelial dysfunction in a model of renovascular hypertension

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    C.H. Santuzzi

    2015-01-01

    Full Text Available Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK and L-arginine treatment both alone and in combination on blood pressure (BP, and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C hypertension, 2K1C+ALSK (ALSK, 2K1C+L-arginine (L-arg, and 2K1C+ALSK+L-arginine (ALSK+L-arg treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.

  20. Corneal endothelial dysfunction in Pearson syndrome.

    Science.gov (United States)

    Kasbekar, Shivani A; Gonzalez-Martin, Jose A; Shafiq, Ayad E; Chandna, Arvind; Willoughby, Colin E

    2013-01-01

    Mitochondrial disorders are associated with well recognized ocular manifestations. Pearson syndrome is an often fatal, multisystem, mitochondrial disorder that causes variable bone marrow, hepatic, renal and pancreatic exocrine dysfunction. Phenotypic progression of ocular disease in a 12-year-old male with Pearson syndrome is described. This case illustrates phenotypic drift from Pearson syndrome to Kearns-Sayre syndrome given the patient's longevity. Persistent corneal endothelial failure was noted in addition to ptosis, chronic external ophthalmoplegia and mid-peripheral pigmentary retinopathy. We propose that corneal edema resulting from corneal endothelial metabolic pump failure occurs within a spectrum of mitochondrial disorders.

  1. Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction.

    Science.gov (United States)

    Sankrityayan, Himanshu; Majumdar, Anuradha S

    2016-01-01

    Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.

  2. Imaging of the endothelial dysfunction in coronary atherosclerosis

    International Nuclear Information System (INIS)

    Kuikka, J.T.; Raitakari, O.T.; Gould, K.L.

    2001-01-01

    Coronary endothelial dysfunction is characterised by coronary vasoconstrictive responses to endothelium-dependent vasodilators. It is associated with coronary artery disease (CAD) and is considered an early phase of coronary atherosclerosis. Patients with CAD benefit from vigorous risk factor interventions and medical treatment, with a marked decrease in coronary events and an improvement in survival that are not reported following revascularisation procedures. Therefore, early detection of anatomical and functional changes in the coronary vasculature due to atherosclerosis provides the basis for integrated pharmacological, dietary and lifestyle modifications to prevent cardiovascular events and revascularisation procedures. The question arises as to whether these alterations in regional myocardial tone can be detected by any of the current non-invasive methods. Several methods are reviewed. We consider that intracoronary ultrasonography is the most accurate method, but non-invasive positron emission tomography and magnetic resonance imaging technology is of growing importance for identifying endothelial dysfunction of early coronary atherosclerosis. (orig.)

  3. Maternal biomarkers of endothelial dysfunction and preterm delivery.

    Directory of Open Access Journals (Sweden)

    Xinhua Chen

    Full Text Available Endothelial dysfunction is key to the development of atherosclerosis. Preterm delivery foreshadows later maternal cardiovascular disease (CVD, but it is not known if endothelial dysfunction also occurs. We prospectively measured circulating biomarkers of endothelial dysfunction in pregnant women with preterm or term delivery.We conducted a case-control study nested within a large prospective epidemiological study of young, generally healthy pregnant women. Women who delivered preterm (<37 completed weeks gestation, n = 240 and controls who delivered at term (n = 439 were included. Pregnancies complicated by preeclampsia were analyzed separately. Circulating endothelial dysfunction biomarkers included soluble intercellular adhesion molecule-1 (sICAM-1, vascular cell adhesion molecule-1 (sVCAM-1 and soluble E-selectin (sE-selectin.Elevated levels of sICAM-1 and sVCAM-1 were positively associated with preterm delivery independent of usual risk factors. At entry (∼16 wks, the adjusted odds ratio (AOR was 1.73 (95% confidence interval (CI 1.09-2.74 for the highest quartile of sICAM-1 versus the lowest quartile and for sVCAM-1 the AOR was 2.17 (95% CI 1.36-3.46. When analysis was limited to cases with a spontaneous preterm delivery, the results were unchanged. Similar results were obtained for the 3rd trimester (∼30 wks. Elevated sE-selectin was increased only in preterm delivery complicated by preeclampsia; risk was increased at entry (AOR 2.32, 95% CI 1.22-4.40 and in the 3rd trimester (AOR 3.37, 95% CI 1.78-6.39.Impaired endothelial function as indicated by increased levels of soluble molecules commonly secreted by endothelial cells is a pathogenic precursor to CVD that is also present in women with preterm delivery. Our findings underscore the need for follow-up studies to determine if improving endothelial function prevents later CVD risk in women.

  4. Brain endothelial dysfunction in cerebral adrenoleukodystrophy.

    Science.gov (United States)

    Musolino, Patricia L; Gong, Yi; Snyder, Juliet M T; Jimenez, Sandra; Lok, Josephine; Lo, Eng H; Moser, Ann B; Grabowski, Eric F; Frosch, Matthew P; Eichler, Florian S

    2015-11-01

    See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Endothelial dysfunction – A predictor of atherosclerosis | Chhabra ...

    African Journals Online (AJOL)

    Endothelial dysfunction is a systemic disorder and a critical element in the pathogenesis of atherosclerotic diseases and its complications. Growing evidences suggest that the individual burden of currently known cardiovascular risk factors is not the only determinant of endothelial function; rather endothelial integrity ...

  6. Mechanisms of endothelial dysfunction during aging: Predisposition to thrombosis.

    Science.gov (United States)

    Sepúlveda, Cesar; Palomo, Iván; Fuentes, Eduardo

    2017-06-01

    One of the risk factors for developing cardiovascular disease (CVD) is aging. In the elderly endothelial dysfunction occurs as altered endothelial ability to regulate hemostasis, vascular tone and cell permeability. In addition, there are changes in the expression and plasma levels of important endothelial components related to endothelial-mediated modulation in hemostasis. These include alterations in the metabolism of nitric oxide and prostanoides, endothelin-1, thrombomodulin and Von Willebrand factor. These alterations potentiate the pro-coagulant status developed with aging, highlighting the endothelial role in the development of thrombosis in aging. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction.

    Directory of Open Access Journals (Sweden)

    Maria Giovanna Scioli

    Full Text Available Impaired wound healing represents a high cost for health care systems. Endothelial dysfunction characterizes dermal microangiopathy and contributes to delayed wound healing and chronic ulcers. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO production and the increase of oxidative stress and inflammation. Propionyl-L-carnitine (PLC is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery.We investigated the effects of PLC in rat skin flap and cutaneous wound healing. A daily oral PLC treatment improved skin flap viability and associated with reactive oxygen species (ROS reduction, inducible nitric oxide synthase (iNOS and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation for iNOS, vascular endothelial growth factor (VEGF, placental growth factor (PlGF and reduction of NADPH-oxidase 4 (Nox4 expression. In serum-deprived human dermal microvascular endothelial cell cultures, PLC ameliorated endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO level. In addition, PLC counteracted serum deprivation-induced impairment of mitochondrial β-oxidation, Nox4 and cellular adhesion molecule (CAM expression, ROS generation and leukocyte adhesion. Moreover, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction.PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis. The beneficial effects of PLC likely derived from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction. Antioxidant therapy and

  8. Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction.

    Science.gov (United States)

    Scioli, Maria Giovanna; Lo Giudice, Pietro; Bielli, Alessandra; Tarallo, Valeria; De Rosa, Alfonso; De Falco, Sandro; Orlandi, Augusto

    2015-01-01

    Impaired wound healing represents a high cost for health care systems. Endothelial dysfunction characterizes dermal microangiopathy and contributes to delayed wound healing and chronic ulcers. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and the increase of oxidative stress and inflammation. Propionyl-L-carnitine (PLC) is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery. We investigated the effects of PLC in rat skin flap and cutaneous wound healing. A daily oral PLC treatment improved skin flap viability and associated with reactive oxygen species (ROS) reduction, inducible nitric oxide synthase (iNOS) and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation for iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and reduction of NADPH-oxidase 4 (Nox4) expression. In serum-deprived human dermal microvascular endothelial cell cultures, PLC ameliorated endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO level. In addition, PLC counteracted serum deprivation-induced impairment of mitochondrial β-oxidation, Nox4 and cellular adhesion molecule (CAM) expression, ROS generation and leukocyte adhesion. Moreover, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction. PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis. The beneficial effects of PLC likely derived from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction. Antioxidant therapy and pharmacological

  9. Chronic rhinosinusitis, endothelial dysfunction, and atherosclerosis.

    Science.gov (United States)

    Elcioglu, Omer Celal; Afsar, Baris; Bakan, Ali; Takir, Mumtaz; Ozkok, Abdullah; Oral, Alihan; Kostek, Osman; Basci, Semih; Kanbay, Asiye; Toprak, Aybala Erek; Bahat, Kubra Aydin; Kalcioglu, M Tayyar; Kanbay, Mehmet

    2016-05-01

    Chronic inflammation is associated with accelerated atherosclerosis, endothelial dysfunction (ED), and cardiovascular diseases. Because chronic rhinosinusitis (CRS) is an inflammatory disease, it may be associated with the development of ED and accelerated atherosclerosis. To investigate the relationship between CRS and carotid intima-media thickness (CIMT), flow-mediated dilation (FMD) of the brachial artery, and microalbuminuria. This cross-sectional study included 38 patients with CRS and 29 healthy controls. In addition to measuring spot urine albumin-creatinine ratios, FMD of the brachial artery and CIMT were assessed noninvasively. Patients with CRS had lower FMD scores (p = 0.031), higher CIMT scores (p = 0.005), and a higher urinary albumin-creatinine ratio (p = 0.036) compared with healthy controls. In a multivariate analysis, CIMT and FMD were independently associated with the presence of CRS. However, the relationship between urinary albumin and creatinine, and the presence of CRS was no longer observed. CRS is associated with ED and atherosclerosis, as indicated by decreased FMD and increased CIMT in patients with CRS. Further studies are necessary to identify the exact pathophysiologic mechanisms responsible for our findings.

  10. Rosuvastatin improves endothelial dysfunction in ankylosing spondylitis.

    Science.gov (United States)

    Garg, Nidhi; Krishan, Pawan; Syngle, Ashit

    2015-06-01

    Enhanced cardiovascular risk in ankylosing spondylitis (AS) provides a strong rationale for early therapeutical intervention. In view of the proven benefit of statins in atherosclerotic vascular disease, we aimed to investigate the effect of rosuvastatin on endothelial dysfunction (ED) and inflammatory disease activity in AS. In a single-blind, placebo-controlled, parallel study, 32 AS patients were randomized to receive 24 weeks of treatment with rosuvastatin (10 mg/day, n = 17) and placebo (n = 15) as an adjunct to existing stable antirheumatic drugs. Flow-mediated dilatation (FMD) was assessed by AngioDefender™ (Everest Genomic Ann Arbor, USA). Inflammatory measures (BASDAI, BASFI, CRP and ESR) and pro-inflammatory cytokines (tumour necrosis factor-alpha [TNF-α], interleukin-6 [IL-6] and interleukin-1 [IL-1]) were measured at baseline and after treatment. Lipids and adhesion molecules (intracellular adhesion molecule [ICAM-1] and vascular cell adhesion molecule [VCAM-1]) were estimated at baseline and after treatment. At baseline, inflammatory measures, pro inflammatory cytokines and adhesion molecules were elevated among both groups. After treatment with rosuvastatin, FMD improved significantly (p pathways. Rosuvastatin can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation of AS.

  11. Magnesium deficiency and endothelial dysfunction: is oxidative stress involved?

    NARCIS (Netherlands)

    Wolf, F.I.; Trapani, V.; Simonacci, M.; Ferre, S.; Maier, J.A.

    2008-01-01

    Low magnesium (Mg) has been associated with oxidative stress, an important player in aging, atherosclerosis and other vascular diseases. In vivo, low Mg and immune system activation seem to cooperate to promote endothelial dysfunction. We therefore evaluated whether exposure of human endothelial

  12. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure

    DEFF Research Database (Denmark)

    Bjerre, M.; Kistorp, C.; Hansen, T.K.

    2010-01-01

    CRP), endothelial activation (soluble E-selectin, sEsel)), endothelial damage/dysfunction (von Willebrand factor, vWf) and insulin resistance (IR) and prognosis in CHF remains unknown. Design. We investigated the association(s) between plasma sMAC, hsCRP, sEsel, vWf and IR (assessed by homeostatic model assessment...

  13. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome

    Directory of Open Access Journals (Sweden)

    Hadi AR Hadi

    2005-10-01

    Full Text Available Hadi AR Hadi, Cornelia S Carr, Jassim Al SuwaidiDepartment of Cardiology and Cardiovascular Surgery, Hamad General Hospital – Hamad Medical Corporation, Doha, State of QatarAbstract: Endothelial dysfunction is a well established response to cardiovascular risk factors and precedes the development of atherosclerosis. Endothelial dysfunction is involved in lesion formation by the promotion of both the early and late mechanisms of atherosclerosis including up-regulation of adhesion molecules, increased chemokine secretion and leukocyte adherence, increased cell permeability, enhanced low-density lipoprotein oxidation, platelet activation, cytokine elaboration, and vascular smooth muscle cell proliferation and migration. Endothelial dysfunction is a term that covers diminished production/availability of nitric oxide and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. Also, when cardiovascular risk factors are treated the endothelial dysfunction is reversed and it is an independent predictor of cardiac events. We review the literature concerning endothelial dysfunction in regard to its pathogenesis, treatment, and outcome.Keywords: endothelial dysfunction, coronary atherosclerosis, coronary artery disease

  14. Exercise training reverses endothelial dysfunction in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Pugh, Christopher J A; Spring, Victoria S; Kemp, Graham J; Richardson, Paul; Shojaee-Moradie, Fariba; Umpleby, A Margot; Green, Daniel J; Cable, N Timothy; Jones, Helen; Cuthbertson, Daniel J

    2014-11-01

    Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness [peak oxygen uptake (V̇o2 peak)] (48 ± 2 vs. 47 ± 2 yr; 27 ± 1 vs. 26 ± 2 ml·kg−1·min−1−1). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training (n = 13) or conventional care (n = 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat [11.6% (95% CI = 7.4, 18.1), P < 0.0005] and VAT [1.6 liters (95% CI = 1.2, 2.0), P < 0.0001] than controls and exhibited impaired FMD compared with controls [−3.6% (95% CI = −4.9, −2.2), P < 0.0001]. FMD was inversely correlated with VAT (r = −0.54, P = 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95% CI = 1.8, 4.5), P < 0.001]. Exercise training, but not conventional care, significantly improved V̇o2 peak [9.1 ml·kg−1·min−1 (95% CI = 4.1, 14.1); P = 0.001] and FMD [3.6% (95% CI = 1.6, 5.7), P = 0.002]. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD.

  15. Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

    Science.gov (United States)

    Possomato-Vieira, José S.; Khalil, Raouf A.

    2016-01-01

    Preeclampsia is a pregnancy-related disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia. PMID:27451103

  16. Assessment of Endothelial Dysfunction in Childhood Obesity and Clinical Use

    Directory of Open Access Journals (Sweden)

    Luc Bruyndonckx

    2013-01-01

    Full Text Available The association of obesity with noncommunicable diseases, such as cardiovascular complications and diabetes, is considered a major threat to the management of health care worldwide. Epidemiological findings show that childhood obesity is rapidly rising in Western society, as well as in developing countries. This pandemic is not without consequences and can affect the risk of future cardiovascular disease in these children. Childhood obesity is associated with endothelial dysfunction, the first yet still reversible step towards atherosclerosis. Advanced research techniques have added further insight on how childhood obesity and associated comorbidities lead to endothelial dysfunction. Techniques used to measure endothelial function were further brought to perfection, and novel biomarkers, including endothelial progenitor cells, were discovered. The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity. Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given. Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.

  17. INSTRUMENTAL AND DIAGNOSTIC CRITERIA OF HEMODYNAMIC DISORDERS AND ENDOTHELIAL DYSFUNCTION CORRECTION IN PREGNANTS WITH ARTERIAL HYPERTENSION

    Directory of Open Access Journals (Sweden)

    S. M. Heryak

    2014-12-01

    Conclusions. It was found that the brachial artery ultrasound measuring and occlusive plethysmography procedure by Dietz is an early and safe method of endothelial dysfunction diagnostic in pregnants with hypertension. Doppler ultrasound of blood flow in uterine, umbilical arteries, and middle cerebral arteries of the fetus allows timely diagnosis of the side effect of antihypertensive drugs on the fetus. The therapy of choice for pregnants with Stage II Arterial Hypertension should be based on methyldopa and calcium channel antagonists or selective beta-blockers combination. Highly selective beta-blockers with vasodilative effect (nebivolol hydrochloride and L-arginine (Tivortin allow to prevent perinatal adverse effects of antihypertensive therapy, to correct hemodynamic disorders and endothelial dysfunction in pregnants with arterial hypertension. KEY WORDS: arterial hypertension, uterine-placental hemodynamics, endothelial dysfunction

  18. Na(+), K(+)-ATPase dysfunction causes cerebrovascular endothelial cell degeneration in rat prefrontal cortex slice cultures.

    Science.gov (United States)

    Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Katsuki, Hiroshi

    2016-08-01

    Cerebrovascular endothelial cell dysfunction resulting in imbalance of cerebral blood flow contributes to the onset of psychiatric disorders such as depression, schizophrenia and bipolar disorder. Although decrease in Na(+), K(+)-ATPase activity has been reported in the patients with schizophrenia and bipolar disorder, the contribution of Na(+), K(+)-ATPase to endothelial cell dysfunction remains poorly understood. Here, by using rat neonatal prefrontal cortex slice cultures, we demonstrated that pharmacological inhibition of Na(+), K(+)-ATPase by ouabain induced endothelial cell injury. Treatment with ouabain significantly decreased immunoreactive area of rat endothelial cell antigen-1 (RECA-1), a marker of endothelial cells, in a time-dependent manner. Ouabain also decreased Bcl-2/Bax ratio and phosphorylation level of glycogen synthase kinase 3β (GSK3β) (Ser9), which were prevented by lithium carbonate. On the other hand, ouabain-induced endothelial cell injury was exacerbated by concomitant treatment with LY294002, an inhibitor of phosphoinositide 3- (PI3-) kinase. We also found that xestospongin C, an inhibitor of inositol triphosphate (IP3) receptor, but not SEA0400, an inhibitor of Na(+), Ca(2+) exchanger (NCX), protected endothelial cells from cytotoxicity of ouabain. These results suggest that cerebrovascular endothelial cell degeneration induced by Na(+), K(+)-ATPase inhibition resulting in Ca(2+) release from endoplasmic reticulum (ER) and activation of GSK3β signaling underlies pathogenesis of these psychiatric disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Prior exercise and standing as strategies to circumvent sitting-induced leg endothelial dysfunction.

    Science.gov (United States)

    Morishima, Takuma; Restaino, Robert M; Walsh, Lauren K; Kanaley, Jill A; Padilla, Jaume

    2017-06-01

    We have previously shown that local heating or leg fidgeting can prevent prolonged sitting-induced leg endothelial dysfunction. However, whether physical activity prevents subsequent sitting-induced leg endothelial dysfunction remains unknown. Herein, we tested the hypothesis that sitting-induced leg endothelial dysfunction would be prevented by prior exercise. We also examined if, in the absence of exercise, standing is an effective alternative strategy to sitting for conserving leg endothelial function. Fifteen young healthy subjects completed three randomized experimental trials: (1) sitting without prior exercise; (2) sitting with prior exercise; and (3) standing without prior exercise. Following baseline popliteal artery flow-mediated dilation (FMD) measurements, subjects maintained a supine position for 45 min in the sitting and standing trials, without prior exercise, or performed 45 min of leg cycling before sitting (i.e. sitting with prior exercise trial). Thereafter, subjects were positioned into a seated or standing position, according to the trial, for 3 h. Popliteal artery FMD measures were then repeated. Three hours of sitting without prior exercise caused a significant impairment in popliteal artery FMD (baseline: 3.8±0.5%, post-sitting: 1.5±0.5%, P sitting was preceded by a bout of cycling exercise (baseline: 3.8±0.5%, post-sitting: 3.6±0.7%, P >0.05). Three hours of standing did not significantly alter popliteal artery FMD (baseline: 4.1±0.4%, post-standing: 4.3±0.4%, P >0.05). In conclusion, prolonged sitting-induced leg endothelial dysfunction can be prevented by prior aerobic exercise. In addition, in the absence of exercise, standing represents an effective substitute to sitting for preserving leg conduit artery endothelial function. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  20. Is there a role for exosomes in foetoplacental endothelial dysfunction in gestational diabetes mellitus?

    NARCIS (Netherlands)

    Saez, Tamara; de Vos, Paul; Sobrevia, Luis; Faas, Marijke M.

    Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with endothelial dysfunction in the foetoplacental vasculature. Foetoplacental endothelial dysfunction is characterized by changes in the L-arginine-adenosine signalling pathway and inflammation. The mechanisms involved in

  1. Associations of low grade inflammation and endothelial dysfunction with depression : The Maastricht study

    NARCIS (Netherlands)

    van Dooren, F.E.P.; Schram, M.T.; Schalkwijk, C.G.; Stehouwer, C.D.; Henry, R.M.; Dagnelie, P.C.; Schaper, N.C.; van der Kallen, C. J.; Koster, A.; Sep, S. J.; Denollet, J.; Verhey, F.R.J.; Pouwer, F.

    2016-01-01

    Background The pathogenesis of depression may involve low-grade inflammation and endothelial dysfunction. We aimed to evaluate the independent associations of inflammation and endothelial dysfunction with depressive symptoms and depressive disorder, and the role of lifestyle factors in this

  2. Endothelial dysfunction, vascular disease and stroke: the ARTICO study.

    Science.gov (United States)

    Roquer, J; Segura, T; Serena, J; Castillo, J

    2009-01-01

    Endothelial dysfunction is a fundamental step in the atherosclerotic disease process. Its presence is a risk factor for the development of clinical events, and may represent a marker of atherothrombotic burden. Also, endothelial dysfunction contributes to enhanced plaque vulnerability, may trigger plaque rupture, and favors thrombus formation. The assessment of endothelial vasomotion is a useful marker of atherosclerotic vascular disease. There are different methods to assess endothelial function: endothelium-dependent vasodilatation brachial flow-mediated dilation, cerebrovascular reactivity to L-arginine, and the determination of some biomarkers such as microalbuminuria, platelet function, and C-reactive protein. Endothelial dysfunction has been observed in stroke patients and has been related to stroke physiopathology, stroke subtypes, clinical severity and outcome. Resting ankle-brachial index (ABI) is also considered an indicator of generalized atherosclerosis, and a low ABI is associated with an increase in stroke incidence in the elderly. Despite all these data, there are no studies analyzing the predictive value of ABI for new cardiovascular events in patients after suffering an acute ischemic stroke. ARTICO is an ongoing prospective, observational, multicenter study being performed in 50 Spanish hospitals. The aim of the ARTICO study is to evaluate the prognostic value of a pathological ABI (ARTICO study will increase the knowledge of patient outcome after ischemic stroke and may help to improve our ability to detect patients at high risk of stroke recurrence or major cardiovascular events. (c) 2009 S. Karger AG, Basel.

  3. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia.

    Science.gov (United States)

    Boeldt, D S; Bird, I M

    2017-01-01

    Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca 2+ signaling events and chronically promoting the breakdown of endothelial cell-cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy. © 2017 Society for Endocrinology.

  4. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure

    DEFF Research Database (Denmark)

    Bjerre, M.; Kistorp, C.; Hansen, T.K.

    2010-01-01

    Objectives. Patients with chronic heart failure (CHF) have an exaggerated immune response, endothelial damage/dysfunction, and increased risk of diabetes mellitus (DM). The inter-relationship(s) between indices of complement activation (soluble membrane attack complex, sMAC), inflammation (hs......, IR was an independent predictor of sMAC in the CHF group beta = 0.37 (p complement system and thus...

  5. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure

    DEFF Research Database (Denmark)

    Bjerre, M.; Kistorp, C.; Hansen, T.K.

    2010-01-01

    Objectives. Patients with chronic heart failure (CHF) have an exaggerated immune response, endothelial damage/dysfunction, and increased risk of diabetes mellitus (DM). The inter-relationship(s) between indices of complement activation (soluble membrane attack complex, sMAC), inflammation (hs......CRP), endothelial activation (soluble E-selectin, sEsel)), endothelial damage/dysfunction (von Willebrand factor, vWf) and insulin resistance (IR) and prognosis in CHF remains unknown. Design. We investigated the association(s) between plasma sMAC, hsCRP, sEsel, vWf and IR (assessed by homeostatic model assessment......, HOMA) in a prospective study including a total of 193 patients with CHF, and assessed whether high levels of these biomarkers had a prognostic impact. Biomarker levels in CHF patients were compared to 100 age-matched controls. Results. Plasma sMAC levels were elevated in patients with CHF due...

  6. Role of glutathione biosynthesis in endothelial dysfunction and fibrosis

    Directory of Open Access Journals (Sweden)

    Cristina Espinosa-Díez

    2018-04-01

    Full Text Available Glutathione (GSH biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL, which is composed of the catalytic (GCLc and the modulatory (GCLm subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice. In murine lung endothelial cells (MLEC derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177 and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+ male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+ mice. We observed that obstructed kidneys from Gclc(e/+ mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses. Keywords: Glutamate-cysteine ligase, ROS, Glutathione, Endothelial dysfunction, Kidney Fibrosis

  7. Arterial ageing: from endothelial dysfunction to vascular calcification.

    Science.gov (United States)

    Tesauro, M; Mauriello, A; Rovella, V; Annicchiarico-Petruzzelli, M; Cardillo, C; Melino, G; Di Daniele, N

    2017-05-01

    Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to 'synthetic' determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low-level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well-established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing-related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed. © 2017 The Association for the Publication of the Journal of Internal Medicine.

  8. NON-PHARMACOLOGICAL CONCEPTS OF ENDOTHELIAL DYSFUNCTION IMPROVEMENT

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    Mirjana Bakic

    2007-04-01

    Full Text Available Endothelium plays an important role in maintaining normal vascular tonus and blood fluidity reducing thrombocyte activity and adhesion of leukocytes as well as limiting response of vascular inflammation. However, in certain pathological conditions such as hypercholesterolemia, hypertension, and diabetes, endothelium improves vasoconstriction, inflammation and thrombocytic events.Non-pharmacological concept is based on recognition of genetic factors, environmental factors, or combination of risk factors for the occurrence of endothelial dysfunction, general and individual education of the significance of adequate nutrition, physical activity and regulation of body weight, regular check-ups and the application of antioxidants which can regulate and protect several aspects of endothelial functions.

  9. The effect of uric acid on homocysteine-induced endothelial dysfunction in bovine aortic endothelial cells

    Czech Academy of Sciences Publication Activity Database

    Papežíková, Ivana; Pekarová, Michaela; Lojek, Antonín; Kubala, Lukáš

    2009-01-01

    Roč. 30, č. 1 (2009), s. 112-115 ISSN 0172-780X R&D Projects: GA ČR(CZ) GP204/07/P539 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : uric acid * homocysteine * endothelial dysfunction Subject RIV: BO - Biophysics Impact factor: 1.047, year: 2009

  10. Selective endothelial overexpression of arginase II induces endothelial dysfunction and hypertension and enhances atherosclerosis in mice.

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    Boris L Vaisman

    Full Text Available Cardiovascular disorders associated with endothelial dysfunction, such as atherosclerosis, have decreased nitric oxide (NO bioavailability. Arginase in the vasculature can compete with eNOS for L-arginine and has been implicated in atherosclerosis. The aim of this study was to evaluate the effect of endothelial-specific elevation of arginase II expression on endothelial function and the development of atherosclerosis.Transgenic mice on a C57BL/6 background with endothelial-specific overexpression of human arginase II (hArgII gene under the control of the Tie2 promoter were produced. The hArgII mice had elevated tissue arginase activity except in liver and in resident peritoneal macrophages, confirming endothelial specificity of the transgene. Using small-vessel myography, aorta from these mice exhibited endothelial dysfunction when compared to their non-transgenic littermate controls. The blood pressure of the hArgII mice was 17% higher than their littermate controls and, when crossed with apoE -/- mice, hArgII mice had increased aortic atherosclerotic lesions.We conclude that overexpression of arginase II in the endothelium is detrimental to the cardiovascular system.

  11. Mechanisms of endothelial dysfunction in obesity-associated hypertension

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    N.S. Lobato

    2012-05-01

    Full Text Available Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.

  12. The effect of uric acid on homocysteine-induced endothelial dysfunction in bovine aortic endothelial cells.

    Science.gov (United States)

    Papezikova, Ivana; Pekarova, Michaela; Lojek, Antonin; Kubala, Lukas

    2009-01-01

    Elevated plasma uric acid indicates an increased risk of cardiovascular diseases associated with endothelial dysfunction. However, the role of uric acid in the pathogenesis of endothelial dysfunction is still a matter of debate. It is not clear whether uric acid is a real causative risk factor, an inert marker, or even a protective molecule with respect to its antioxidant properties. We have studied the effect of uric acid on intact endothelial cells as well as cells with homocysteine-induced endothelial dysfunction. Bovine aortic endothelial cells were treated with uric acid (100 - 600 muM) and homocysteine (100 muM) or with uric acid only. After 24 hours, the cells were stimulated with 1 mug/ml of calcium ionophore A23187, and nitric oxide (NO) production was measured electrochemically with the use of a NO-sensitive microelectrode. The expression of endothelial nitric oxide synthase (eNOS) and eNOS phosphorylation at Ser1179 was estimated with the use of Western blotting. Interaction between NO and uric acid was measured with a NO electrode. Superoxide generation was measured with the use of the fluorescence dye MitoSox Red. Homocysteine strongly diminished A23187-induced NO release. 100 muM uric acid slightly restored NO production; higher concentrations were ineffective. Interestingly, a dose-dependent decrease of NO release was observed in the cells treated only with uric acid. Uric acid did not scavenge NO and did not change eNOS protein expression or phosphorylation at Ser1179, but dose-dependently increased superoxide production in A23187-stimulated cells. In conclusion, uric acid decreased NO bioavailability and enhanced superoxide generation in A23187-stimulated bovine aortic endothelial cells.

  13. Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

    Science.gov (United States)

    Rossman, Matthew J; Kaplon, Rachelle E; Hill, Sierra D; McNamara, Molly N; Santos-Parker, Jessica R; Pierce, Gary L; Seals, Douglas R; Donato, Anthony J

    2017-11-01

    Cellular senescence is emerging as a key mechanism of age-related vascular endothelial dysfunction, but evidence in healthy humans is lacking. Moreover, the influence of lifestyle factors such as habitual exercise on endothelial cell (EC) senescence is unknown. We tested the hypothesis that EC senescence increases with sedentary, but not physically active, aging and is associated with vascular endothelial dysfunction. Protein expression (quantitative immunofluorescence) of p53, a transcription factor related to increased cellular senescence, and the cyclin-dependent kinase inhibitors p21 and p16 were 116%, 119%, and 128% greater (all P 0.05) in venous ECs from older exercising adults (57 ± 1 yr, n = 13). Furthermore, venous EC protein levels of p53 ( r  = -0.49, P = 0.003), p21 ( r  = -0.38, P = 0.03), and p16 ( r  = -0.58, P = 0.002) were inversely associated with vascular endothelial function (brachial artery flow-mediated dilation). Similarly, protein expression of p53 and p21 was 26% and 23% higher (both P 0.05) in older habitually exercising adults (59 ± 1 yr, n = 14). These data indicate that EC senescence is associated with sedentary aging and is linked to endothelial dysfunction. Moreover, these data suggest that prevention of EC senescence may be one mechanism by which aerobic exercise protects against endothelial dysfunction with age. NEW & NOTEWORTHY Our study provides novel evidence in humans of increased endothelial cell senescence with sedentary aging, which is associated with impaired vascular endothelial function. Furthermore, our data suggest an absence of age-related increases in endothelial cell senescence in older exercising adults, which is linked with preserved vascular endothelial function. Copyright © 2017 the American Physiological Society.

  14. Measurement of endothelial dysfunction via peripheral arterial tonometry predicts vasculogenic erectile dysfunction

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    Kovac, Jason R.; Gomez, Lissette; Smith, Ryan P.; Coward, Robert M.; Gonzales, Marshall A.; Khera, Mohit; Lamb, Dolores J.; Lipshultz, Larry I.

    2014-01-01

    Introduction Endothelial cell dysfunction is associated with cardiovascular disease and vasculogenic erectile dysfunction (ED). Measured via Peripheral Artery Tonometry (PAT), endothelial dysfunction in the penis is an independent predictor of future cardiovascular events. Aim Determine whether measurement of endothelial dysfunction differentiates men with vasculogenic ED identified by duplex ultrasound from those without. Methods A total of 142 men were retrospectively assessed using patient history, penile duplex ultrasonography (US) and PAT (EndoPAT 2000). ED was self reported and identified on history. Vasculogenic ED was identified in men who exhibited a peak systolic velocity (PSV) of ≤25 cm/s obtained 15 minutes following vasodilator injection. The reactive hyperemia index (RHI), a measurement of endothelial dysfunction in medium/small arteries and the Augmentation Index (AI), a measurement of arterial stiffness, were recorded via PAT. Results Penile duplex US separated men into those with ED (n=111) and without (n=31). The cohort with ED had a PSV of 21±1 cm/s (left cavernous artery) and 22±1 cm/s (Right). The control group without ED had values of 39±2 cm/s (Left) and 39±2 (Right). Given the potential for altered endothelial function in diabetes mellitus, we confirmed that hemoglobin A1c, urinary microalbumin, and vibration pulse threshold were not different in men with vasculogenic ED and those without. RHI in patients with ED (1.85±0.06) was significantly decreased compared to controls (2.15±0.2) (p<0.05). The AI was unchanged when examined in isolation, and when standardized to heart rate. Conclusions Measurement of endothelial function with EndoPAT differentiates men with vasculogenic ED from those without. RHI could be used as a non-invasive surrogate in the assessment of vasculogenic ED and to identify those patients with higher cardiovascular risk. PMID:24784889

  15. Effects of Huang Qi Decoction on Endothelial Dysfunction Induced by Homocysteine

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    Shuang Chu

    2016-01-01

    Full Text Available Vascular endothelial dysfunction can be induced by homocysteine (Hcy through promoted oxidative stress. Huang Qi decoction (HQD is a traditional Chinese medical formula and its components possess antioxidant effect. The study herein was therefore designed to investigate the effects of HQD at different dosage on endothelial dysfunction induced by Hcy. Tempol and apocynin were used to investigate whether antioxidant mechanisms were involved. Endothelium-dependent relaxation of rat aortas was investigated by isometric tension recordings. Reactive oxygen species (ROS in human umbilical vein endothelial cells (HUVECs was determined by DHE staining. The assessment related to oxidative stress and NO bioavailability was performed by assay kits and western blot. In isometric tension experiment, HQD at the dose of 30 or 100 μg/mL, tempol, or apocynin prevented impaired endothelium-dependent relaxation in isolated aortas elicited by Hcy. In cellular experiments, substantial enhancement in NADPH oxidase and ROS generation and reduction in NO bioavailability triggered by Hcy were reversed by pretreatment of HQD at the dose of 100 μg/mL, tempol, or apocynin. The results proved that HQD at an appropriate dosage presented favorable effects on endothelial dysfunction initiated by Hcy through antioxidant mechanisms. HQD can act as a potent prescription for the treatment of endothelium related vascular complications.

  16. Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction

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    James R. Wodicka

    2017-03-01

    Full Text Available Endothelial cell (EC dysfunction is associated with many disease states including deep vein thrombosis (DVT, chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.

  17. Endothelial dysfunction in patients with sudden sensorineural hearing loss

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    Nezamoddin Berjis

    2016-01-01

    Full Text Available Background: Endothelial dysfunction probably has a role in the etiology of sudden sensorineural hearing loss (SSNHL. The aim of this study was determining of the relationship between endothelial dysfunction and SSNHL. Materials and Methods: In a case-control study, 30 patients with SSNHL and 30 otherwise healthy age and sex-matched controls were studied. Demographic data gathered included age, gender, family history of SSNHL, and history of smoking, cardiovascular disease, hypertension, diabetes, and dyslipidemia. Laboratory data included measurement of hemoglobin, fasting blood sugar (FBS and lipid profile. Endothelial function was assessed by measuring flow-mediated dilation (FMD. Results: The two groups were the same in age (47.9 ± 9.3 and 48.1 ± 9.6 years, P = 0.946 with female/male ratio of 1:1 in both groups. Diabetes and dyslipidemia were more frequent in patients than controls (20% vs. 0%, P = 0.024. Brachial artery diameter was greater in patients than controls before (4.24 ± 0.39 vs. 3.84 ± 0.23 mm, P < 0.001 and after ischemia (4.51 ± 0.43 vs. 4.28 ± 0.27 mm, P = 0.020, but FMD was lower in patients than controls (6.21 ± 3.0 vs. 11.52 ± 2.30%, P < 0.001. Binary logistic regression analysis showed that FMD was associated with SSNHL independent from FBS and lipid profile (odds ratio [95% confidence interval] =0.439 [0.260-0.740], P = 0.002. Conclusion: Endothelial dysfunction, among other cardiovascular risk factors, is associated with SSNHL. This association is independent from other cardiovascular risk factors including diabetes and dyslipidemia.

  18. Activation of K{sup +} channels and Na{sup +}/K{sup +} ATPase prevents aortic endothelial dysfunction in 7-day lead-treated rats

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    Fiorim, Jonaina, E-mail: nanafiorim@hotmail.com [Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES (Brazil); Ribeiro Júnior, Rogério Faustino, E-mail: faustino43@oi.com.br [Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES (Brazil); Azevedo, Bruna Fernades, E-mail: brunafernandes.azevedo@gmail.com [Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES (Brazil); Simões, Maylla Ronacher, E-mail: yllars@hotmail.com [Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES (Brazil); Padilha, Alessandra Simão, E-mail: ale_spadilha@yahoo.com.br [Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES (Brazil); Stefanon, Ivanita, E-mail: ivanita@pq.cnpq.br [Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES (Brazil); Alonso, Maria Jesus, E-mail: mariajesus.alonso@urjc.es [Departamento de Ciencias de la Salud III, Universidad Rey Juan Carlos, Alcorcón (Spain); Salaices, Mercedes, E-mail: mercedes.salaices@uam.es [Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPaz) (Spain); Vassallo, Dalton Valentim, E-mail: daltonv2@terra.com.br [Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES (Brazil)

    2012-07-01

    Seven day exposure to a low concentration of lead acetate increases nitric oxide bioavailability suggesting a putative role of K{sup +} channels affecting vascular reactivity. This could be an adaptive mechanism at the initial stages of toxicity from lead exposure due to oxidative stress. We evaluated whether lead alters the participation of K{sup +} channels and Na{sup +}/K{sup +}-ATPase (NKA) on vascular function. Wistar rats were treated with lead (1st dose 4 μg/100 g, subsequent doses 0.05 μg/100 g, im, 7 days) or vehicle. Lead treatment reduced the contractile response of aortic rings to phenylephrine (PHE) without changing the vasodilator response to acetylcholine (ACh) or sodium nitroprusside (SNP). Furthermore, this treatment increased basal O{sub 2}{sup −} production, and apocynin (0.3 μM), superoxide dismutase (150 U/mL) and catalase (1000 U/mL) reduced the response to PHE only in the treated group. Lead also increased aortic functional NKA activity evaluated by K{sup +}-induced relaxation curves. Ouabain (100 μM) plus L-NAME (100 μM), aminoguanidine (50 μM) or tetraethylammonium (TEA, 2 mM) reduced the K{sup +}-induced relaxation only in lead-treated rats. When aortic rings were precontracted with KCl (60 mM/L) or preincubated with TEA (2 mM), 4-aminopyridine (4-AP, 5 mM), iberiotoxin (IbTX, 30 nM), apamin (0.5 μM) or charybdotoxin (0.1 μM), the ACh-induced relaxation was more reduced in the lead-treated rats. Additionally, 4-AP and IbTX reduced the relaxation elicited by SNP more in the lead-treated rats. Results suggest that lead treatment promoted NKA and K{sup +} channels activation and these effects might contribute to the preservation of aortic endothelial function against oxidative stress. -- Highlights: ► Increased free radicals production ► Increased Na{sup +}/K{sup +} ATPase activity ► Promotes activation of the K{sup +} channels and reduced vascular reactivity ► These effects preserve endothelial function against oxidative

  19. Arginase promotes endothelial dysfunction and hypertension in obese rats.

    Science.gov (United States)

    Johnson, Fruzsina K; Peyton, Kelly J; Liu, Xiao-Ming; Azam, Mohammed A; Shebib, Ahmad R; Johnson, Robert A; Durante, William

    2015-02-01

    This study investigated whether arginase contributes to endothelial dysfunction and hypertension in obese rats. Endothelial function and arginase expression were examined in skeletal muscle arterioles from lean and obese Zucker rats (ZRs). Arginase activity, arginine bioavailability, and blood pressure were measured in lean and obese animals. Arginase activity and expression was increased while global arginine bioavailability decreased in obese ZRs. Acetylcholine or luminal flow caused dilation of isolated skeletal muscle arterioles, but this was reduced or absent in vessels from obese ZRs. Treatment of arterioles with a nitric oxide synthase inhibitor blocked dilation in lean arterioles and eliminated differences among lean and obese vessels. In contrast, arginase inhibitors or l-arginine enhanced vasodilation in obese ZRs and abolished differences between lean and obese animals, while d-arginine had no effect. Finally, mean arterial blood pressure was significantly increased in obese ZRs. However, administration of l-arginine or arginase inhibitors lowered blood pressure in obese but not lean animals, and this was associated with an improvement in systemic arginine bioavailability. Arginase promotes endothelial dysfunction and hypertension in obesity by reducing arginine bioavailability. Therapeutic approaches targeting arginase represent a promising approach in treating obesity-related vascular disease. © 2014 The Obesity Society.

  20. Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

    Science.gov (United States)

    Nguyen, Minh Cong; Park, Jong Taek; Jeon, Yeong Gwan; Jeon, Byeong Hwa; Hoe, Kwang Lae; Kim, Young Myeong

    2016-01-01

    Purpose Peroxynitrite plays a critical role in vascular pathophysiology by increasing arginase activity and decreasing endothelial nitric oxide synthase (eNOS) activity. Therefore, the aims of this study were to investigate whether arginase inhibition and L-arginine supplement could restore peroxynitrite-induced endothelial dysfunction and determine the involved mechanism. Materials and Methods Human umbilical vein endothelial cells (HUVECs) were treated with SIN-1, a peroxynitrite generator, and arginase activity, nitrite/nitrate production, and expression levels of proteins were measured. eNOS activation was evaluated via Western blot and dimer blot analysis. We also tested nitric oxide (NO) and reactive oxygen species (ROS) production and performed a vascular tension assay. Results SIN-1 treatment increased arginase activity in a time- and dose-dependent manner and reciprocally decreased nitrite/nitrate production that was prevented by peroxynitrite scavenger in HUVECs. Furthermore, SIN-1 induced an increase in the expression level of arginase I and II, though not in eNOS protein. The decreased eNOS phosphorylation at Ser1177 and the increased at Thr495 by SIN-1 were restored with arginase inhibitor and L-arginine. The changed eNOS phosphorylation was consistent in the stability of eNOS dimers. SIN-1 decreased NO production and increased ROS generation in the aortic endothelium, all of which was reversed by arginase inhibitor or L-arginine. NG-Nitro-L-arginine methyl ester (L-NAME) prevented SIN-1-induced ROS generation. In the vascular tension assay, SIN-1 enhanced vasoconstrictor responses to U46619 and attenuated vasorelaxant responses to acetylcholine that were reversed by arginase inhibition. Conclusion These findings may explain the beneficial effect of arginase inhibition and L-arginine supplement on endothelial dysfunction under redox imbalance-dependent pathophysiological conditions. PMID:27593859

  1. Hypothyroidism Is Associated With Coronary Endothelial Dysfunction in Women

    Science.gov (United States)

    Sara, Jaskanwal D; Zhang, Ming; Gharib, Hossein; Lerman, Lilach O; Lerman, Amir

    2015-01-01

    Background Hypothyroidism is associated with an increased risk of coronary artery disease, beyond that which can be explained by its association with conventional cardiovascular risk factors. Coronary endothelial dysfunction precedes atherosclerosis, has been linked to adverse cardiovascular events, and may account for some of the increased risk in patients with hypothyroidism. The aim of this study was to determine whether there is an association between epicardial and microvascular coronary endothelial dysfunction and hypothyroidism. Methods and Results In 1388 patients (mean age 50.5 [12.3] years, 34% male) presenting with stable chest pain to Mayo Clinic, Rochester, MN for diagnostic coronary angiography, and who were found to have nonobstructive coronary artery disease (hypothyroidism, defined as a documented history of hypothyroidism or a thyroid-stimulating hormone (TSH) >10.0 mU/mL, n=188, and euthyroidism, defined as an absence of a history of hypothyroidism in the clinical record and/or 0.3hypothyroidism had a significantly lower % Δ CBF Ach (48.26 [80.66] versus 64.58 [128.30]) compared to patients with euthyroidism, while the % Δ CAD Ach did not vary significantly between groups. After adjusting for covariates, females with hypothyroidism still had a significantly lower % Δ CBF Ach (estimated difference in % Δ CBF Ach [SE]: −16.79 [8.18]). Conclusions Hypothyroidism in women is associated with microvascular endothelial dysfunction, even after adjusting for confounders, and may explain some of the increased risk of cardiovascular disease in these patients. PMID:26224049

  2. Gastrodia elata Ameliorates High-Fructose Diet-Induced Lipid Metabolism and Endothelial Dysfunction

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    Min Chul Kho

    2014-01-01

    Full Text Available Overconsumption of fructose results in dyslipidemia, hypertension, and impaired glucose tolerance, which have documented correlation with metabolic syndrome. Gastrodia elata, a widely used traditional herbal medicine, was reported with anti-inflammatory and antidiabetes activities. Thus, this study examined whether ethanol extract of Gastrodia elata Blume (EGB attenuate lipid metabolism and endothelial dysfunction in a high-fructose (HF diet animal model. Rats were fed the 65% HF diet with/without EGB 100 mg/kg/day for 8 weeks. Treatment with EGB significantly suppressed the increments of epididymal fat weight, blood pressure, plasma triglyceride, total cholesterol levels, and oral glucose tolerance, respectively. In addition, EGB markedly prevented increase of adipocyte size and hepatic accumulation of triglycerides. EGB ameliorated endothelial dysfunction by downregulation of endothelin-1 (ET-1 and adhesion molecules in the aorta. Moreover, EGB significantly recovered the impairment of vasorelaxation to acetylcholine and levels of endothelial nitric oxide synthase (eNOS expression and induced markedly upregulation of phosphorylation AMP-activated protein kinase (AMPKα in the liver, muscle, and fat. These results indicate that EGB ameliorates dyslipidemia, hypertension, and insulin resistance as well as impaired vascular endothelial function in HF diet rats. Taken together, EGB may be a beneficial therapeutic approach for metabolic syndrome.

  3. Exercise blood pressure and endothelial dysfunction in hypertension.

    Science.gov (United States)

    Tzemos, N; Lim, P O; MacDonald, T M

    2009-02-01

    Hypertensive patients with persistent endothelial dysfunction have adverse cardiovascular prognosis. However, current methods aimed to assess endothelial dysfunction in those patients who possess clinical applicability. We hypothesised that such individuals could potentially be identified by an exaggerated systolic blood pressure (BP) response to a submaximal exercise. We studied 22 male patients with essential hypertension who were categorised into two age-matched groups depending on their exercise systolic BP (ExSBP) rise during the 3-min exercise step test; the exaggerated ExSBP group [hyper-responders (> or = 40 mmHg)] and the low ExSBP responder group [hypo-responders (healthy volunteers matched for age were used as control. Clinic and daytime ambulatory BP were assessed after 14 days of anti-hypertensive treatment withdrawal, which were not significantly different between groups. Vascular reactivity in response to intra-arterial infusions of acetylcholine, N(G)-monomethyl-l-arginine (l-NMMA) and sodium nitroprusside was assessed using forearm venous occlusion plethysmography. The hyper-responder group had significantly less forearm vasodilatation to acetylcholine compared with the hypo-responder group [percentage change in the forearm blood flow 125 (17) vs. 260 (28), mean (SEM); p routine clinical practice to aid risk stratification in hypertensive patients.

  4. Development of novel arginase inhibitors for therapy of endothelial dysfunction

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    Jochen eSteppan

    2013-09-01

    Full Text Available Endothelial dysfunction and resulting vascular pathology have been identified as an early hallmark of multiple diseases, including diabetes mellitus. One of the major contributors to endothelial dysfunction is a decrease in nitric oxide (NO bioavailability, impaired NO signaling and an increase in the amount of reactive oxygen species (ROS. In the endothelium NO is produced by eNOS (endothelial nitric oxide synthase, for which L-arginine is a substrate. Arginase, an enzyme critical in the urea cycle also metabolizes L-arginine, thereby directly competing with eNOS for their common substrate and constraining its bioavailability for eNOS, thereby compromising NO production. Arginase expression and activity is upregulated in many cardiovascular diseases including ischemia reperfusion injury, hypertension, atherosclerosis, and diabetes mellitus. More importantly, since the 1990s, specific arginase inhibitors such as N-hydroxy-guanidinium or N-hydroxy-nor-L-arginine, and boronic acid derivatives, such as, 2(S-amino-6-boronohexanoic acid, and S-(2-boronoethyl-L-cysteine (BEC, that can bridge the binuclear manganese cluster of arginase have been developed. These highly potent and specific inhibitors can now be used to probe arginase function and thereby modulate the redox milieu of the cell by changing the balance between NO and ROS. Inspired by this success, drug discovery programs have recently led to the identification of α-α-disubstituted amino acid based arginase inhibitors (such as (R-2-amino-6-borono-2-(2-(piperidin-1-ylethylhexanoic acid, that are currently under early investigation as therapeutics. Finally, some investigators concentrate on identification of plant derived compounds with arginase inhibitory capability, such as piceatannol-3'-O-β-D-glucopyranoside (PG. All of these synthesized or naturally derived small molecules may represent novel therapeutics for vascular disease particularly that associated with diabetes.

  5. Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

    Science.gov (United States)

    Lu, Qing; Mundy, Miles; Chambers, Eboni; Lange, Thilo; Newton, Julie; Borgas, Diana; Yao, Hongwei; Choudhary, Gaurav; Basak, Rajshekhar; Oldham, Mahogany; Rounds, Sharon

    2017-12-01

    Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

  6. Targeting Pulmonary Endothelial Hemoglobin α Improves Nitric Oxide Signaling and Reverses Pulmonary Artery Endothelial Dysfunction.

    Science.gov (United States)

    Alvarez, Roger A; Miller, Megan P; Hahn, Scott A; Galley, Joseph C; Bauer, Eileen; Bachman, Timothy; Hu, Jian; Sembrat, John; Goncharov, Dmitry; Mora, Ana L; Rojas, Mauricio; Goncharova, Elena; Straub, Adam C

    2017-12-01

    Pulmonary hypertension is characterized by pulmonary endothelial dysfunction. Previous work showed that systemic artery endothelial cells (ECs) express hemoglobin (Hb) α to control nitric oxide (NO) diffusion, but the role of this system in pulmonary circulation has not been evaluated. We hypothesized that up-regulation of Hb α in pulmonary ECs contributes to NO depletion and pulmonary vascular dysfunction in pulmonary hypertension. Primary distal pulmonary arterial vascular smooth muscle cells, lung tissue sections from unused donor (control) and idiopathic pulmonary artery (PA) hypertension lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. Cocultures of human pulmonary microvascular ECs and distal pulmonary arterial vascular smooth muscle cells, lung tissue from control and pulmonary hypertensive lungs, and a mouse model of chronic hypoxia-induced PH were used. Immunohistochemical, immunoblot analyses, spectrophotometry, and blood vessel myography experiments were performed in this study. We find increased expression of Hb α in pulmonary endothelium from humans and mice with PH compared with controls. In addition, we show up-regulation of Hb α in human pulmonary ECs cocultured with PA smooth muscle cells in hypoxia. We treated pulmonary ECs with a Hb α mimetic peptide that disrupts the association of Hb α with endothelial NO synthase, and found that cells treated with the peptide exhibited increased NO signaling compared with a scrambled peptide. Myography experiments using pulmonary arteries from hypoxic mice show that the Hb α mimetic peptide enhanced vasodilation in response to acetylcholine. Our findings reveal that endothelial Hb α functions as an endogenous scavenger of NO in the pulmonary endothelium

  7. Predictors of endothelial dysfunction and atherosclerosis in rheumatoid arthritis in Indian population

    Directory of Open Access Journals (Sweden)

    Inderjeet Verma

    2017-03-01

    Conclusions: In the present study, FMD and CIMT were impaired in RA, indicating endothelial dysfunction and accelerated atherosclerosis respectively. CRP, TNF-α, serum nitrite, DAS-28 and depleted EPC population predicted endothelial dysfunction. Age, IL-6, HDL, LDL and depleted EPC population predicted accelerated atherosclerosis.

  8. Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1.

    Science.gov (United States)

    Bhatta, Anil; Yao, Lin; Xu, Zhimin; Toque, Haroldo A; Chen, Jijun; Atawia, Reem T; Fouda, Abdelrahman Y; Bagi, Zsolt; Lucas, Rudolf; Caldwell, Ruth B; Caldwell, Robert W

    2017-11-01

    Elevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology. To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment. Vascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome. Published

  9. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins

    Science.gov (United States)

    2011-01-01

    Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk. PMID:21736746

  10. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins

    Directory of Open Access Journals (Sweden)

    Koska Juraj

    2011-07-01

    Full Text Available Abstract Cardiovascular disease (CVD risk in type 2 diabetes (T2DM is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1 the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2 the ability of incretins to modulate postprandial hyperlipidemia and (3 the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.

  11. Association between periodontal disease and endothelial dysfunction in smoking patients.

    Science.gov (United States)

    Velosa-Porras, Juliana; Escobar-Arregoces, Francina; Latorre-Uriza, Catalina; Ferro-Camargo, María B; Ruiz, Álvaro J; Uriza-Carrasco, Luis F

    2016-04-01

    Over the past two decades, there has been increasing interest in the impact of oral health on cardiovascular disease, particularly regarding the effects of chronic infections such as periodontitis on the endothelium. The aim of this study was to evaluate in healthy smokers whether there are any significant differences in the frequency of endothelial dysfunction between subjects with chronic moderate to severe periodontal disease and periodontally healthy subjects. An observational cross-sectional study was conducted. The target population was adults older than 40 years of age. Blood tests were performed to determine values of CBC, glycaemia, total cholesterol, HDL-C, and LDLC. Periodontal examinations and probing were conducted with a Florida Probe®, and standardized procedures were used to measure flow-mediated dilation. Out of 150 subjects [69 male (46%) and 81 female (54%)], 75 (50%) had chronic periodontitis. The mean value for baseline flow-mediated dilation was 4.04% and the mean value for final flow-mediated dilation was 4.66%, with a 0.62% mean difference showing a statistically significant increase (pperiodontally healthy subjects and those with periodontitis, in contrast to the literature, which suggests a negative impact of periodontal disease on endothelial function. Sociedad Argentina de Investigación Odontológica.

  12. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications

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    Miroslav Radenkovic

    2016-01-01

    Full Text Available The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation.

  13. Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling.

    Science.gov (United States)

    Honavar, Jaideep; Samal, Andrey A; Bradley, Kelley M; Brandon, Angela; Balanay, Joann; Squadrito, Giuseppe L; MohanKumar, Krishnan; Maheshwari, Akhil; Postlethwait, Edward M; Matalon, Sadis; Patel, Rakesh P

    2011-08-01

    Chlorine gas (Cl(2)) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl(2) exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl(2) promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl(2) for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl(2) dose (0-400 ppm) and time after exposure (0-48 h) were determined. Exposure to Cl(2) (250-400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (∼ 60%) in aorta isolated from Cl(2)-exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl(2) exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl(2)-exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl(2) exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms.

  14. Chlorine Gas Exposure Causes Systemic Endothelial Dysfunction by Inhibiting Endothelial Nitric Oxide Synthase–Dependent Signaling

    Science.gov (United States)

    Honavar, Jaideep; Samal, Andrey A.; Bradley, Kelley M.; Brandon, Angela; Balanay, Joann; Squadrito, Giuseppe L.; MohanKumar, Krishnan; Maheshwari, Akhil; Postlethwait, Edward M.; Matalon, Sadis; Patel, Rakesh P.

    2011-01-01

    Chlorine gas (Cl2) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl2 exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl2 promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl2 for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl2 dose (0–400 ppm) and time after exposure (0–48 h) were determined. Exposure to Cl2 (250–400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (∼ 60%) in aorta isolated from Cl2–exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl2 exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl2–exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl2 exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms. PMID:21131444

  15. Endothelial dysfunction in the early postoperative period after major colon cancer surgery

    DEFF Research Database (Denmark)

    Ekeloef, S; Larsen, M H H; Schou-Pedersen, A M V

    2017-01-01

    BACKGROUND: Evidence suggests that endothelial dysfunction in the early postoperative period promotes myocardial injury after non-cardiac surgery. The aim of this study was to investigate the impact of colon cancer surgery on endothelial function and the association with the l-arginine-nitric oxide...... pathway postoperatively. METHODS: Patients undergoing elective colon cancer surgery (n = 31) were included in this prospective observational cohort study. Endothelial function, as measured using the reactive hyperaemia index (RHI), was assessed non-invasively using digital pulse tonometry. RHI and plasma...... was attenuated in the first days after colon cancer surgery indicating acute endothelial dysfunction. Endothelial dysfunction correlated with disturbances in the L-arginine - nitric oxide pathway. Our findings provide a rationale for investigating the hypothesized association between acute endothelial...

  16. Circulating Markers of Endothelial Dysfunction Interact With Proteinuria in Predicting Mortality in Renal Transplant Recipients

    NARCIS (Netherlands)

    van Ree, Rutger M.; Oterdoom, Leendert H.; de Vries, Aiko P.J.; Homan van der Heide, Jaap J.; van Son, Willem J.; Navis, Gerjan; Gans, Reinold O.B.; Bakker, Stephan J L

    2008-01-01

    BACKGROUND: Proteinuria is associated with endothelial dysfunction (ED) and increased mortality. We investigated whether urinary protein excretion (UPE) is correlated with markers of ED and whether these markers affect the association of proteinuria with mortality in renal transplant recipients

  17. Circulating markers of endothelial dysfunction interact with proteinuria in predicting mortality in renal transplant recipients

    NARCIS (Netherlands)

    van Ree, Rutger M.; Oterdoom, Leendert H.; de Vries, Aiko P. J.; Homan van der Heide, Jaap J.; van Son, Willem J.; Navis, Gerjan; Gans, Reinold O. B.; Bakker, Stephan J. L.

    2008-01-01

    Proteinuria is associated with endothelial dysfunction (ED) and increased mortality. We investigated whether urinary protein excretion (UPE) is correlated with markers of ED and whether these markers affect the association of proteinuria with mortality in renal transplant recipients (RTR). Six

  18. Effect of High Inspiratory Oxygen Fraction on Endothelial Dysfunction in Healthy Volunteers

    DEFF Research Database (Denmark)

    Larsen, Mikkel Hjordt Holm; Ekeløf, Sara; Kokotovic, Dunja

    2017-01-01

    It has been suggested that high inspiratory oxygen concentrations during anesthesia may be associated with higher postoperative mortality due to endothelial dysfunction. A randomized controlled crossover study was conducted with 25 healthy male volunteers. They inhaled an oxygen concentration of ...

  19. Endothelial dysfunction marker YKL-40 is elevated in male patients with idiopathic infertility.

    Science.gov (United States)

    Hanafy, S M; Sabry, H H; Sabry, J H; Hamed, A M

    2018-02-02

    Metabolic syndrome represents a collection of cardiovascular risk factors, including overweight, hypertension, dyslipidemia and impaired glucose metabolism, with insulin resistance. In recent years, the potential relationship between metabolic syndrome and male factor infertility has been studied. As endothelial dysfunction is the hallmark of metabolic syndrome, the aim of this work was to assess serum levels of YKL-40 as a marker of endothelial dysfunction in male patients with idiopathic infertility. The study revealed that YKL-40 levels were elevated in patients than controls denoting that endothelial dysfunction might play a role in the pathogenesis of idiopathic infertility and that YKL-40 as a marker of endothelial dysfunction could be a useful marker of idiopathic infertility. © 2018 Blackwell Verlag GmbH.

  20. The phytoestrogen alpha-zearalenol reverses endothelial dysfunction induced by oophorectomy in rats.

    Science.gov (United States)

    Altavilla, D; Saitta, A; Galeano, M; Squadrito, G; Marino, D; Minutoli, L; Calapai, G; Deodato, B; D'Anna, R; Corrado, F; Caputi, A P; Squadrito, F

    2001-02-01

    It has been shown recently that alpha-zearalenol, a resorcyclic acid lactone, prevents bone loss in a rat model of postmenopausal bone loss. We have therefore investigated the effects of this phytoestrogen on endothelial dysfunction induced by estrogen deficiency in rats. Female mature Sprague-Dawley rats underwent a bilateral oophorectomy (OVX rats). Sham-operated animals (sham OVX rats) were used as controls. Three weeks after surgery, animals were randomized to the following treatments: alpha-zearalenol (1 mg/kg/day, i.m., for 4 weeks), 17beta-estradiol (20 microg/kg/day, i.m., for 4 weeks), or their vehicle (100 microl, i.m., of cottonseed oil). Two other groups of rats were treated with alpha-zearalenol or 17beta-estradiol plus the pure estrogen receptor antagonist ICI 182780 (2.5 mg/kg/day, i.m., for 4 weeks). Mean arterial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasma estradiol, and plasma alpha-zearalenol were studied. We also investigated endothelial-dependent (acetylcholine, 10 nM to 10 microM) and endothelial-independent (sodium nitroprusside, 15 nM to 30 nM) relaxation of aortic rings, as well as N(G)-methyl-L-arginine (L-NMA: 10 to 100 microM)-induced vasoconstriction and calcium-dependent nitric oxide synthase (cNOS) activity in homogenates of lungs taken from both sham OVX rats and OVX rats. Untreated OVX rats had, compared with sham OVX animals, unchanged body weight, MAP, HR, and plasma cholesterol. In contrast oophorectomy reduced plasma estradiol levels (OVX, 2 +/- 0.5 pg/ml; sham OVX, 35 +/- 6 pg/ml), impaired endothelial-dependent relaxation and blunted L-NMA-induced contraction (L-NMA 100 microM: sham OVX, 2.7 +/- 0.3 g/mg tissue; OVX, 1.3 +/- 0.1 g/mg tissue). Moreover OVX rats showed a reduced calcium-dependent NO synthase (cNOS) activity. Treatment with alpha-zearalenol or with 17beta-estradiol reverted the endothelial dysfunction and increased cNOS activity in lung homogenates. These effects were abolished by the

  1. Contribution of Cyclooxygenase End Products and Oxidative Stress to Intrahepatic Endothelial Dysfunction in Early Non-Alcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Gonzalez-Paredes

    Full Text Available Metabolic syndrome induces endothelial dysfunction, a surrogate marker of cardiovascular disease. In parallel, metabolic syndrome is frequently associated with non-alcoholic fatty liver disease (NAFLD, which may progress to cirrhosis. The aim of the present study was to evaluate intrahepatic endothelial dysfunction related to cyclooxygenase end products and oxidative stress as possible mechanisms involved in the pathophysiology of NAFLD.Sprague-Dawley rats were fed standard diet (control-diet, CD or high-fat-diet (HFD for 6 weeks. Metabolic syndrome was assessed by recording arterial pressure, lipids, glycemia and rat body weight. Splanchnic hemodynamics were measured, and endothelial dysfunction was evaluated using concentration-effect curves to acetylcholine. Response was assessed with either vehicle, L-NG-Nitroarginine (L-NNA, indomethacin, tempol, or a thromboxane receptor antagonist, SQ 29548. We quantified inflammation, fibrosis, oxidative stress, nitric oxide (NO bioavailability and thromboxane B2 levels.HFD rats exhibited metabolic syndrome together with the presence of NAFLD. Compared to control-diet livers, HFD livers showed increased hepatic vascular resistance unrelated to inflammation or fibrosis, but with decreased NO activity and increased oxidative stress. Endothelial dysfunction was observed in HFD livers compared with CD rats and improved after cyclooxygenase inhibition or tempol pre-incubation. However, pre-incubation with SQ 29548 did not modify acetylcholine response.Our study provides evidence that endothelial dysfunction at an early stage of NAFLD is associated with reduced NO bioavailability together with increased cyclooxygenase end products and oxidative stress, which suggests that both pathways are involved in the pathophysiology and may be worth exploring as therapeutic targets to prevent progression of the disease.

  2. Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury

    OpenAIRE

    Zhang, Cuihua; Wu, Junxi; Xu, Xiangbin; Potter, Barry J.; Gao, Xue

    2010-01-01

    We previously found that myocardial ischemia/reperfusion (I/R) initiates expression of tumor necrosis factor-α (TNF) leading to coronary endothelial dysfunction. However, it is not clear whether there is a direct relationship between levels of TNF expression and endothelial dysfunction in reperfusion injury. We studied levels of TNF expression by using different transgenic animals expressing varying amounts of TNF in I/R. We crossed TNF overexpression (TNF++/++) with TNF knockout (TNF−/−) mic...

  3. Protective role of adiponectin on endothelial dysfunction induced by AGEs: a clinical and experimental approach

    OpenAIRE

    Del Turco, Serena; Navarra, Teresa; Gastaldelli, Amalia; Basta, Giuseppina

    2011-01-01

    Objective: Obesity is characterized by low levels of adiponectin, an adipocytes derived hormone, and by an inflammatory component. Endothelial dysfunction is often found in overweight/obesity, diabetes, and atherosclerosis. Advanced glycation end products (AGEs) induce endothelial dysfunction and are linked to diabetes and increased atherogenicity and inflammation. The aim of the study was to investigate the possible link between adiponectin and N(epsilon)-(carboxymethyl) lysine (CML), the pr...

  4. Endothelial Dysfunction and Its Correction in Patients with Essential Hypertension and Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    A.S. Shalimova

    2014-03-01

    Full Text Available The article provides the results of studying the effectiveness of α-lipoic acid impact as a part of complex therapy on endothelial dysfunction in patients with essential hypertension and type 2 diabetes mellitus. There were revealed a significant improvement in metabolic homeostasis, decreased severity of endothelial dysfunction, reduced levels of inflammatory cytokines under additional use of α-lipoic acid compared with standard therapy.

  5. Therapeutic Approach in the Improvement of Endothelial Dysfunction: The Current State of the Art

    Directory of Open Access Journals (Sweden)

    Miroslav Radenković

    2013-01-01

    Full Text Available The endothelium has a central role in the regulation of blood flow through continuous modulation of vascular tone. This is primarily accomplished by balanced release of endothelial relaxing and contractile factors. The healthy endothelial cells are essential for maintenance of vascular homeostasis involving antioxidant, anti-inflammatory, pro-fibrinolytic, anti-adhesive, or anticoagulant effects. Oppositely, endothelial dysfunction is primarily characterized by impaired regulation of vascular tone as a result of reduced endothelial nitric oxide (NO synthase activity, lack of cofactors for NO synthesis, attenuated NO release, or increased NO degradation. So far, the pharmacological approach in improving/reversal of endothelial dysfunction was shown to be beneficial in clinical trials that have investigated actions of different cardiovascular drugs. The aim of this paper was to summarize some of the latest clinical findings related to therapeutic possibilities for improving endothelial dysfunction in different pathological conditions. In the majority of presented clinical investigations, the assessment of improvement or reversal of endothelial dysfunction was performed through the flow-mediated dilatation measurement, and in some of those endothelial progenitor cells’ count was used for the same purpose. Still, given the fast and continuous development of this field, the evidence acquisition included the MEDLINE data base screening and the selection of articles published between 2010 and 2012.

  6. Portulaca oleracea Ameliorates Diabetic Vascular Inflammation and Endothelial Dysfunction in db/db Mice

    Science.gov (United States)

    Lee, An Sook; Lee, Yun Jung; Lee, So Min; Yoon, Jung Joo; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

    2012-01-01

    Type 2 diabetes is associated with significantly accelerated rates of micro- and macrovascular complications such as diabetic vascular inflammation and endothelial dysfunction. In the present study, we investigated the protective effect of the aqueous extract of Portulaca oleracea L. (AP), an edible plant used as a folk medicine, on diabetic vascular complications. The db/db mice were treated with AP (300 mg/kg/day, p.o.) for 10 weeks, and AP treatment markedly lowered blood glucose, plasma triglyceride, plasma level of LDL-cholesterol, and systolic blood pressure in diabetic db/db mice. Furthermore, AP significantly increased plasma level of HDL-cholesterol and insulin level. The impairment of ACh- and SNP-induced vascular relaxation of aortic rings were ameliorated by AP treatment in diabetic db/db mice. This study also showed that overexpression of VCAM-1, ICAM-1, E-selectin, MMP-2, and ET-1 were observed in aortic tissues of untreated db/db mice, which were significantly suppressed by treatment with AP. We also found that the insulin immunoreactivity of the pancreatic islets remarkably increased in AP treated db/db mice compared with untreated db/db mice. Taken together, AP suppresses hyperglycemia and diabetic vascular inflammation, and prevents the development of diabetic endothelial dysfunction for the development of diabetes and its vascular complications. PMID:22474522

  7. Protective effects of exercise training on endothelial dysfunction induced by total sleep deprivation in healthy subjects.

    Science.gov (United States)

    Sauvet, Fabien; Arnal, Pierrick J; Tardo-Dino, Pierre Emmanuel; Drogou, Catherine; Van Beers, Pascal; Bougard, Clément; Rabat, Arnaud; Dispersyn, Garance; Malgoyre, Alexandra; Leger, Damien; Gomez-Merino, Danielle; Chennaoui, Mounir

    2017-04-01

    Sleep loss is a risk factor for cardiovascular events mediated through endothelial dysfunction. To determine if 7weeks of exercise training can limit cardiovascular dysfunction induced by total sleep deprivation (TSD) in healthy young men. 16 subjects were examined during 40-h TSD, both before and after 7weeks of interval exercise training. Vasodilatation induced by ACh, insulin and heat (42°C) and pulse wave velocity (PWV), blood pressure and heart rate (HR) were assessed before TSD (controlday), during TSD, and after one night of sleep recovery. Biomarkers of endothelial activation, inflammation, and hormones were measured from morning blood samples. Before training, ACh-, insulin- and heat-induced vasodilatations were significantly decreased during TSD and recovery as compared with the control day, with no difference after training. Training prevented the decrease of ACh-induced vasodilation related to TSD after sleep recovery, as well as the PWV increase after TSD. A global lowering effect of training was found on HR values during TSD, but not on blood pressure. Training induces the decrease of TNF-α concentration after TSD and prevents the increase of MCP-1 after sleep recovery. Before training, IL-6 concentrations increased. Cortisol and testosterone decreased after TSD as compared with the control day, while insulin and E-selectin increased after sleep recovery. No effect of TSD or training was found on CRP and sICAM-1. In healthy young men, a moderate to high-intensity interval training is effective at improving aerobic fitness and limiting vascular dysfunction induced by TSD, possibly through pro-inflammatory cytokine responses.(ClinicalTrial:NCT02820649). Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Sirt1 Protects Endothelial Cells against LPS-Induced Barrier Dysfunction

    Science.gov (United States)

    Guo, Xiaohua; Liu, Yanan; He, Jing; Wang, Ruiting

    2017-01-01

    Sepsis is a threatening health problem and characterized by microvascular dysfunction. In this study, we verified that LPS caused the downregulation of Sirt1 and the hyperpermeability of endothelial cells. Inhibition of Sirt1 with ex527 or Sirt1 siRNA displayed a higher permeability, while activation of Sirt1 with SRT1720 reversed the LPS-induced hyperpermeability, formation of fiber stress, and disruption of VE-cadherin distribution. In pulmonary microvascular vein endothelial cells isolated from wild-type mice, Sirt1 was attenuated upon LPS, while Sirt1 was preserved in a receptor of advanced glycation end product-knockout mice. The RAGE antibody could also diminish the downregulation and ubiquitination of Sirt1 in LPS-exposed human umbilical vein endothelial cells. An LPS-induced decrease in Sirt1 activity was attenuated by the RAGE antibody and TLR4 inhibitor. In vivo study also demonstrated the attenuating role of Sirt1 and RAGE knockout in LPS-induced increases in dextran leakage of mesenteric venules. Furthermore, activation of Sirt1 prevented LPS-induced decreases in the activity and expression of superoxide dismutase 2, as well as the increases in NADPH oxidase 4 and reactive oxygen species, while inhibition of Sirt1 aggravated the SOD2 decline. It also demonstrated that Sirt1-deacetylated p53 is required for p53 inactivation, which reversed the downregulation of β-catenin caused by LPS. PMID:29209448

  9. Physalis minima Leaves Extract Induces Re-Endothelialization in Deoxycorticosterone Acetate-Salt-Induced Endothelial Dysfunction in Rats

    Directory of Open Access Journals (Sweden)

    Dian Nugrahenny

    2018-02-01

    Full Text Available The administration of deoxy-corticosterone acetate (DOCA-salt can induce oxidative stress leading to decrease the bioavailability of nitric oxide (NO, increase senescence of circulating endothelial progenitor cells (EPCs, thus contributing to endothelial dysfunction. This study was aimed to investigate the effects of Physalis minima L. leaves extract on serum NO levels, circulating EPCs number, and histopathology of tail artery endothelial cells in DOCA-salt-induced endothelial dysfunction in rats. Twenty-five male Wistar rats were randomly divided into five groups: rats without any treatment (normal, rats treated with DOCA (10 mg/kgBW s.c. twice weekly and given 0.9% NaCl to drink ad libitum for 6 weeks, and DOCA-salt-induced rats orally supplemented with P. minima leaves extract at doses of 500, 1500, or 2500 mg/kgBW for 4 weeks. Serum NO levels were measured by colorimetry. The number of circulating EPCs (CD34+/CD133+ cells was determined by flow cytometry. The tail artery sections were histologically processed with hematoxylin-eosin staining. DOCA-salt-induced rats showed significantly (p<0.05 decrease in serum NO levels and circulating EPCs number compared to the normal. There was also more detached tail artery endothelial cells in DOCA-salt-induced rats. P. minima leaves extract at a dose of 500 mg/kgBW significantly (p<0.05 increased serum NO level and circulating EPCs number, and also induced an optimal re-endothelialization in DOCA-salt-induced rats. P. minima leave extract dose-dependently increases NO bioavailability contributing to enhanced EPCs mobilization, thereby promoting re-endothelialization in DOCA-salt-induced endothelial dysfunction in rats.

  10. Vascular dysfunction associated with major depression-like symptoms: monoamine homeostasis and endothelial dysfunction

    DEFF Research Database (Denmark)

    Bouzinova, Elena; Andresen, Jørgen; Wiborg, Ove

    and reduced expression of extra-neuronal transporter (OCT-2) in anhedonic arteries. The contractility of middle cerebral arteries to 5-HT was reduced by CMS but recovered by anti-depressant treatment. Resistance arteries from anhedonic rats were less sensitive to acetylcholine compared to non......Major depression and cardiovascular diseases have strong co-morbidity but the reason for this is unknown. In Chronic Mild Stress (CMS) model of depression only some rats develop depression-like symptoms (i.e. anhedonia, measured by sucrose intake) while others are resilient to 8 weeks of CMS......-like response) was significantly reduced in anhedonic rats. This was associated with decreased transcription of intermediate-conductance Ca2+-activated K+ channels. Our results indicate that CMS-induced depression-like symptoms in rats are associated with changes in monoamine uptake and endothelial dysfunctions...

  11. Inflammation-Induced Increases in Plasma Endocan Levels are Associated With Endothelial Dysfunction in Humans in vivo

    NARCIS (Netherlands)

    Cox, L.A.E.; Eijk, L.T.G.J. van; Ramakers, B.P.C.; Dorresteijn, M.J.; Gerretsen, J.; Kox, M.; Pickkers, P.

    2015-01-01

    Although endothelial dysfunction is central to the pathogenesis of sepsis, no specific and clinically applicable marker for endothelial dysfunction is currently available. Endocan, a proteoglycan excreted by endothelial cells in response to inflammatory cytokines, may serve as such a marker. Our

  12. Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure.

    Science.gov (United States)

    Amabile, Nicolas; Guérin, Alain P; Leroyer, Aurélie; Mallat, Ziad; Nguyen, Clément; Boddaert, Jacques; London, Gérard M; Tedgui, Alain; Boulanger, Chantal M

    2005-11-01

    Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk in patients with end-stage renal failure (ESRF). Microparticles are membrane fragments shed from damaged or activated cells. Because microparticles can affect endothelial cells, this study investigated the relationship between circulating microparticles and arterial dysfunction in patients with ESRF and identified the cellular origin of microparticles associated with these alterations. Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that circulating levels of Annexin V+ microparticles were increased compared with 32 healthy subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets (16.5-fold), and erythrocytes (1.6-fold). However, when arterial function was evaluated noninvasively in patients with ESRF, only endothelial microparticle levels correlated highly with loss of flow-mediated dilation (r = -0.543; P = 0.004), increased aortic pulse wave velocity (r = 0.642, P < 0.0001), and increased common carotid artery augmentation index (r = 0.463, P = 0.0017), whereas platelet-derived, erythrocyte-derived, and Annexin V+ microparticle levels did not. In vitro, microparticles from patients with ESRF impaired endothelium-dependent relaxations and cyclic guanosine monophosphate generation, whereas microparticles from healthy subjects did not. Moreover, in vitro endothelial dysfunction correlated with endothelial-derived (r = 0.891; P = 0.003) but not platelet-derived microparticle concentrations. In fact, endothelial microparticles alone decreased endothelial nitric oxide release by 59 +/- 7% (P = 0.025). This study suggests that circulating microparticles of endothelial origin are tightly associated with endothelial dysfunction and arterial dysfunction in ESRF.

  13. Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

    Science.gov (United States)

    Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

    2017-08-01

    Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese

  14. Endothelial dysfunction: a unifying hypothesis for the burden of cardiovascular diseases in sub-Saharan Africa.

    Science.gov (United States)

    Sampson, Uchechukwu K A; Engelgau, Michael M; Peprah, Emmanuel K; Mensah, George A

    2015-01-01

    It is well established that the leading causes of death and disability worldwide are cardiovascular diseases (CVD), chief among which is ischaemic heart disease. However, it is also recognised that ischaemic heart disease frequently coexists with other vascular conditions, such as cerebrovascular, renovascular and peripheral vascular disease, thus raising the notion of a common underlying pathobiology, albeit with differing manifestations, dictated by the implicated vascular bed. The understanding that common metabolic and behavioural risk factors as well as social determinants and drivers are convergent in the development of CVD evokes the idea that the dysfunction of a common bio-molecular platform is central to the occurrence of these diseases. The state of endothelial activation, otherwise known as endothelial dysfunction, occurs when reactive oxygen signalling predominates due to an uncoupled state of endothelial nitric oxide synthase (eNOS). This can be a physiological response to stimulation of the innate immune system or a pathophysiological response triggered by cardiovascular disease risk factors. The conventional wisdom is that the endothelium plays an important role in the initiation, progression and development of CVD and other non-communicable diseases. Consequently, the endothelium has remarkable relevance in clinical and public health practice as well as in health education, health promotion, and disease- and risk-factor prevention strategies. It also presents a plausible unifying hypothesis for the burden of CVD seen globally and in sub-Saharan Africa. Importantly, the heterogeneity in individual responses to metabolic, behavioural, and social drivers of CVD may stem from a complex interplay of these drivers with genomic, epigenetic and environmental factors that underpin eNOS uncoupling. Therefore, further biomedical research into the underlying genetic and other mechanisms of eNOS uncoupling may enlighten and shape strategies for addressing the

  15. [Hypogonadism, erectile dysfunction and endothelial dysfunction among HIV-infected men].

    Science.gov (United States)

    Moreno-Pérez, Oscar; Picó Alfonso, Antonio Miguel; Portilla, Joaquín

    2009-03-07

    HIV-associated hypogonadism is known to be a prevalent endocrine disorder, with a multifactorial etiology. Low testosterone levels are associated with decreased muscle mass, exercise capacity loss, erectile dysfunction, cognitive impairment, depression and decreased quality of life. In the same way, hypogonadism in HIV-infected men is associated with decreased muscle mass quantity and function, changes in corporal fat mass distribution and quantity, secretion of adipocytokines and endothelial dysfunction. This combined effect renders the entire body less sensitive to insulin, promoting development of atherosclerosis and glucose metabolism disorders. The clinical presentation is non-specific and hypogonadism screening scales are not useful in this population. Diagnostic procedures must include determination of free testosterone (FTc) in any HIV-infected men at the time of first HIV diagnosis and periodically, because of the clinical implications and the absence of specific predictive disease factors. Substitutive hormonal treatment must be offered only for HIV-infected men with FTc under reference levels and when reversible causes have been ruled out. Metabolic impact of hypogonadism suggests the incorporation of low testosterone levels to the list of cardiovascular risk factor in HIV-infected men.

  16. Perturbations in Endothelial Dysfunction-Associated Pathways in the Nitrofen-Induced Congenital Diaphragmatic Hernia Model.

    Science.gov (United States)

    Zhaorigetu, Siqin; Bair, Henry; Lu, Jonathan; Jin, Di; Olson, Scott D; Harting, Matthew T

    2018-01-01

    Although it is well known that nitrofen induces congenital diaphragmatic hernia (CDH), including CDH-associated lung hypoplasia and pulmonary hypertension (PH) in rodents, the mechanism of pathogenesis remains largely unclear. It has been reported that pulmonary artery (PA) endothelial cell (EC) dysfunction contributes to the development of PH in CDH. Thus, we hypothesized that there is significant alteration of endothelial dysfunction-associated proteins in nitrofen-induced CDH PAs. Pregnant SD rats received either nitrofen or olive oil on gestational day 9.5. The newborn rats were sacrificed and divided into a CDH (n = 81) and a control (n = 23) group. After PA isolation, the expression of PA endothelial dysfunction-associated proteins was assessed on Western blot and immunostaining. We demonstrate that the expression of C-reactive protein and endothelin-1 and its receptors, ETA and ETB, were significantly increased in the CDH PAs. Levels of phosphorylated myosin light chain were significantly elevated, but those of phosphorylated endothelial nitric oxide synthase, caveolin-1, and mechanistic target of rapamycin were significantly decreased in the CDH PAs. In this work, we elucidate alterations in the expression of endothelial dysfunction-associated proteins specific to nitrofen-induced CDH rodent PAs, thereby advancing our understanding of the critical role of endothelial dysfunction-associated pathways in the pathogenesis of nitrofen-induced CDH. © 2017 S. Karger AG, Basel.

  17. Anthocyanin increases adiponectin secretion and protects against diabetes-related endothelial dysfunction.

    Science.gov (United States)

    Liu, Yan; Li, Dan; Zhang, Yuhua; Sun, Ruifang; Xia, Min

    2014-04-15

    Adiponectin is an adipose tissue-secreted adipokine with beneficial effects on the cardiovascular system. In this study, we evaluated a potential role for adiponectin in the protective effects of anthocyanin on diabetes-related endothelial dysfunction. We treated db/db mice on a normal diet with anthocyanin cyanidin-3-O-β-glucoside (C3G; 2 g/kg diet) for 8 wk. Endothelium-dependent and -independent relaxations of the aorta were then evaluated. Adiponectin expression and secretion were also measured. C3G treatment restores endothelium-dependent relaxation of the aorta in db/db mice, whereas diabetic mice treated with an anti-adiponectin antibody do not respond. C3G treatment induces adiponectin expression and secretion in cultured 3T3 adipocytes through transcription factor forkhead box O1 (Foxo1). Silencing Foxo1 expression prevented C3G-stimulated induction of adiponectin expression. In contrast, overexpression of Foxo1-ADA promoted adiponectin expression in adipocytes. C3G activates Foxo1 by increasing its deacetylation via silent mating type information regulation 2 homolog 1 (Sirt1). Furthermore, purified anthocyanin supplementation significantly improved flow-mediated dilation (FMD) and increased serum adiponectin concentrations in patients with type 2 diabetes. Changes in adiponectin concentrations positively correlated with FMD in the anthocyanin group. Mechanistically, adiponectin activates cAMP-PKA-eNOS signaling pathways in human aortic endothelial cells, increasing endothelial nitric oxide bioavailability. These results demonstrate that adipocyte-derived adiponectin is required for anthocyanin C3G-mediated improvement of endothelial function in diabetes.

  18. Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction.

    Science.gov (United States)

    Stühlinger, Markus C; Stanger, Olaf

    2005-02-01

    Hyperhomocyst(e)inemia is associated with an increased risk for atherosclerotic disease and venous thromboembolism. The impact of elevated plasma homocysteine levels seems to be clinically relevant, since the total cardiovascular risk of hyperhomocyst(e)inemia is comparable to the risk associated with hyperlipidemia or smoking. There is substantial evidence for impairment of endothelial function in human and animal models of atherosclerosis, occurring even before development of overt plaques. Interestingly endothelial dysfunction appears to be a sensitive indicator of the process of atherosclerotic lesion development and predicts future vascular events. NO is the most potent endogenous vasodilator known. It is released by the endothelium, and reduced NO bioavailability is responsible for impaired endothelium-dependent vasorelaxation in hyperhomocyst(e)inemia and other metabolic disorders associated with vascular disease. Substances leading to impaired endothelial function as a consequence of reduced NO generation are endogenous NO synthase inhibitors such as ADMA. Indeed there is accumulating evidence from animal and human studies that ADMA, endothelial function and homocyst(e)ine might be closely interrelated. Specifically elevations of ADMA associated with impaired endothelium-dependent relaxation were found in chronic hyperhomocyst(e)inemia, as well as after acute elevation of plasma homocyst(e)ine following oral methionine intake. The postulated mechanisms for ADMA accumulation are increased methylation of arginine residues within proteins, as well as reduced metabolism of ADMA by the enzyme DDAH, but they still need to be confirmed to be operative in vivo. Hyperhomocyst(e)inemia, as well as subsequent endothelial dysfunction can be successfully treated by application of folate and B vitamins. Since ADMA seems to play a central role in homocyst(e)ine-induced endothelial dysfunction, another way of preventing vascular disease in patients with elevated homocyst

  19. Olive Oil Supplements Ameliorate Endothelial Dysfunction Caused by Concentrated Ambient Particulate Matter Exposure in Healthy Human Volunteers

    Science.gov (United States)

    Context: Exposure to ambient particulate matter (PM) induces endothelial dysfunction, a risk factor for clinical cardiovascular events and progression of atherosclerosis. Dietary supplements such as olive oil and fish oil have beneficial effects on endothelial function, and ther...

  20. Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice.

    Science.gov (United States)

    Oh, Yun K; Bachar, Adi R; Zacharias, David G; Kim, Sung Gyun; Wan, Junxiang; Cobb, Laura J; Lerman, Lilach O; Cohen, Pinchas; Lerman, Amir

    2011-11-01

    Humanin (HN) is a cytoprotective peptide derived from endogenous mitochondria, expressed in the endothelial layer of human vessels, but its role in atherogenesis in vivo is not known. In vitro study, however, HN reduced oxidized low-density lipoprotein induced formation of reactive oxygen species and apoptosis. The present study tested the hypothesis that long term treatment with HN will have a protective role against endothelial dysfunction and progression of atherosclerosis in vivo. Daily intraperitonial injection of the HN analogue HNGF6A for 16 weeks prevented endothelial dysfunction and decreased atherosclerotic plaque size in the proximal aorta of ApoE-deficient mice fed on a high cholesterol diet, without showing direct vasoactive effects or cholesterol-reducing effects. HN was expressed in the endothelial layer on the aortic plaques. HNGF6A treatment reduced apoptosis and nitrotyrosine immunoreactivity in the aortic plaques without affecting the systemic cytokine profile. HNGF6A also preserved expression of endothelial nitric oxide synthase in aorta. HN may have a protective effect on endothelial function and progression of atherosclerosis by modulating oxidative stress and apoptosis in the developing plaque. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  1. Contribution of Oxidative stress to Endothelial Dysfunction in Hereditary Hemorrhagic Telangiectasia

    Directory of Open Access Journals (Sweden)

    Mirjana eJerkic

    2015-02-01

    Full Text Available Oxidative stress causes endothelial dysfunction and is implicated in the pathogenesis of cardiovascular diseases. Our studies suggested that reactive oxygen species (ROS play a crucial role in Hereditary Hemorrhagic Telangiectasia (HHT disease, a vascular dysplasia affecting 1 in 5,000-8,000 people. Mutations in endoglin (ENG and activin receptor-like kinase (ACVRL1 genes are responsible for HHT1 and HHT2 and are associated with arteriovenous malformations. Endoglin and ACVRL1 interact with endothelial NO synthase (eNOS and regulate its activation. Mice heterozygous for these genes (Eng+/− and Acvrl1+/- show reduced endoglin or ACVRL1 protein levels in endothelial cells causing eNOS uncoupling, generation of reactive oxygen species (ROS rather than nitric oxide (NO•, leading to impaired NO• mediated vasodilation. ROS production is increased in several organs of Eng+/− and Acvrl1+/− mice, including lungs, liver, and colon, affected in HHT. The major source of increased oxidative stress in these tissues is eNOS-derived ROS and not mitochondrial or NADPH oxidase-dependent ROS. Eng+/− and Acvrl1+/− mice also develop with age signs of pulmonary arterial hypertension (PH attributable to eNOS-derived ROS, which was preventable by antioxidant treatment. To date, only one pilot study has been carried out in HHT patients, and it showed beneficial effects of antioxidant therapy on epistaxis. We suggest that more clinical studies are warranted to investigate whether antioxidants would prevent, delay or attenuate manifestations of disease in individuals with HHT, based on our experimental data in mouse models.

  2. Acetone fraction from Sechium edule (Jacq.) S.w. edible roots exhibits anti-endothelial dysfunction activity.

    Science.gov (United States)

    Moreno, Celeste Trejo; Martínez, Gabriela Castro; Martínez, Marisol Méndez; Ferrer, Jesús Enrique Jiménez; Chaverri, José Pedraza; Arrellín, Gerardo; Zamilpa, Alejandro; Campos, Omar Noel Medina; Earl, Galia Lombardo; Cruz, Gerardo Joel Barrita; Hernández, Beatriz; Ramírez, Christian Carlos; Santana, María Angélica; Fragoso, Gladis; Rosas, Gabriela

    2018-03-01

    A recent ethnomedical survey on medicinal plants grown in Mexico revealed that Sechium edule (Jacq.) Sw. (Cucurbitaceae) is one of the most valued plant species to treat cardiovascular diseases, including hypertension. Fruits, young leaves, buds, stems, and tuberous roots of the plant are edible. Considering that endothelial dysfunction induced by Angiotensin II plays an important role in the pathogenesis of hypertension and is accompanied by a prooxidative condition, which in turn induces an inflammatory state, vascular remodeling, and tissue damage, and that S. edule has been reported to possess antioxidant, anti-inflammatory and antihypertensive activity, its capability to control endothelial dysfunction was also assessed. To assess in vivo the anti-endothelial dysfunction activity of the acetone fraction (rSe-ACE) of the hydroalcoholic extract from S. edule roots. Endothelial dysfunction was induced in female C57BL/6J mice by a daily intraperitoneal injection of angiotensin II for 10 weeks. Either rSe-ACE or losartan (as a control) were co-administered with angiotensin II for the same period. Blood pressure was measured at weeks 0, 5, and 10. Kidney extracts were prepared to determine IL1β, IL4, IL6, IL10, IL17, IFNγ, TNFα, and TGFβ levels by ELISA, along with the prooxidative status as assessed by the activity of antioxidant enzymes. The expression of ICAM-1 was evaluated by immunohistochemistry in kidney histological sections. Kidney and hepatic damage, as well as vascular tissue remodeling, were studied. The rSe-ACE fraction administered at a dose of 10mg/kg was able to control hypertension, as well as the prooxidative and proinflammatory status in kidney as efficiently as losartan, returning mice to normotensive levels. Additionally, the fraction was more efficient than losartan to prevent liver and kidney damage. Phytochemical characterization identified cinnamic acid as a major compound, and linoleic, palmitic, and myristic acids as the most abundant

  3. Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

    Directory of Open Access Journals (Sweden)

    Pei Wang

    2013-09-01

    Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

  4. Endothelial Dysfunction in Experimental Models of Arterial Hypertension: Cause or Consequence?

    Directory of Open Access Journals (Sweden)

    Iveta Bernatova

    2014-01-01

    Full Text Available Hypertension is a risk factor for other cardiovascular diseases and endothelial dysfunction was found in humans as well as in various commonly employed animal experimental models of arterial hypertension. Data from the literature indicate that, in general, endothelial dysfunction would not be the cause of experimental hypertension and may rather be secondary, that is, resulting from high blood pressure (BP. The initial mechanism of endothelial dysfunction itself may be associated with a lack of endothelium-derived relaxing factors (mainly nitric oxide and/or accentuation of various endothelium-derived constricting factors. The involvement and role of endothelium-derived factors in the development of endothelial dysfunction in individual experimental models of hypertension may vary, depending on the triggering stimulus, strain, age, and vascular bed investigated. This brief review was focused on the participation of endothelial dysfunction, individual endothelium-derived factors, and their mechanisms of action in the development of high BP in the most frequently used rodent experimental models of arterial hypertension, including nitric oxide deficient models, spontaneous (prehypertension, stress-induced hypertension, and selected pharmacological and diet-induced models.

  5. [Prospects of endothelial dysfunction reversion in patients with congestive heart failure].

    Science.gov (United States)

    Vizir, V A; Berezin, A E

    2000-01-01

    The aim of the study was to investigate the effect of angiotensin-converting enzyme inhibitor enalapril and non-peptide blocker of AT1 receptors losartan on endothelial function of the shoulder artery in patients with congestive cardiac insufficiency. The examination covered 96 patients (mean age 46.71 +/- 4.13) with stable effort angina (functional class II-III) and circulatory insufficiency (NYHA functional class II-III) having end-diastolic left-ventricular volume > 160 ml, left ventricular ejection fraction 0.55 units. Patients with fibrillar tachyarrhythmia, high grade blocks, pacemaker migration, artificial pacemaker, myocardial infarction were not included in the trial. The patients were randomized into 3 groups 32 patients each. In addition to basic therapy patients of group 1 received long-acting nitrates, digoxin, aspirin and furosemide; group 2--enalapril in daily dose 10 mg; group 3--losartan in daily dose 25 mg. A course of treatment lasted 12 weeks. Endothelial function was assessed by high resolution echography, dopplerography performed before and after temporary occlusion of the shoulder artery and sublingual nitroglycerin. In patients with cardiac insufficiency, accelerated blood flow in the shoulder artery after its temporary occlusion promoted realization of the vasoconstrictory reaction. This was verified as endothelial dysfunction. In the course of the treatment all the patients achieved insignificant increase of the shoulder artery initial diameter. After sublingual intake of nitroglycerin vasodilation was also insignificant. 12-week enalapril and losartan prevented vasoconstriction in the shoulder artery in response to quicker circulation following arterial occlusion. However, higher maximal flow speed did not correspond to the increment in the artery diameter after the occlusion in any group. The flow-induced vasodilation was more pronounced in the enalapril group. Losartan group had a trend to an increase in the inner diameter of the

  6. Ferulic acid combined with astragaloside IV protects against vascular endothelial dysfunction in diabetic rats.

    Science.gov (United States)

    Yin, Yonghui; Qi, Fanghua; Song, Zhenhua; Zhang, Bo; Teng, Jialin

    2014-08-01

    Dysfunction of the endothelium is regarded as an important factor in the pathogenesis of vascular disease in diabetes mellitus (DM). Unfortunately, prevention of the progression of vascular complications of DM remains pessimistic. Ferulic acid and astragaloside IV, isolated from traditional Chinese medicine Angelica sinensis and Radix astragali respectively, exhibit potential cardio-protective and anti-hyperglycemic properties. In the present study, we investigated the protective effects and underlying mechanism of ferulic acid and astragaloside IV against vascular endothelial dysfunction in diabetic rats. After the diabetic rat model was established using streptozotocin, sixty rats were divided into 6 groups (control, model, ferulic acid, astragaloside IV, ferulic acid + astragaloside IV, and metformin) and treated for 10 weeks. Blood samples were collected to measure levels of hemoglobin A1c (HbAlc), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), low density lipoproteins (Ox-LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine (Cr), nitric oxide (NO) and endothelial nitric oxide synthase (eNOS), and abdominal aorta tissue samples were collected for observing histological morphology changes of endothelium and detecting gene and protein expression of nuclear factor-κB (NF-κB) P65, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNF-α). We found that ferulic acid combined with astragaloside IV was capable of improving the structure of the aortic endothelium wall, attenuating the increase of HbAlc, TG, TC, LDL-C and Ox-LDL, promoting the release of NO and eNOS, and inhibiting over-activation of MCP-1, TNF-α, and NF-κB P65, without damage to liver and kidney function. In conclusion, ferulic acid combined with astragaloside IV exhibited significant protective effects against vascular endothelial dysfunction in diabetic rats through the NF-κB pathway involving

  7. Poor oral health, that is, decreased frequency of tooth brushing, is associated with endothelial dysfunction.

    Science.gov (United States)

    Kajikawa, Masato; Nakashima, Ayumu; Maruhashi, Tatsuya; Iwamoto, Yumiko; Iwamoto, Akimichi; Matsumoto, Takeshi; Hidaka, Takayuki; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Taguchi, Akira; Noma, Kensuke; Higashi, Yukihito

    2014-01-01

     Poor oral health is an independent predictor of cardiovascular outcome. Endothelial dysfunction is the initial step of atherosclerosis, resulting in cardiovascular outcomes; but there is no information on the association between oral health and endothelial function. The purpose of this study was to determine the relationships between oral health and endothelial function.  A total of 190 subjects who underwent health examinations (mean age, 57±18 years), including patients with cardiovascular disease, completed a questionnaire on oral health and frequency of tooth brushing, and underwent measurement of vascular function, flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation. The subjects were divided into 2 groups according to frequency of tooth brushing (≥twice/day and Poor oral health, that is, decreased frequency of tooth brushing, is associated with endothelial dysfunction.  

  8. Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders.

    Science.gov (United States)

    Janus, A; Szahidewicz-Krupska, E; Mazur, G; Doroszko, A

    2016-01-01

    Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes.

  9. Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders

    Directory of Open Access Journals (Sweden)

    A. Janus

    2016-01-01

    Full Text Available Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes.

  10. CURRENT METHODS OF ENDOTHELIAL DYSFUNCTION ASSESSMENT AND THEIR POSSIBLE USE IN THE PRACTICAL MEDICINE

    Directory of Open Access Journals (Sweden)

    A. V. Shabrov

    2016-01-01

    Full Text Available A review contains a description of the most common methods of evaluation and monitoring of "endothelial dysfunction" that are assessed in terms of their information content and applicability in the practice of medicine. The term "endothelial function" is interpreted primarily as a function of the regulation of capillary blood flow, carried out by the expense of the dynamic change of the phase of vasoconstriction and vasodilatation in vessels of resistive type (in accordance with the changing needs of cellular metabolism. Assessment of endothelial dysfunction is understood as a generalized indicator of the extent and nature of violations of the regulation of peripheral circulation. It includes an assessment of imbalances between endotheliumdependent vasoconstrictor and vasodilating factors or mismatch of the local and central regulation of capillary blood flow in response to various functional tests or other effects (eg, cold test, or test with local ischemia. All methods of endothelial dysfunction assessment in the survey are divided into invasive and non-invasive. The main feature of invasive methods lies in the direct effect on the endothelium of the coronary or other vessels by introducing into these vessels vasoactive substances such as acetylcholine. Response to the test (vasoconstriction or vasodilation is evaluated by coronary angiography or by ultrasound. Non-invasive methods of the assessment of endothelial dysfunction or functions of regulation of the peripheral circulation are regarded as the most promising for widespread use. There are two basic methods that underlie functional tests: methods PAT (peripheral arterial tone and PHG (polyhepatography. Assessment of endothelial dysfunction in many modern scientific researches is important. They are regarded as the causative factors of many different diseases. Such assessments can be useful in everyday medical practice. Assessment of endothelial function provides the clinician with

  11. Poly(ADP-ribose) polymerase-1 protects from oxidative stress induced endothelial dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Gebhard, Catherine; Staehli, Barbara E. [Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Cardiology, Cardiovascular Center, University Hospital Zurich, Raemistrasse 100, 8091 Zurich (Switzerland); Shi, Yi; Camici, Giovanni G.; Akhmedov, Alexander; Hoegger, Lisa; Lohmann, Christine [Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Matter, Christian M. [Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Cardiology, Cardiovascular Center, University Hospital Zurich, Raemistrasse 100, 8091 Zurich (Switzerland); Hassa, Paul O.; Hottiger, Michael O. [Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Malinski, Tadeusz [Department of Chemistry and Biochemistry, Ohio University, Athens, OH (United States); Luescher, Thomas F. [Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland); Cardiology, Cardiovascular Center, University Hospital Zurich, Raemistrasse 100, 8091 Zurich (Switzerland); and others

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer The nuclear enzyme PARP-1 is a downstream effector of oxidative stress. Black-Right-Pointing-Pointer PARP-1 protects from oxidative stress induced endothelial dysfunction. Black-Right-Pointing-Pointer This effect is mediated through inhibition of vasoconstrictor prostanoid production. Black-Right-Pointing-Pointer Thus, PARP-1 may play a protective role as antioxidant defense mechanism. -- Abstract: Background: Generation of reactive oxygen species (ROS) is a key feature of vascular disease. Activation of the nuclear enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) is a downstream effector of oxidative stress. Methods: PARP-1(-/-) and PARP-1(+/+) mice were injected with paraquat (PQ; 10 mg/kg i.p.) to induce intracellular oxidative stress. Aortic rings were suspended in organ chambers for isometric tension recording to analyze vascular function. Results: PQ treatment markedly impaired endothelium-dependent relaxations to acetylcholine in PARP-1(-/-), but not PARP-1(+/+) mice (p < 0.0001). Maximal relaxation was 45% in PQ treated PARP-1(-/-) mice compared to 79% in PARP-1(+/+) mice. In contrast, endothelium-independent relaxations to sodium nitroprusside (SNP) were not altered. After PQ treatment, L-NAME enhanced contractions to norepinephrine by 2.0-fold in PARP-1(-/-) mice, and those to acetylcholine by 3.3-fold, respectively, as compared to PARP-1(+/+) mice. PEG-superoxide dismutase (SOD) and PEG-catalase prevented the effect of PQ on endothelium-dependent relaxations to acetylcholine in PARP-1(-/-) mice (p < 0.001 vs. PQ treated PARP-1(+/+) mice. Indomethacin restored endothelium-dependent relaxations to acetylcholine in PQ treated PARP-1(-/-) mice (p < 0.05 vs. PQ treated PARP-1(+/+). Conclusion: PARP-1 protects from acute intracellular oxidative stress induced endothelial dysfunction by inhibiting ROS induced production of vasoconstrictor prostanoids.

  12. Endothelial dysfunction and reduced heart rate variability in patients with metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Elena Nikolaevna Smirnova

    2018-03-01

    Full Text Available According to experts of the World Health Organization (WHO, metabolic syndrome (MS can be considered as pandemy of the XXI century, because its prevalence among the population of developed countries is about 25-35%. In this study with the purpose of complex investigation of the autonomic nervous system and endothelial function we included 66 patients with MS between the ages of 25 and 61 (46.9±9.9 years. A comparison group of apparently healthy individuals (16 individuals, average age of 45.3±2.3 years; P>0.05 was studied. To evaluate the response of microvascular tone, we used the method of wavelet analysis of skin temperature oscillations during cooling of the limb. All patients underwent the study of heart rate variability. The levels of insulin, endothelin-1, and vascular endothelial growth factor were determined using enzyme immunoassay. Patients with MS had significant differences in all metabolic parameters. Our study showed that in the group of MS there is a decrease of the variability of heart rhythm compared with the healthy group. Conducting cold test revealed signs of endothelial dysfunction in the MS group, which was manifested by the decrease of the index of vasodilation in the endothelial and neurogenic frequency range. In the study group we determined the increase in biochemical markers of endothelial dysfunction, which correlated with parameters of vasodilation. Also, the presence of endothelial dysfunction significantly correlated with signs of reduction of the variability of the heart rhythm.

  13. Statin ameliorates endothelial dysfunction and insulin resistance in Tibet women with polycystic ovary syndrome.

    Science.gov (United States)

    Yang, B; Sun, Z-J; Chen, B; Zhang, J; Zhao, H; Li, C-W; Cao, Y-K; Cao, F

    2016-01-01

    Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. In Tibet population, little is known about the correlation between PCOS and endothelial function and insulin resistance. In this study, we investigated the efficacy of simvastatin on ameliorating endothelial dysfunction and insulin resistance in Tibet patients with PCOS. A group of 21 PCOS women was compared with 21 age-paired controls for blood pressure, body mass index (BMI), lipids, glucose and insulin levels. Plasma ET-1 was quantitated using a commercially available ELISA kits. The invasive vascular endothelial function was evaluated through the measurement of brachial artery flow-mediated dilation (FMD) in the fasting state using high-resolution B-mode ultrasound and ankle-brachial index (ABI) by using a blood pressure cuff and a Doppler instrument. PCOS women had higher BMI (p Tibet PCOS patients present a clustering of atherosclerosis risk factors (obesity, adverse lipid profile, hypertension and hyperglycemia) and more prevalent in insulin resistance and endothelial dysfunction than non-PCOS women. The endothelial function and insulin resistance of PCOS patients were ameliorated The endothelial function and insulin resistance of PCOS patients were ameliorated after statin administration.

  14. Ameliorative effect of astaxanthin on endothelial dysfunction in streptozotocin-induced diabetes in male rats.

    Science.gov (United States)

    Zhao, Zi-Wen; Cai, Wei; Lin, Yun-Ling; Lin, Qing-Fei; Jiang, Qiong; Lin, Zhang; Chen, Liang-Long

    2011-01-01

    The present study was designed to examine whether astaxanthin (ASX, 3,3-dihydroxybeta, beta-carotene-4,4-dione, CAS 472-61-7), a dietary antioxidant carotenoid that is naturally present in algae, crustaceans, and fish, has a protective effect on endothelial dysfunction of aortas in diabetic rats and the possible molecular mechanism involved. Male Wistar rats were randomly divided into four groups: control rats, diabetic rats, diabetic rats treated with ASX (10 mg/kg/d), and control rats treated with ASX. Type 1 diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/ kg). STZ-induced diabetes in rats was complicated with excessive oxidative stress and endothelial dysfunction, increased serum oxidized low-density lipoprotein (ox-LDL) and aortic malondialdehyde (MDA) levels, inhibited endothelium-dependent vasorelaxation to acetylcholine (ACh) and unaffected endothelium-dependent vasorelaxation to sodium nitroprusside (SNP). Simultaneously, lectin-like oxLDL receptor-i (LOX-1) expression was enhanced and endothelial nitric oxide (NO) synthase (eNOS) expression was reduced in the aortas of diabetic rats. ASX treatment could significantly decrease serum oxLDL and aortic MDA levels, attenuate blunted endothelium-dependent vasodilator responses to ACh, upregulate eNOS expression, and decrease LOX-1 expression. These results indicated that ASX could ameliorate diabetic endothelial dysfunction by inhibiting the ox-LDLLOX-1-eNOS pathway. Treatment with ASX might be clinically useful for diabetic complications associated with endothelial dysfunction.

  15. Endothelial dysfunction, ambulatory pulse pressure and albuminuria are associated in Type 2 diabetic subjects

    DEFF Research Database (Denmark)

    Knudsen, Søren Tang; Jeppesen, Peter; Frederiksen, Christian Alcaraz

    2007-01-01

    examined. We examined the relation between PP, markers of endothelial activation and albuminuria in Type 2 diabetic patients. METHODS: In 46 Type 2 diabetic patients and 19 non-diabetic subjects, we performed 24-h ambulatory blood pressure (AMBP) monitoring. Urinary albumin excretion rate was measured......: Increased PP is associated with endothelial activation and albuminuria in Type 2 diabetic patients. Thus, endothelial dysfunction may represent a pathophysiological link between an elevated PP and microvascular complications in these subjects. Prospective studies are needed to further elucidate...

  16. Association between the female athlete triad and endothelial dysfunction in dancers.

    Science.gov (United States)

    Hoch, Anne Z; Papanek, Paula; Szabo, Aniko; Widlansky, Michael E; Schimke, Jane E; Gutterman, David D

    2011-03-01

    To determine the prevalence of the 3 components of the female athlete triad [disordered eating, menstrual dysfunction, low bone mineral density (BMD)] and their relationships with brachial artery flow-mediated dilation in professional dancers. Prospective study. Academic institution in the Midwest. Twenty-two professional ballet dancers volunteered for this study. The prevalence of the female athlete triad and its relationship to endothelial dysfunction. Subjects completed questionnaires to assess disordered eating and menstrual status/history. They also completed a 3-day food record and wore an accelerometer for 3 days to determine energy availability. Serum baseline thyrotropin, prolactin, and hormonal concentrations were obtained. Bone mineral density and body composition were measured with a GE Lunar Prodigy dual-energy X-ray absorptiometry. Endothelial function was determined as flow-mediated vasodilation measured by high-frequency ultrasound in the brachial artery. An increase in brachial diameter <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Seventeen dancers (77%) had evidence of low/negative energy availability. Thirty-two percent had disordered eating (EDE-Q score). Thirty-six percent had menstrual dysfunction and 14% were currently using hormone contraception. Twenty-three percent had evidence of low bone density (Z-score < -1.0). Sixty-four percent had abnormal brachial artery flow-mediated dilation (<5%). Flow-mediated dilation values were significantly correlated with serum estrogen and whole-body and lumbar BMD. All the 3 components of the triad plus endothelial dysfunction were present in 14% of the subjects. Endothelial dysfunction was correlated with reduced BMD, menstrual dysfunction, and low serum estrogen. These findings may have profound implications for cardiovascular and bone health in professional women dancers.

  17. Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA)

    DEFF Research Database (Denmark)

    Meyer, Anna Sina P; Ostrowski, Sisse Rye; Kjærgaard, Jesper

    2016-01-01

    BACKGROUND: Morbidity and mortality following initial survival of cardiac arrest remain high despite great efforts to improve resuscitation techniques and post-resuscitation care, in part due to the ischemia-reperfusion injury secondary to the restoration of the blood circulation. Patients...... resuscitated from cardiac arrest display evidence of endothelial injury and coagulopathy (hypocoagulability, hyperfibrinolysis), which in associated with poor outcome. Recent randomized controlled trials have revealed that treatment with infusion of prostacyclin reduces endothelial damage after major surgery...... and AMI. Thus, a study is pertinent to investigate if prostacyclin infusion as a therapeutic intervention reduces endothelial damage without compromising, or even improving, the hemostatic competence in resuscitated cardiac arrest patients. Post-cardiac arrest patients frequently have a need...

  18. HIV antiretroviral drug combination induces endothelial mitochondrial dysfunction and reactive oxygen species production, but not apoptosis

    International Nuclear Information System (INIS)

    Jiang Bo; Hebert, Valeria Y.; Li, Yuchi; Mathis, J. Michael; Alexander, J. Steven; Dugas, Tammy R.

    2007-01-01

    Numerous reports now indicate that HIV patients administered long-term antiretroviral therapy (ART) are at a greater risk for developing cardiovascular diseases. Endothelial dysfunction is an initiating event in atherogenesis and may contribute to HIV-associated atherosclerosis. We previously reported that ART induces direct endothelial dysfunction in rodents. In vitro treatment of human umbilical vein endothelial cells (HUVEC) with ART indicated endothelial mitochondrial dysfunction and a significant increase in the production of reactive oxygen species (ROS). In this study, we determined whether ART-induced endothelial dysfunction is mediated via mitochondria-derived ROS and whether this mitochondrial injury culminates in endothelial cell apoptosis. Two major components of ART combination therapy, a nucleoside reverse transcriptase inhibitor and a protease inhibitor, were tested, using AZT and indinavir as representatives for each. Microscopy utilizing fluorescent indicators of ROS and mitochondria demonstrated the mitochondrial localization of ART-induced ROS. MnTBAP, a cell-permeable metalloporphyrin antioxidant, abolished ART-induced ROS production. As a final step in confirming the mitochondrial origin of the ART-induced ROS, HUVEC were transduced with a cytosolic- compared to a mitochondria-targeted catalase. Transduction with the mitochondria-targeted catalase was more effective than cytoplasmic catalase in inhibiting the ROS and 8-isoprostane (8-iso-PGF 2α ) produced after treatment with either AZT or indinavir. However, both mitochondrial and cytoplasmic catalase attenuated ROS and 8-iso-PGF 2α production induced by the combination treatment, suggesting that in this case, the formation of cytoplasmic ROS may also occur, and thus, that the mechanism of toxicity in the combination treatment group may be different compared to treatment with AZT or indinavir alone. Finally, to determine whether ART-induced mitochondrial dysfunction and ROS production

  19. Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction - implications for treating preeclampsia.

    Science.gov (United States)

    Kaitu'u-Lino, Tu'uhevaha J; Brownfoot, Fiona C; Beard, Sally; Cannon, Ping; Hastie, Roxanne; Nguyen, Tuong V; Binder, Natalie K; Tong, Stephen; Hannan, Natalie J

    2018-01-01

    The discovery of new treatments that prevent or treat preeclampsia would be a major advance. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. We recently identified metformin and esomeprazole as potential treatments for preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction. We set out to assess whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (verses drug alone). Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-α (TNF-α) was added to endothelial cells to induce dysfunction in vitro. We examined the ability of metformin + esomeprazole to rescue TNF-α induced vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (ET-1) expression, leukocyte adhesion (markers of endothelial dysfunction). Combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-α-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-α induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression. In conclusion combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction. The combination of metformin and

  20. Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction – implications for treating preeclampsia

    Science.gov (United States)

    Beard, Sally; Cannon, Ping; Hastie, Roxanne; Nguyen, Tuong V.; Binder, Natalie K.; Tong, Stephen

    2018-01-01

    Introduction The discovery of new treatments that prevent or treat preeclampsia would be a major advance. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. We recently identified metformin and esomeprazole as potential treatments for preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction. Objectives We set out to assess whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (verses drug alone). Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-α (TNF-α) was added to endothelial cells to induce dysfunction in vitro. We examined the ability of metformin + esomeprazole to rescue TNF-α induced vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (ET-1) expression, leukocyte adhesion (markers of endothelial dysfunction). Results Combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-α-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-α induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression. Conclusions In conclusion combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction

  1. Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction - implications for treating preeclampsia.

    Directory of Open Access Journals (Sweden)

    Tu'uhevaha J Kaitu'u-Lino

    Full Text Available The discovery of new treatments that prevent or treat preeclampsia would be a major advance. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1 and soluble endoglin (sENG are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. We recently identified metformin and esomeprazole as potential treatments for preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction.We set out to assess whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (verses drug alone. Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-α (TNF-α was added to endothelial cells to induce dysfunction in vitro. We examined the ability of metformin + esomeprazole to rescue TNF-α induced vascular cell adhesion molecule-1 (VCAM-1 and Endothelin-1 (ET-1 expression, leukocyte adhesion (markers of endothelial dysfunction.Combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-α-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-α induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression.In conclusion combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction. The combination of metformin and

  2. c-Myc is essential to prevent endothelial pro-inflammatory senescent phenotype.

    Directory of Open Access Journals (Sweden)

    Victoria Florea

    Full Text Available The proto-oncogene c-Myc is vital for vascular development and promotes tumor angiogenesis, but the mechanisms by which it controls blood vessel growth remain unclear. In the present work we investigated the effects of c-Myc knockdown in endothelial cell functions essential for angiogenesis to define its role in the vasculature. We provide the first evidence that reduction in c-Myc expression in endothelial cells leads to a pro-inflammatory senescent phenotype, features typically observed during vascular aging and pathologies associated with endothelial dysfunction. c-Myc knockdown in human umbilical vein endothelial cells using lentivirus expressing specific anti-c-Myc shRNA reduced proliferation and tube formation. These functional defects were associated with morphological changes, increase in senescence-associated-β-galactosidase activity, upregulation of cell cycle inhibitors and accumulation of c-Myc-deficient cells in G1-phase, indicating that c-Myc knockdown in endothelial cells induces senescence. Gene expression analysis of c-Myc-deficient endothelial cells showed that senescent phenotype was accompanied by significant upregulation of growth factors, adhesion molecules, extracellular-matrix components and remodeling proteins, and a cluster of pro-inflammatory mediators, which include Angptl4, Cxcl12, Mdk, Tgfb2 and Tnfsf15. At the peak of expression of these cytokines, transcription factors known to be involved in growth control (E2f1, Id1 and Myb were downregulated, while those involved in inflammatory responses (RelB, Stat1, Stat2 and Stat4 were upregulated. Our results demonstrate a novel role for c-Myc in the prevention of vascular pro-inflammatory phenotype, supporting an important physiological function as a central regulator of inflammation and endothelial dysfunction.

  3. The novel organic mononitrate NDHP attenuates hypertension and endothelial dysfunction in hypertensive rats

    Directory of Open Access Journals (Sweden)

    Luciano L. Paulo

    2018-05-01

    Conclusion: Acute treatment with the novel organic nitrate NDHP increases NO formation, which is associated with vasorelaxation and a significant reduction of blood pressure in hypertensive animals. Chronic NDHP treatment attenuates the progression of hypertension and endothelial dysfunction, suggesting a potential for therapeutic applications in cardiovascular disease.

  4. Endothelial dysfunction and low-grade inflammation and the progression of retinopathy in Type 2 diabetes

    NARCIS (Netherlands)

    Spijkerman, A.M.W.; Gall, M.A.; Tarnow, L.; Twisk, J.W.R.; Lauritzen, E.; Lund-Andersen, H.; Emeis, J.; Parving, H.H.; Stehouwer, C.D.A.

    2007-01-01

    Aims: To study whether microalbuminuria, endothelial dysfunction and low-grade inflammation are associated with the presence and progression of diabetic retinopathy. Methods: Patients with Type 2 diabetes (n = 328) attending a diabetes clinic were followed for 10 years and examined annually during

  5. 2,3,7,8-TCDD exposure, endothelial dysfunction and impaired microvascular reactivity

    Czech Academy of Sciences Publication Activity Database

    Pelclová, D.; Prázdný, M.; Škrha, J.; Fenclová, Z.; Kalousová, M.; Urban, P.; Navrátil, Tomáš; Šenholdová, Z.; Šmerhovský, Z.

    2007-01-01

    Roč. 26, - (2007), s. 705-713 ISSN 0960-3271 Institutional research plan: CEZ:AV0Z40400503 Keywords : 2,3,7,8-TCDD * endothelial dysfunction * oxidative stress * superoxide dismutase Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 1.335, year: 2007

  6. Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series).

    Science.gov (United States)

    Ranchoux, Benoît; Harvey, Lloyd D; Ayon, Ramon J; Babicheva, Aleksandra; Bonnet, Sebastien; Chan, Stephen Y; Yuan, Jason X-J; Perez, Vinicio de Jesus

    2018-01-01

    Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.

  7. Pulmonary artery endothelial cell dysfunction and decreased populations of highly proliferative endothelial cells in experimental congenital diaphragmatic hernia

    Science.gov (United States)

    Seedorf, Gregory J.; Abman, Steven H.; Nozik-Grayck, Eva; Partrick, David A.; Gien, Jason

    2013-01-01

    Decreased lung vascular growth and pulmonary hypertension contribute to poor outcomes in congenital diaphragmatic hernia (CDH). Mechanisms that impair angiogenesis in CDH are poorly understood. We hypothesize that decreased vessel growth in CDH is caused by pulmonary artery endothelial cell (PAEC) dysfunction with loss of a highly proliferative population of PAECs (HP-PAEC). PAECs were harvested from near-term fetal sheep that underwent surgical disruption of the diaphragm at 60–70 days gestational age. Highly proliferative potential was measured via single cell assay. PAEC function was assessed by assays of growth and tube formation and response to known proangiogenic stimuli, vascular endothelial growth factor (VEGF), and nitric oxide (NO). Western blot analysis was used to measure content of angiogenic proteins, and superoxide production was assessed. By single cell assay, the proportion of HP-PAEC with growth of >1,000 cells was markedly reduced in the CDH PAEC, from 29% (controls) to 1% (CDH) (P CDH PAEC growth and tube formation were decreased by 31% (P = 0.012) and 54% (P CDH PAEC growth and tube formation. VEGF and VEGF-R2 proteins were increased in CDH PAEC; however, eNOS and extracellular superoxide dismutase proteins were decreased by 29 and 88%, respectively. We conclude that surgically induced CDH in fetal sheep causes endothelial dysfunction and marked reduction of the HP-PAEC population. We speculate that this CDH PAEC phenotype contributes to impaired vascular growth in CDH. PMID:24124189

  8. N-Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs.

    Science.gov (United States)

    Herrera, Emilio A; Cifuentes-Zúñiga, Francisca; Figueroa, Esteban; Villanueva, Cristian; Hernández, Cherie; Alegría, René; Arroyo-Jousse, Viviana; Peñaloza, Estefania; Farías, Marcelo; Uauy, Ricardo; Casanello, Paola; Krause, Bernardo J

    2017-02-15

    Intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial epigenetic programming of the umbilical vessels. There is no evidence that this epigenetic programming is occurring on systemic fetal arteries. In IUGR guinea pigs we studied the functional and epigenetic programming of endothelial nitric oxide synthase (eNOS) (Nos3 gene) in umbilical and systemic fetal arteries, addressing the role of oxidative stress in this process by maternal treatment with N-acetylcysteine (NAC) during the second half of gestation. The present study suggests that IUGR endothelial cells have common molecular markers of programming in umbilical and systemic arteries. Notably, maternal treatment with NAC restores fetal growth by increasing placental efficiency and reverting the functional and epigenetic programming of eNOS in arterial endothelium in IUGR guinea pigs. In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetylcysteine (NAC) on fetal endothelial function and endothelial nitric oxide synthase (eNOS) programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, half of the sows receiving NAC in the drinking water (from day 34 until term). Fetal biometry and placental vascular resistance were followed by ultrasound throughout gestation. At term, umbilical arteries and fetal aortae were isolated to assess endothelial function by wire-myography. Primary cultures of endothelial cells (ECs) from fetal aorta, femoral and umbilical arteries were used to determine eNOS mRNA levels by quantitative PCR and analyse DNA methylation in the Nos3 promoter by pyrosequencing. Doppler ultrasound measurements showed that NAC reduced placental vascular resistance

  9. Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema.

    Science.gov (United States)

    Yu, Jinyan; Ma, Zhongsen; Shetty, Sreerama; Ma, Mengshi; Fu, Jian

    2016-07-01

    Lung endothelial damage contributes to the pathogenesis of acute lung injury. New strategies against lung endothelial barrier dysfunction may provide therapeutic benefits against lung vascular injury. Cell-cell junctions and microtubule cytoskeleton are basic components in maintaining endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate nonnuclear protein function through deacetylation. Both α-tubulin and β-catenin are substrates for HDAC6. Here, we examined the effects of tubastatin A, a highly selective HDAC6 inhibitor, on TNF-α induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Selective HDAC6 inhibition by tubastatin A blocked TNF-α-induced lung endothelial cell hyperpermeability, which was associated with increased α-tubulin acetylation and microtubule stability. Tubastatin A pretreatment inhibited TNF-α-induced endothelial cell contraction and actin stress fiber formation with reduced myosin light chain phosphorylation. Selective HDAC6 inhibition by tubastatin A also induced β-catenin acetylation in human lung endothelial cells, which was associated with increased membrane localization of β-catenin and stabilization of adherens junctions. HDAC6 knockdown by small interfering RNA also prevented TNF-α-induced barrier dysfunction and increased α-tubulin and β-catenin acetylation in endothelial cells. Furthermore, in a mouse model of endotoxemia, tubastatin A was able to prevent endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues, which was associated with reduced pulmonary edema. Collectively, our data indicate that selective HDAC6 inhibition by tubastatin A is a potent approach against lung endothelial barrier dysfunction. Copyright © 2016 the American Physiological Society.

  10. In Vivo Confocal Microscopic Evaluation of Corneal Endothelial Dysfunction Induced by Phacoemulcification in Rhesus Monkey Models.

    Science.gov (United States)

    Wu, Min; Hu, Zhu-lin; Sun, Xiao-mei; Dai, Jie-jie

    2016-02-01

    To observe the characteristic morphological changes of corneal endothelial dysfunction induced by phacoemulcification in rhesus monkey models under confocal microscope. The corneal endothelial dysfunction models were established by phacoemulcification power on the central corneal of 7 to 9 mm diameter in the right eyes of 4 rhesus monkeys (the modeling group). The left eyes of 4 rhesus monkeys were set as blank control group. The structural changes in different corneal layers were evaluated by slit lamp microscope and in vivo confocal microscope before surgery and 1, 2, 3, and 4 weeks after surgery. SPSS 19.0 software was applied to analyze data. Paired-t test was used to compare the number of nerve plexus in Bowman's layer and corneal endothelial cell density. Analysis of variance (ANOVA) was used to analyze corneal thickness. After phacoemulcification, the changes of cornea occurred gradually in the endothelial layer, stroma, Bowman's membrane, and basal epithelial layer. In the early stage, the interspace of corneal endothelial cells enlarged and few activated stromal cells were detected in the stroma. The cell morphology of stroma altered. The thickness of stroma increased. Two weeks after surgery, the nerve plexus in Bowman's layer decreased and edema of stroma and endothelial layer increased. Three weeks after surgery, the interspace of basal epithelial cells increased with a few Langerhans' cells infiltration and edema of stroma and endothelial layer increased. Four weeks after the surgery, a large amount of Langerhans' cells presented in basal epithelial layer. Only a few nerve lexus could be seen in Bowman's layer. The stroma and endothelial cells had severe edema. A large number of activated stromal cells could be found in stromal layer. Two weeks after the surgery, the number of nerve plexus in Bowman's layer (t=6.9192, P=0.002) and corneal endothelial cell density (t=7.8936, P<0.0001) in the modeling group were significantly lower than that in control

  11. Testosterone Deficiency Causes Endothelial Dysfunction via Elevation of Asymmetric Dimethylarginine and Oxidative Stress in Castrated Rats.

    Science.gov (United States)

    Kataoka, Tomoya; Hotta, Yuji; Maeda, Yasuhiro; Kimura, Kazunori

    2017-12-01

    Testosterone is believed to mediate the penile erectile response by producing adequate nitric oxide; therefore, testosterone deficiency results in erectile dysfunction through decreased nitric oxide bioavailability. However, the mechanisms underlying endothelial dysfunction in testosterone deficiency remain unclear. To investigate the mechanism of endothelial dysfunction in a rat model of testosterone deficiency. Rats were distributed into 3 groups: castrated (Cast), castrated and supplemented with testosterone (Cast + T), and sham (Sham). In the Cast + T group, castrated rats were treated daily with subcutaneous testosterone (3 mg/kg daily) for 4 weeks; Sham and Cast rats received only the vehicle. Erectile function using intracavernosal pressure and mean arterial pressure measurements after electrical stimulation of the cavernous nerve, endothelial function using isometric tension, asymmetric dimethylarginine (ADMA) levels using ultra-performance liquid chromatography and tandem mass spectrometry, and inflammatory biomarker expression were performed 4 weeks after the operation. In the Cast group, the ratio of intracavernosal pressure to mean arterial pressure significantly decreased, acetylcholine-induced relaxation was lower, and serum ADMA, oxidative stress, and inflammation biomarker levels were significantly increased (P Testosterone injection significantly improved each of these parameters (P testosterone deficiency on erectile function and the effect of testosterone replacement therapy. This study provides evidence of the influence of testosterone deficiency on endothelial function by investigating ADMA and oxidative stress. A major limitation of this study is the lack of a direct link of increased ADMA by oxidative stress to inflammation. Testosterone deficiency increased not only ADMA levels but also oxidative stress and inflammation in castrated rats, which can cause damage to the corpus cavernosum, resulting in erectile dysfunction. Kataoka T, Hotta Y

  12. Circulating Microparticles Carry a Functional Endothelial Nitric Oxide Synthase That Is Decreased in Patients With Endothelial Dysfunction

    Science.gov (United States)

    Horn, Patrick; Cortese‐Krott, Miriam Margherita; Amabile, Nicolas; Hundsdörfer, Claas; Kröncke, Klaus‐Dietrich; Kelm, Malte; Heiss, Christian

    2013-01-01

    Background Microparticles (MPs) are circulating membrane particles of less than a micrometer in diameter shed from endothelial and blood cells. Recent literature suggests that MPs are not just functionally inert cell debris but may possess biological functions and mediate the communication between vascular cells. As a significant proportion of MPs originate from platelets and endothelial cells, we hypothesized that MPs may harbor functional enzymes including an endothelial NO synthase (eNOS). Methods and Results Using immunoprecipitation and Western blot analysis, we found that human circulating MPs carry an eNOS. Ca2+ and l‐arginine‐dependent NOS activity of crude enzyme extract from MPs was determined by measuring the conversion of [3H]‐L‐arginine to [3H]‐citrulline and NOS‐dependent nitrite production. NOS‐dependent NO production in intact MPs was assessed by the NO‐specific fluorescent probe MNIP‐Cu. In patients with cardiovascular disease, endothelial dysfunction was associated with an increase in the total number of circulating MPs as well as a significant decrease in the expression and activity of eNOS in MPs. No difference in reactive oxygen species was noted in MPs isolated from either group. Conclusions Our data further support the concept that circulating MPs may not only retain phenotypic markers but also preserve the functionality of enzymes of the cells they originate from, including eNOS. PMID:23525410

  13. Hypothyroidism is associated with signs of endothelial dysfunction despite 1-year replacement therapy with levothyroxine

    DEFF Research Database (Denmark)

    Clausen, P.; Mersebach, H.; Nielsen, B.

    2009-01-01

    OBJECTIVE: Hypothyroidism is associated with elevated cardiovascular risk, not fully explained by classical risk factors. Instead, endothelial dysfunction may link hypothyroidism to atherosclerosis. The effect of levothyroxine substitution on endothelial function has been sparsely studied...... and the results are unclear. This study tested endothelial function as estimated by concomitant measurements of endothelial dependent vascular dilatory capacity and plasma concentration of von Willebrand factor antigen in patients with hypothyroidism and further examined the impact of subsequent levothyroxine...... substitution. DESIGN AND PATIENTS: Sixteen consecutive patients (13 women, 3 men, aged 46 +/- 11 years) with hypothyroidism were included and compared to 16 matched healthy controls (13 women, 3 men, aged 49 +/- 11 years). Patients with hypothyroidism were reexamined after 3, 6 and 12 months of levothyroxine...

  14. Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension

    Science.gov (United States)

    Wojciak-Stothard, Beata; Abdul-Salam, Vahitha B.; Lao, Ka Hou; Tsang, Hilda; Irwin, David C.; Lisk, Christina; Loomis, Zoe; Stenmark, Kurt R.; Edwards, John C; Yuspa, Stuart H.; Howard, Luke S.; Edwards, Robert J.; Rhodes, Christopher J.; Gibbs, J Simon R.; Wharton, John; Zhao, Lan; Wilkins, Martin R.

    2014-01-01

    Background Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodelled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension (PAH). CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of PAH. Methods and Results CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic PAH (IPAH) and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, while CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with IPAH attenuated the abnormal angiogenic behaviour that characterises these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-κB, followed by stabilisation of hypoxia-inducible factor-1α and increased downstream production of vascular endothelial growth factor and endothelin-1. Conclusions Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension. PMID:24503951

  15. Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

    DEFF Research Database (Denmark)

    Brouwers, Olaf; Niessen, Petra M G; Miyata, Toshio

    2014-01-01

    the MGO-detoxifying enzyme glyoxalase-I (GLO-I), to determine the impact of intracellular glycation on vascular function and the development of early renal changes in diabetes. METHODS: Wild-type and Glo1-overexpressing rats were rendered diabetic for a period of 24 weeks by intravenous injection...... measured with ELISA-based techniques. RESULTS: Diabetes-induced formation of AGEs in mesenteric arteries and endothelial dysfunction were reduced by Glo1 overexpression. Despite the absence of advanced nephrotic lesions, early markers of renal dysfunction (i.e. increased glomerular volume, decreased...... and early renal impairment in experimental diabetes. Modulating the GLO-I pathway therefore may provide a novel approach to prevent vascular complications in diabetes....

  16. Salidroside Improves Homocysteine-Induced Endothelial Dysfunction by Reducing Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Sin Bond Leung

    2013-01-01

    Full Text Available Hyperhomocysteinemia is associated with an increased risk for cardiovascular diseases through increased oxidative stress. Salidroside is an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties. However, the vascular benefits of salidroside against endothelial dysfunction have yet to be explored. The present study, therefore, aimed to investigate the protective effect of salidroside on homocysteine-induced endothelial dysfunction. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. DHE imaging was used to evaluate the reactive oxygen species (ROS level in aortic wall and endothelial cells. Western blotting was performed to assess the protein expression associated with oxidative stress and nitric oxide (NO bioavailability. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. Salidroside inhibited homocystein-induced elevation in the NOX2 expression and ROS overproduction in both aortas and cultured endothelial cells and increased phosphorylation of eNOS which was diminished by homocysteine. The present study shows that salidroside is effective in preserving the NO bioavailability and thus protects against homocysteine-induced impairment of endothelium-dependent relaxations, largely through inhibiting the NOX2 expression and ROS production. Our results indicate a therapeutic potential of salidroside in the management of oxidative-stress-associated cardiovascular dysfunction.

  17. Salidroside Improves Homocysteine-Induced Endothelial Dysfunction by Reducing Oxidative Stress

    Science.gov (United States)

    Leung, Sin Bond; Zhang, Huina; Lau, Chi Wai; Huang, Yu; Lin, Zhixiu

    2013-01-01

    Hyperhomocysteinemia is associated with an increased risk for cardiovascular diseases through increased oxidative stress. Salidroside is an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties. However, the vascular benefits of salidroside against endothelial dysfunction have yet to be explored. The present study, therefore, aimed to investigate the protective effect of salidroside on homocysteine-induced endothelial dysfunction. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. DHE imaging was used to evaluate the reactive oxygen species (ROS) level in aortic wall and endothelial cells. Western blotting was performed to assess the protein expression associated with oxidative stress and nitric oxide (NO) bioavailability. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. Salidroside inhibited homocystein-induced elevation in the NOX2 expression and ROS overproduction in both aortas and cultured endothelial cells and increased phosphorylation of eNOS which was diminished by homocysteine. The present study shows that salidroside is effective in preserving the NO bioavailability and thus protects against homocysteine-induced impairment of endothelium-dependent relaxations, largely through inhibiting the NOX2 expression and ROS production. Our results indicate a therapeutic potential of salidroside in the management of oxidative-stress-associated cardiovascular dysfunction. PMID:23589720

  18. Fluctuating plasma phosphorus level by changes in dietary phosphorus intake induces endothelial dysfunction.

    Science.gov (United States)

    Watari, Eriko; Taketani, Yutaka; Kitamura, Tomoyo; Tanaka, Terumi; Ohminami, Hirokazu; Abuduli, Maerjianghan; Harada, Nagakatsu; Yamanaka-Okumura, Hisami; Yamamoto, Hironori; Takeda, Eiji

    2015-01-01

    High serum phosphorus (P) impairs endothelial function by increasing oxidative stress and decreasing nitric oxide production. Serum P levels fluctuate due to circadian rhythms or dietary P intake in healthy people and due to dialysis in end-stage chronic kidney disease patients. Here we examined whether fluctuating plasma P caused by changes in dietary P intake may be involved in endothelial dysfunction, resulting in increased cardiovascular risk. Rats were fed a diet containing 0.6% P for 16 days (control group), or a diet alternating between 0.02% P and 1.2% P (LH group) or between 1.2% P and 0.02% P (HL group) every 2 days; the total amount of P intake among the groups during the feeding period was similar. In the LH and HL groups, endothelial-dependent vasodilation significantly decreased plasma 8-(OH)dG level significantly increased, and the expression of inflammatory factors such as MCP-1 increased in the endothelium as compared with the control group. These data indicate that repetitive fluctuations of plasma P caused by varying dietary P intake can impair endothelial function via increased oxidative stress and inflammatory response. Taken together, these results suggest that habitual fluctuation of dietary P intake might be a cause of cardiovascular disease through endothelial dysfunction, especially in chronic kidney disease patients.

  19. Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction.

    Science.gov (United States)

    Qin, Qing; Delrio, Silvia; Wan, Junxiang; Jay Widmer, R; Cohen, Pinchas; Lerman, Lilach O; Lerman, Amir

    2018-03-01

    MOTS-c is one of the newly identified mitochondrial-derived peptides which play a role in regulating metabolic homeostasis. The current study aimed to investigate whether circulating MOTS-c levels are also associated with endothelial dysfunction(ED) in patients without significant structural coronary lesions. Forty patients undergoing coronary angiography and endothelial function testing for clinical indications of recurrent angina with no structural coronary lesions were included in the study. They were divided into two groups based on coronary blood flow response to intracoronary acetylcholine (ACh) as normal endothelial function (≥ 50% increase from baseline) or ED, (n=20 each). Aortic plasma samples were collected at the time of catheterization for analysis of circulating MOTS-c levels by ELISA. The effect of MOTS-c on vascular reactivity was assessed in organ chambers using aortic rings collected from rats and renal artery stenosis (RAS) mice. Baseline characteristics were similar between the two groups. MOTS-c plasma levels were lower in patients with ED compared with patients with normal endothelial function (p=0.007). Furthermore, plasma MOTS-c levels were positively correlated with microvascular (p=0.01) and epicardial (p=0.02) coronary endothelial function. Although MOTS-c did not have direct vasoactive effects, pretreating aortic rings from rats or RAS mice with MOTS-c (2μg/ml) improved vessel responsiveness to ACh compared with vessels without MOTS-c treatment. Lower circulating endogenous MOTS-c levels in human subjects are associated with impaired coronary endothelial function. In rodents, MOTS-c improves endothelial function in vitro. Thus, MOTS-c represents a novel potential therapeutic target in patients with ED. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  20. ER stress mediates homocysteine-induced endothelial dysfunction: Modulation of IKCa and SKCa channels.

    Science.gov (United States)

    Wang, Xiang-Chong; Sun, Wen-Tao; Yu, Cheuk-Man; Pun, Shun-Hay; Underwood, Malcolm John; He, Guo-Wei; Yang, Qin

    2015-09-01

    It remains incompletely understood how homocysteine impairs endothelial function. Whether mechanisms such as calcium-activated potassium (KCa) channels are involved is uncertain and the significance of endoplasmic reticulum (ER) stress in KCa channel-dependent endothelial function in hyperhomocysteinemia remains unexplored. We investigated the effect of homocysteine on endothelial KCa channels in coronary vasculature with further exploration of the role of ER stress. Vasorelaxation mediated by intermediate- and small-conductance KCa (IKCa and SKCa) channels was studied in porcine coronary arteries in a myograph. IKCa and SKCa channel currents were recorded by whole-cell patch-clamp in coronary endothelial cells. Protein levels of endothelial IKCa and SKCa channels were determined for both whole-cell and surface expressions. Homocysteine impaired bradykinin-induced IKCa and SKCa-dependent EDHF-type relaxation and attenuated the vasorelaxant response to the channel activator. IKCa and SKCa currents were suppressed by homocysteine. Inhibition of ER stress during homocysteine exposure enhanced IKCa and SKCa currents, associated with improved EDHF-type response and channel activator-induced relaxation. Homocysteine did not alter whole-cell protein levels of IKCa and SKCa whereas lowered surface expressions of these channels, which were restored by ER stress inhibition. Homocysteine induces endothelial dysfunction through a mechanism involving ER stress-mediated suppression of IKCa and SKCa channels. Inhibition of cell surface expression of these channels by ER stress is, at least partially, responsible for the suppressive effect of homocysteine on the channel function. This study provides new mechanistic insights into homocysteine-induced endothelial dysfunction and advances our knowledge of the significance of ER stress in vascular disorders. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  1. Impact of diabetic serum on endothelial cells: An in-vitro-analysis of endothelial dysfunction in diabetes mellitus type 2

    International Nuclear Information System (INIS)

    Muenzel, Daniela; Lehle, Karla; Haubner, Frank; Schmid, Christof; Birnbaum, Dietrich E.; Preuner, Juergen G.

    2007-01-01

    Diabetic endothelial dysfunction was characterized by altered levels of adhesion molecules and cytokines. Aim of our study was to evaluate the effects of diabetic serum on cell-growth and proinflammatory markers in human saphenous vein endothelial cells (HSVEC) from diabetic and non-diabetic patients. Diabetic serum showed (1) complementary proliferative activity for non-diabetic and diabetic HSVEC, (2) unchanged surface expression of adhesion molecules, and (3) elevated levels of sICAM-1 in HSVEC of all donors. The concentration of sVCAM-1 was increased only in diabetic cells. The proinflammatory state of diabetic HSVEC characterized by increased levels of cytokines was compensated. We concluded that even under normoglycemic conditions the serum itself contains critical factors leading to abnormal regulation of inflammation in diabetics. We introduced an in vitro model of diabetes representing the endothelial situation at the beginning of diabetes (non-diabetic cells/diabetic serum) as well as the diabetic chronic state (diabetic cells/diabetic serum)

  2. Lisinopril improves endothelial dysfunction in hypertensive NIDDM subjects with diabetic nephropathy

    DEFF Research Database (Denmark)

    Nielsen, F S; Rossing, P; Gall, M A

    1997-01-01

    Endothelial dysfunction is a prevalent phenomenon in non-insulin dependent diabetic (NIDDM) patients with hypertension and albuminuria, and may contribute to the development and progression of cardiovascular disease, which is the main cause of the high morbidity and mortality observed...... in these patients. Therefore the aim of our study was to evaluate whether inhibition of angiotensin-converting enzyme (with lisinopril 10-20 mg day-1) could ameliorate endothelial dysfunction more than reducing blood pressure with conventional antihypertensive treatment (atenolol 50-100 mg day-1), usually...... in combination with a diuretic. We performed a 12-month prospective, randomized, double-blind, parallel study in 43 hypertensive NIDDM patients with diabetic nephropathy (21 treated with lisinopril and 22 with atenolol). The following variables were measured: 24-h ambulatory blood pressure (ABP); transcapillary...

  3. Endothelial Dysfunction and Blood Viscosity Inpatients with Unstable Angina in Different Periods of a Solar Activity

    Science.gov (United States)

    Parshina, S. S.; Tokaeva, L. K.; Dolgova, E. M.; Afanas'yeva, T. N.; Strelnikova, O. A.

    The origin of hemorheologic and endothelial defects in patients with unstable angina (comparing with healthy persons) is determined by a solar activity period: the blood viscosity increases in a period of high solar activity in the vessels of small, medium and macro diameters, a local decompensate dysfunction of small vessels endothelium had been fixed (microcirculation area). In the period of a low solar activity there is an increase of a blood viscosity in vessels of all diameters, generalized subcompensated endothelial dysfunction is developed (on the background of the III phase blood clotting activating). In the period of a high solar activity a higher blood viscosity had been fixed, comparing with the period of a low solar activity.

  4. Endothelial dysfunction and low-grade inflammation and the progression of retinopathy in Type 2 diabetes

    DEFF Research Database (Denmark)

    Spijkerman, Annemieke M W; Gall, Mari-Anne; Tarnow, L

    2007-01-01

    AIMS: To study whether microalbuminuria, endothelial dysfunction and low-grade inflammation are associated with the presence and progression of diabetic retinopathy. METHODS: Patients with Type 2 diabetes (n = 328) attending a diabetes clinic were followed for 10 years and examined annually during......E-selectin), and soluble vascular cell adhesion molecule 1) and inflammatory activity (C-reactive protein and fibrinogen) were determined. RESULTS: The prevalence of retinopathy was 33.8%. The median diabetes duration at baseline was 7 years (interquartile range 2-12 years). The highest tertiles of baseline urinary.......65 (1.21-2.25). CONCLUSIONS: In this population of patients with Type 2 diabetes who attended a diabetes clinic, there was some evidence for a role of endothelial dysfunction in the progression of retinopathy. We could not demonstrate a role for low-grade inflammation. Our study emphasizes...

  5. Glycemic control with ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in streptozotocin-induced diabetic mouse

    Directory of Open Access Journals (Sweden)

    Hotimah Masdan Salim

    2016-10-01

    , VCAM-1, and ICAM-1 in HUVEC.Conclusion: Ipragliflozin improved hyperglycemia and prevented the development of endothelial dysfunction under a hyperglycemic state, at least partially by attenuation of oxidative stress.

  6. Endothelial dysfunction in the early postoperative period after major colon cancer surgery

    DEFF Research Database (Denmark)

    Ekeløf, Sara; Larsen, Mikkel Hjordt; Schou-Pedersen, Anne Marie Voigt

    2017-01-01

    Background. Evidence suggests that endothelial dysfunction in the early postoperative period promotes myocardial injury after non-cardiac surgery. The aim of this study was to investigate the impact of colon cancer surgery on endothelial function and the association with the l-arginine-nitric oxide...... pathway postoperatively. Methods. Patients undergoing elective colon cancer surgery (n = 31) were included in this prospective observational cohort study. Endothelial function, as measured using the reactive hyperaemia index (RHI), was assessed non-invasively using digital pulse tonometry. RHI and plasma...... concentrations of L-arginine, asymmetric dimethylarginine (ADMA), dihydrobiopterin and biopterin metabolites, tetrahydrobiopterin (BH4) and total biopterin were measured before surgery, at four h after surgery and at postoperative day one and two. Cardiac troponin I was measured before surgery and once daily...

  7. Endothelial dysfunction in rectal cancer patients chronically exposed to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Rakhypbekov, Tolebay; Pak, Laura; Chaizhunusova, Nailya; Manambayeva, Zukhra; Tokanova, Sholpan; Madiyeva, Madina [Semey State Medical University, Semey (Kazakhstan); Inoue, Ken [Kochi University, Health Service Center, Kochi (Japan); Kawano, Noriyuki; Hoshi, Masaharu [Hiroshima University, Hiroshima (Japan); Takeichi, Nobuo [Takeichi Clinic, Hiroshima (Japan); Noso, Yoshihiro [Shimane University, Department of General Surgery, Faculty of Medicine, Shimane (Japan); Khozhayev, Arman; Molgazhdarov, Maulen [The Kazakh National Medical University of S.D.Asfendiyarov, Department of Oncology, Almaty (Kazakhstan); Olzhaev, Sayakhat [Almaty Regional Oncologic Hospital, Department of Oncology, Almaty (Kazakhstan)

    2017-08-15

    We sought to identify the features of endothelial function in rectal cancer patients who were exposed to chronic ionizing radiation from a nuclear test site in Kazakhstan. We examined 146 individuals, 76 of whom were rectal cancer patients. The existence of a complex of disturbances of the endothelium and hemostasis systems in patients vs non-patients was revealed. Endothelial dysfunction was expressed as an increase of nitric oxide (NO) production along with decreases in vasodilatation function, and increased levels of von Willebrand factor in blood, along with an increase in the number of circulating endotheliocytes. Significant correlations between indicators of endothelial function and vascular-platelet hemostasis were observed. These changes and their interrelations were expressed more strongly in the patients who lived in the contaminated area around the nuclear test site. Such patients could have an increased risk of thrombosis and other complications after the treatment of a malignant neoplasm. (orig.)

  8. The Krebs cycle and mitochondrial mass are early victims of endothelial dysfunction: proteomic approach.

    Science.gov (United States)

    Addabbo, Francesco; Ratliff, Brian; Park, Hyeong-Cheon; Kuo, Mei-Chuan; Ungvari, Zoltan; Csiszar, Anna; Ciszar, Anna; Krasnikov, Boris; Krasnikof, Boris; Sodhi, Komal; Zhang, Fung; Nasjletti, Alberto; Goligorsky, Michael S

    2009-01-01

    Endothelial cell dysfunction is associated with bioavailable nitric oxide deficiency and an excessive generation of reactive oxygen species. We modeled this condition by chronically inhibiting nitric oxide generation with subpressor doses of N(G)-monomethyl-L-arginine (L-NMMA) in C57B6 and Tie-2/green fluorescent protein mouse strains. L-NMMA-treated mice exhibited a slight reduction in vasorelaxation ability, as well as detectable abnormalities in soluble adhesion molecules (soluble intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1, and matrix metalloproteinase 9), which represent surrogate indicators of endothelial dysfunction. Proteomic analysis of the isolated microvasculature using 2-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy revealed abnormal expression of a cluster of mitochondrial enzymes, which was confirmed using immunodetection. Aconitase-2 and enoyl-CoA-hydratase-1 expression levels were decreased in L-NMMA-treated animals; this phenotype was absent in nitric oxide synthase-1 and -3 knockout mice. Depletion of aconitase-2 and enoyl-CoA-hydratase-1 resulted in the inhibition of the Krebs cycle and enhanced pyruvate shunting toward the glycolytic pathway. To assess mitochondrial mass in vivo, co-localization of green fluorescent protein and MitoTracker fluorescence was detected by intravital microscopy. Quantitative analysis of fluorescence intensity showed that L-NMMA-treated animals exhibited lower fluorescence of MitoTracker in microvascular endothelia as a result of reduced mitochondrial mass. These findings provide conclusive and unbiased evidence that mitochondriopathy represents an early manifestation of endothelial dysfunction, shifting cell metabolism toward "metabolic hypoxia" through the selective depletion of both aconitase-2 and enoyl-CoA-hydratase-1. These findings may contribute to an early preclinical diagnosis of endothelial dysfunction.

  9. HIV replication, inflammation, and the effect of starting antiretroviral therapy on plasma asymmetric dimethylarginine, a novel marker of endothelial dysfunction

    DEFF Research Database (Denmark)

    Baker, Jason V; Neuhaus, Jacqueline; Duprez, Daniel

    2012-01-01

    HIV infection is associated with premature development of cardiovascular disease. Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce cardiovascular disease risk....

  10. Endothelial dysfunction is associated with activation of the type i interferon system and platelets in patients with systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Tydén, Helena; Lood, Christian; Gullstrand, Birgitta

    2017-01-01

    Objectives Endothelial dysfunction may be connected to cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Type I interferons (IFNs) are central in SLE pathogenesis and are suggested to induce both endothelial dysfunction and platelet activation. In this study, we investigated...... the interplay between endothelial dysfunction, platelets and type I IFN in SLE. Methods We enrolled 148 patients with SLE and 79 sex-matched and age-matched healthy controls (HCs). Type I IFN activity was assessed with a reporter cell assay and platelet activation by flow cytometry. Endothelial dysfunction...... with activation of platelets and the type I IFN system. We suggest that an interplay between the type I IFN system, injured endothelium and activated platelets may contribute to development of CVD in SLE....

  11. Globotriaosylsphingosine accumulation and not alpha-galactosidase-A deficiency causes endothelial dysfunction in Fabry disease.

    Directory of Open Access Journals (Sweden)

    Mehdi Namdar

    Full Text Available BACKGROUND: Fabry disease (FD is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA resulting in the accumulation of globotriaosylsphingosine (Gb3 in a variety of tissues. While GLA deficiency was always considered as the fulcrum of the disease, recent attention shifted towards studying the mechanisms through which Gb3 accumulation in vascular cells leads to endothelial dysfunction and eventually multiorgan failure. In addition to the well-described macrovascular disease, FD is also characterized by abnormalities of microvascular function, which have been demonstrated by measurements of myocardial blood flow and coronary flow reserve. To date, the relative importance of Gb3 accumulation versus GLA deficiency in causing endothelial dysfunction is not fully understood; furthermore, its differential effects on cardiac micro- and macrovascular endothelial cells are not known. METHODS AND RESULTS: In order to assess the effects of Gb3 accumulation versus GLA deficiency, human macro- and microvascular cardiac endothelial cells (ECs were incubated with Gb3 or silenced by siRNA to GLA. Gb3 loading caused deregulation of several key endothelial pathways such as eNOS, iNOS, COX-1 and COX-2, while GLA silencing showed no effects. Cardiac microvascular ECs showed a greater susceptibility to Gb3 loading as compared to macrovascular ECs. CONCLUSIONS: Deregulation of key endothelial pathways as observed in FD vasculopathy is likely caused by intracellular Gb3 accumulation rather than deficiency of GLA. Human microvascular ECs, as opposed to macrovascular ECs, seem to be affected earlier and more severely by Gb3 accumulation and this notion may prove fundamental for future progresses in early diagnosis and management of FD patients.

  12. Arterial stiffness and endothelial dysfunction independently and synergistically predict cardiovascular and renal outcome in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Theilade, S; Lajer, Maria Stenkil; Jorsal, Anders

    2012-01-01

    To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes.......To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes....

  13. The predictive role of markers of Inflammation and endothelial dysfunction on the course of diabetic retinopathy in type 1 diabetes.

    Science.gov (United States)

    Rajab, Hussein A; Baker, Nathaniel L; Hunt, Kelly J; Klein, Richard; Cleary, Patricia A; Lachin, John; Virella, Gabriel; Lopes-Virella, Maria F

    2015-01-01

    This study was undertaken to determine whether levels of inflammation and endothelial dysfunction biomarkers in serum samples collected at baseline in the Diabetes Control and Complications Trial (DCCT) cohort could predict the development of retinopathy. Levels of clotting/fibrinolysis, inflammation and endothelial dysfunction biomarkers were measured in 1391 subjects with type 1 diabetes to determine whether their levels predicted increased risk to develop or accelerate progression of retinopathy during 16years of follow-up. Using regression models adjusted for DCCT treatment group, duration of diabetes, baseline retinopathy scores, HbA1c and albumin excretion rate, the baseline levels of sE-selectin and PAI-1 (active) were significantly associated with increased risk of a 3-step progression in retinopathy score in the primary prevention cohort (PPC). After adjusting for additional covariates (e.g., ACE/ARB and statin therapy), this association persisted. Levels of active and total PAI-1 in the same group were also significantly associated, after similar adjustments, with the time to progress to severe non-proliferative retinopathy during the follow-up period (54 and 29%, respectively of increased risk). No associations were observed in the secondary intervention cohort for any of the outcomes. High levels of sE-selectin and PAI-1 are associated with the development of retinopathy in patients with uncomplicated type 1 diabetes. Published by Elsevier Inc.

  14. Endothelial dysfunction assessment by noninvasive peripheral arterial tonometry in patients with chronic obstructive pulmonary disease compared with healthy subjects.

    Science.gov (United States)

    Malerba, Mario; Radaeli, Alessandro; Nardin, Matteo; Clini, Enrico; Carpagnano, Giovanna Elisiana; Sciatti, Edoardo; Salghetti, Francesca; Bonadei, Ivano; Platto, Fabio; Vizzardi, Enrico

    2017-08-05

    Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of cardiovascular disease. The endothelial dysfunction likely plays a central role in increasing cardiovascular risk. This cross-sectional, study investigated the prevalence and extent of endothelial dysfunction in patients with stable COPD. Peripheral arterial tonometry (PAT) was measured by post-ischemic reactive hyperemia index (RHI) in 16 COPD patients, 16 healthy controls and 16 subjects with treated systemic arterial hypertension (AH) and analysed with covariates condition (dyslipidemia, and medications). The prevalence of endothelial dysfunction was significantly higher in COPD group than in the other groups. Mean RHI was significantly lower in COPD patients compared with the other groups. At linear regression FEV 1 and RHI were directly correlated (Spearman index = 0.553; P = .026). COPD patients in groups C and D according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages showed lower RHI compared with patients classified as A and B (P < .01). At multiple regression analysis the presence of dyslipidemia, COPD and AH were associated with the presence of endothelial dysfunction. Endothelial dysfunction in stable COPD patients is probably implicated in the high cardiovascular comorbidity. This study suggests the potential utility of endothelial dysfunction evaluation in patients with COPD to a timely assessment and treatment for cardiac complications. © 2017 John Wiley & Sons Ltd.

  15. Endocan: a novel predictor of endothelial dysfunction in obstructive sleep apnea syndrome.

    Science.gov (United States)

    Kanbay, Asiye; Ceylan, Erkan; Köseoğlu, Handan İnönü; Çalışkan, Mustafa; Takir, Mumtaz; Tulu, Selcan; Telci Çaklılı, Ozge; Köstek, Osman; Erek, Aybala; Afsar, Baris

    2018-01-01

    Obstructive sleep apnea syndrome (OSA) is an independent risk factor for endothelial dysfunction and cardiometabolic diseases. Plasma endocan levels are elevated in a large number of diseases, and is a novel surrogate endothelial cell dysfunction marker. We aimed to assess the role of serum endocan level as a potential mechanism of endothelial dysfunction in OSA patients. This was a cohort study in which patients who had undergone a sleep study for diagnosis of OSA were recruited. Included patients were grouped according to apnea-hypopnea index (AHI) as mild, moderate and severe OSA. Patients with AHI < 5 served as control group. Endothelial function was evaluated with flow-mediated dilatation (FMD). Plasma endocan level was measured for all patients. One hundred twenty eight OSA patients included (15 controls, 22 with mild, 22 with moderate and 69 with severe OSA). The mean age was 51.6 ± 11.9 years and 43.8% (56/128) of the study population was female. As expected, the prevalence of hypertension, diabetes and cardiovascular disease increased as the severity of OSA increased. Endocan levels were significantly higher and FMD measurements were lower in patients with OSA compared to healthy controls. There was a positive correlation between AHI and serum endocan levels (rho = 0.826, P < 0.0001) and there was a negative correlation between AHI and FMD (rho = -0.686, P < 0.0001) In addition, we observed a strong negative correlation between serum endocan level and FMD (rho = -0.613, P < 0.0001). In linear regression analysis AHI was independently related both with endocan (P < 0.0001) and FMD (P = 0.011). Serum endocan level is strongly associated with the severity of OSA and endothelial dysfunction. Endocan might be a useful early novel marker for premature vascular endothelial system damage in OSA patients. © 2016 John Wiley & Sons Ltd.

  16. Disfunción endotelial y diabetes mellitus Endothelial dysfunction and diabetes mellitus

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    Jeddú Cruz Hernández

    2012-08-01

    Full Text Available Introducción: la disfunción endotelial se presenta con frecuencia en los individuos con diabetes mellitus, debido a que las alteraciones vasculares que aparecen en esta enfermedad y que son provocadas por la hiperglucemia crónica, facilitan su aparición, a lo cual puede contribuir también la hipertensión arterial y la dislipidemia que se presentan en los diabéticos. Objetivo: describir algunos eventos implicados en la aparición de la disfunción endotelial en la diabetes mellitus, y aspectos relacionados con su diagnóstico y tratamiento. Desarrollo: entre los marcadores más importantes de disfunción endotelial en la diabetes mellitus se encuentran, la elevación de las moléculas de adhesión celular y de marcadores de inflamación, la microalbuminuria, la hiperhomocisteinemia, y el incremento de la hemoglobina glucosilada, de la endotelina-1 y del estrés oxidativo. Para el diagnóstico de disfunción endotelial se utilizan la medición de sustancias reguladoras de biofunciones sintetizadas por el endotelio y de otras reconocidas como marcadores de disfunción endotelial, y pruebas indirectas, algunas de las cuales son invasivas; y para su tratamiento, disímiles medidas terapéuticas medicamentosas o no. Conclusiones: es importante identificar la disfunción endotelial tempranamente en los diabéticos y tratarla, en caso de estar presente.Introduction: endothelial dysfunction frequently appears in individuals with diabetes mellitus, because vascular alterations derived from chronic hyperglycemia facilitate the occurrence of the disease, to which blood hypertension and dislipidemia of diabetics also contribute. Objective: to describe some events involved in the onset of endothelial dysfunction in diabetes mellitus and several aspects related to diagnosis and treatment. Development: among the most important markers of endothelial dysfunction in diabetes mellitus are the rises of cell adhesion molecules and inflammation markers

  17. Endothelial dysfunction, platelet activation, thrombogenesis and fibrinolysis in patients with hypertensive crisis.

    Science.gov (United States)

    van den Born, Bert-Jan H; Löwenberg, Ester C; van der Hoeven, Niels V; de Laat, Bas; Meijers, Joost C M; Levi, Marcel; van Montfrans, Gert A

    2011-05-01

    Hypertensive crisis is an extreme phenotype of hypertension and hypertension-related thrombotic complications. This is most evident in patients with hypertensive crisis having advanced retinopathy and thrombotic microangiopathy (TMA). We examined whether hypertensive crisis complicated by advanced retinopathy is associated with endothelial dysfunction, platelet activation, thrombin generation and decreased fibrinolytic activity. In addition, we tested the association between these procoagulant changes and the development of TMA and end-organ dysfunction. Several key mediators of coagulation were assessed in 40 patients with hypertensive crisis with and without retinopathy and compared with 20 age, sex and ethnicity-matched normotensive controls. In patients with hypertensive crisis, associations with markers of TMA and renal dysfunction were assessed by regression analysis. Soluble P-selectin levels were higher in patients with hypertensive crisis compared with controls regardless of the presence or absence of retinopathy (Phypertensive crisis with retinopathy compared with normotensive controls (P-valuesHypertensive crisis with retinopathy confers a prothrombotic state characterized by endothelial dysfunction, platelet activation and increased thrombin generation, whereas fibrinolytic activity is enhanced. The observed changes in prothrombotic and antithrombotic pathways may contribute to the increased risk of ischaemic and haemorrhagic complications in this extreme hypertension phenotype. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

  18. Perinatal testosterone exposure potentiates vascular dysfunction by ERβ suppression in endothelial progenitor cells.

    Science.gov (United States)

    Xie, Weiguo; Ren, Mingming; Li, Ling; Zhu, Yin; Chu, Zhigang; Zhu, Zhigang; Ruan, Qiongfang; Lou, Wenting; Zhang, Haimou; Han, Zhen; Huang, Xiaodong; Xiang, Wei; Wang, Tao; Yao, Paul

    2017-01-01

    Recent clinical cohort study shows that testosterone therapy increases cardiovascular diseases in men with low testosterone levels, excessive circulating androgen levels may play a detrimental role in the vascular system, while the potential mechanism and effect of testosterone exposure on the vascular function in offspring is still unknown. Our preliminary results showed that perinatal testosterone exposure in mice induces estrogen receptor β (ERβ) suppression in endothelial progenitor cells (EPCs) in offspring but not mothers, while estradiol (E2) had no effect. Further investigation showed that ERβ suppression is due to perinatal testosterone exposure-induced epigenetic changes with altered DNA methylation on the ERβ promoter. During aging, EPCs with ERβ suppression mobilize to the vascular wall, differentiate into ERβ-suppressed mouse endothelial cells (MECs) with downregulated expression of SOD2 (mitochondrial superoxide dismutase) and ERRα (estrogen-related receptor α). This results in reactive oxygen species (ROS) generation and DNA damage, and the dysfunction of mitochondria and fatty acid metabolism, subsequently potentiating vascular dysfunction. Bone marrow transplantation of EPCs that overexpressed with either ERβ or a SIRT1 single mutant SIRT1-C152(D) that could modulate SIRT1 phosphorylation significantly ameliorated vascular dysfunction, while ERβ knockdown worsened the problem. We conclude that perinatal testosterone exposure potentiates vascular dysfunction through ERβ suppression in EPCs.

  19. Angiotensin II-Induced Endothelial Dysfunction is Temporally Linked with Increases in Intereukin-6 and Vascular Macrophage Accumulation

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    Sean P Didion

    2014-10-01

    Full Text Available Angiotensin II (Ang II is associated with vascular hypertrophy, endothelial dysfunction and activation of a number of inflammatory molecules, however the linear events involved in the development of hypertension and endothelial dysfunction produced in response to Ang II are not well defined. The goal of this study was to examine the dose- and temporal-dependent development of endothelial dysfunction in response to Ang II. Blood pressure and responses of carotid arteries were examined in control (C57Bl/6 mice and in mice infused with 50, 100, 200, 400, or 1000 ng/kg/min Ang II for either 14 or 28 Days. Infusion of Ang II was associated with graded and marked increases in systolic blood pressure and plasma Ang II concentrations. While low doses of Ang II (ie, 50 and 100 ng/kg/min had little to no effect on blood pressure or endothelial function, high doses of Ang II (e.g., 1000 ng/kg/min were associated with large increases in arterial pressure and marked impairment of endothelial function. In contrast, intermediate doses of Ang II (200 and 400 ng/kg/min while initially having no effect on systolic blood pressure were associated with significant increases in pressure over time. Despite increasing blood pressure, 200 ng/kg/min had no effect on endothelial function, whereas 400 ng/kg/min produced modest impairment on Day 14 and marked impairment of endothelial function on Day 28. The degree of endothelial dysfunction produced by 400 and 1000 ng/kg/min Ang II was reflective of parallel increases in plasma IL-6 levels and vascular macrophage content, suggesting that increases in arterial blood pressure precede the development of endothelial dysfunction. These findings are important as they demonstrate that along with increases in arterial pressure that increases in IL-6 and vascular macrophage accumulation correlate with the impairment of endothelial function produced by Ang II.

  20. HIV-infected persons with type 2 diabetes show evidence of endothelial dysfunction and increased inflammation.

    Science.gov (United States)

    Hove-Skovsgaard, Malene; Gaardbo, Julie Christine; Kolte, Lilian; Winding, Kamilla; Seljeflot, Ingebjørg; Svardal, Asbjørn; Berge, Rolf Kristian; Gerstoft, Jan; Ullum, Henrik; Trøseid, Marius; Nielsen, Susanne Dam

    2017-03-29

    Increased incidence of cardiovascular diseases (CVD) in both HIV infection and type 2 diabetes (T2D) compared to the general population has been described. Little is known about the combined effect of HIV infection and T2D on inflammation and endothelial function, both of which may contribute to elevated risk of CVD. Cross-sectional study including 50 HIV-infected persons on combination anti-retroviral therapy (cART), with HIV RNA inflammation (cut-off 3 mg/L). The marker of endothelial dysfunction asymmetric dimethylarginine (ADMA) was measured using high performance liquid chromatography. Trimethylamine-N-oxide (TMAO), a microbiota-dependent, pro-atherogenic marker was measured using stable isotope dilution LC/MS/MS. The percentage of HIV + T2D+, HIV + T2D-, HIV-T2D+, and HIV-T2D- with hsCRP above cut-off was 50%, 19%, 47%, and 11%, respectively. HIV + T2D+ had elevated ADMA (0.67 μM (0.63-0.72) compared to HIV + T2D- (0.60 μM (0.57-0.64) p = 0.017), HIV-T2D+ (0.57 μM (0.51-63) p = 0.008), and HIV-T2D- (0.55 μM (0.52-0.58) p inflammation and evidence of endothelial dysfunction was found in HIV-infected persons with T2D. The effect on inflammation was mainly driven by T2D, while both HIV infection and T2D may contribute to endothelial dysfunction. Whether gut microbiota is a contributing factor to this remains to be determined.

  1. Endothelial dysfunction in uremic patients on continuous ambulatory peritoneal dialysis (CAPD

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    Senija Rašić

    2011-08-01

    Full Text Available Endothelial dysfunction is associated with diabetic micro- and macroangiopathy as well as with the decline in creatinine clearance. It has been suggested that endothelial dysfunction presents in patients (pts on continuous ambulatory peritoneal dialysis (CAPD. The objective of this study was to examine the plasma biomarkers of endothelial dysfunction and their association with IMT of carotid arteries in diabetic and non-diabetic patients on CAPD. This study included 37 CAPD pts (25 with type II diabetes and 12 non-diabetic pts mean age 59.2 years ± 2.48. Plasma von Willebrand factor (vWF activity, serum albumin, glucose, total cholesterol, triglycerides and lipoprotein (a levels, as well as serum level of homocysteine, parathyroid hormone (PTH in plasma and microalbuminuria was determined. Ultrasound examination of carotid arteries was performed in all patients by measured bilateral intima-media thickness of carotid artery (CIMT. Mean IMT value was significantly higher in type 2 DM patients (0.86 ± 0.04 mm compared to non-diabetic patients (0.52 ± 0.06 mm on peritoneal dialysis (p<0.0001. There was also a significant difference in lipids/triglycerides and Lp (a/, procoagulation (fibrinogen, von Wilebrand factor, factor VIII and inflammatory markers (CRP level between type 2 DM and non-diabetic CAPD patients. A stepwise multiple regression analysis revealed that log triglycerides and factor VIII were independent factors for the IMT. The results of this research impose that diabetic type 2 CAPD patients have developed systemic alteration of endothelial function and higher risk of cardiovascular complications compared to non-diabetic CAPD patients.

  2. Habitual aerobic exercise does not protect against micro- or macrovascular endothelial dysfunction in healthy estrogen-deficient postmenopausal women.

    Science.gov (United States)

    Santos-Parker, Jessica R; Strahler, Talia R; Vorwald, Victoria M; Pierce, Gary L; Seals, Douglas R

    2017-01-01

    Aging causes micro- and macrovascular endothelial dysfunction, as assessed by endothelium-dependent dilation (EDD), which can be prevented and reversed by habitual aerobic exercise (AE) in men. However, in estrogen-deficient postmenopausal women, whole forearm microvascular EDD has not been studied, and a beneficial effect of AE on macrovascular EDD has not been consistently shown. We assessed forearm blood flow in response to brachial artery infusions of acetylcholine (FBF ACh ), a measure of whole forearm microvascular EDD, and brachial artery flow-mediated dilation (FMD), a measure of macrovascular EDD, in 12 premenopausal sedentary women (Pre-S; 24 ± 1 yr; V̇o 2max = 37.5 ± 1.6 ml·kg -1 ·min -1 ), 25 estrogen-deficient postmenopausal sedentary women (Post-S; 62 ± 1 yr; V̇o 2max = 24.7 ± 0.9 ml·kg -1 ·min -1 ), and 16 estrogen-deficient postmenopausal AE-trained women (Post-AE; 59 ± 1 yr; V̇o 2max = 40.4 ± 1.4 ml·kg -1 ·min -1 ). FBF ACh was lower in Post-S and Post-AE compared with Pre-S women (135 ± 9 and 116 ± 17 vs. 193 ± 21 AUC, respectively, both P healthy nonobese estrogen-deficient postmenopausal women, despite being associated with lower systemic markers of inflammation and oxidative stress. This is the first study to demonstrate that habitual aerobic exercise may not protect against age/menopause-related whole forearm microvascular endothelial dysfunction in healthy nonobese estrogen-deficient postmenopausal women, consistent with recent findings regarding macrovascular endothelial function. This is in contrast to what is observed in healthy middle-aged and older aerobic exercise-trained men. Copyright © 2017 the American Physiological Society.

  3. Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.

    Science.gov (United States)

    Karbach, Susanne; Croxford, Andrew L; Oelze, Matthias; Schüler, Rebecca; Minwegen, Daniel; Wegner, Joanna; Koukes, Lija; Yogev, Nir; Nikolaev, Alexei; Reißig, Sonja; Ullmann, Alexander; Knorr, Maike; Waldner, Maximilian; Neurath, Markus F; Li, Huige; Wu, Zhixiong; Brochhausen, Christoph; Scheller, Jürgen; Rose-John, Stefan; Piotrowski, Carolin; Bechmann, Ingo; Radsak, Markus; Wild, Philipp; Daiber, Andreas; von Stebut, Esther; Wenzel, Philip; Waisman, Ari; Münzel, Thomas

    2014-12-01

    Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease. Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-α and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A(ind/+) mice. Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) inflammatory cells. Depletion of the GR-1(+) immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A(ind/+) mice. © 2014 American Heart Association, Inc.

  4. Evaluation the effect of low-dose aspirin on endothelial dysfunction in preeclamptic patients

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    Mohammad Hashemi

    2016-01-01

    Full Text Available Background: Preeclampsia complicates up to 3% of pregnancies in developing countries. Endothelial dysfunction plays an important role in pathogenesis of preeclampsia. In this study, we aim to evaluate the effect of low-dose aspirin on endothelial dysfunction in preeclamptic patients. Materials and Methods: in this triple-blind randomized clinical trial, enrolled patients were divided randomly into two groups. Acetylsalicylic acid (ASA 80 mg or placebo will be taken daily by oral administration from the initiation of diagnosis until 2 months after delivery. Every patient's flow-mediated dilation (FMD were evaluated at the beginning of study and 2 months after delivery with the same experienced operator at a same period of the time (3–5 pm by high-resolution B-mode ultrasonographic. T-test or Mann–Whitney test was used in the comparison of means between the intervention and placebo groups. To compare FMD in each group, before and after the intervention, paired t-test was used. Results: Mean value of FMD in intervention (9.61 ± 5.58 and control group (9.40 ± 4.33 have no significant differences before drug consumption (P = 0.089. FMD in intervention group significantly increased after ASA consumption ([9.61 ± 5.58 vs. 13.65 ± 7.91] [P = 0.044]. Conclusion: Increase mean of FMD in intervention group shows that this supplement can improve endothelial function.

  5. Asymmetric Dimethylarginine Induced Apoptosis and Dysfunction of Endothelial Progenitor Cells: Role of Endoplasmic Reticulum Stress Pathway

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    Sheng Ye

    2017-01-01

    Full Text Available Asymmetric dimethylarginine (ADMA, an inhibitor of nitric oxide synthase, is a novel risk factor of cardiovascular disease. Endothelial progenitor cells (EPCs bear typical endothelial characteristics and are thought to contribute to neovascularization by providing new endothelial cells (ECs after arterial injury. Many studies have shown that ADMA can induce EPC apoptosis and dysfunction, but the underlying mechanism is not well understood. EPCs from umbilical cord blood were cultured in EGM-2 medium with particular growth factors and supplemented with 10% fetal bovine serum. The cells were treated with different concentrations of ADMA (5, 10, and 50 μmol/L. Endoplasmic reticulum (ER stress marker levels were examined by western blot analysis. After 24-hour incubation, ADMA induced apoptosis of EPCs and significantly decreased the proliferation, migration, and vasculogenesis capacity of EPCs. We also found that ADMA treatment activated phosphorylated protein kinase RNA-activated-like ER kinase (PERK, a stress sensor protein in the endoplasmic reticulum (ER. The activated PERK induced 78 kDa glucose-regulated protein (GRP-78 and C/EBP homologous protein (CHOP expression. Additionally, the inhibition of the ER stress pathway by Salubrinal (a specific ER stress inhibitor can attenuate ADMA-induced apoptosis of EPCs. Overall, these observations indicate that ADMA may induce the apoptosis and dysfunction of EPCs through the ER stress pathway.

  6. Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors,  or both? Expectations from The ONTARGET  Trial Programme

    Directory of Open Access Journals (Sweden)

    Luis Miguel  Ruilope

    2007-03-01

    Full Text Available Luis Miguel  Ruilope1, Josep Redón2, Roland Schmieder31Servicio de Nefrologia, Unidad de Hipertension Hospital, 12 de Octubre, Madrid, Spain; 2Department of Internal Medicine, Hospital Clinico University of Valencia, Valencia, Spain; 3Department of Nephrology and Hypertension, Friedrich-Alexander-Universitat, Erlangen-Nurnberg, GermanyAbstract: Endothelial dysfunction is the initial pathophysiological step in a progression of vascular damage that leads to overt cardiovascular and chronic kidney disease. Angiotensin II, the primary agent of the renin–angiotensin system (RAS, has a central role in endothelial dysfunction. Therefore, RAS blockade with an angiotensin receptor blocker (ARB and/or angiotensin-converting enzyme (ACE inhibitor provides a rational approach to reverse endothelial dysfunction, reduce microalbuminuria, and, thus, improves cardiovascular and renal prognosis. ARBs and ACE inhibitors act at different points in the RAS pathway and recent evidence suggests that there are differences regarding their effects on endothelial dysfunction. In addition to blood pressure lowering, studies have shown that ARBs reduce target-organ damage, including improvements in endothelial dysfunction, arterial stiffness, the progression of renal dysfunction in patients with type 2 diabetes, proteinuria, and left ventricular hypertrophy. The ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial (ONTARGET Programme is expected to provide the ultimate evidence of whether improved endothelial func tion translates into reduced cardiovascular and renal events in high-risk patients, and to assess possible differential outcomes with telmisartan, the ACE inhibitor ramipril, or a combination of both (dual RAS blockade. Completion of ONTARGET is expected in 2008. Keywords: angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, endothelial dysfunction, ONTARGET, renin–angiotensin system, telmisartan

  7. Apelin elevates blood pressure in ICR mice with L-NAME-induced endothelial dysfunction

    Science.gov (United States)

    NAGANO, KATSUMASA; ISHIDA, JUNJI; UNNO, MADOKA; MATSUKURA, TANOMU; FUKAMIZU, AKIYOSHI

    2013-01-01

    Apelin is the endogenous ligand of APJ, which belongs to the family of G protein-coupled receptors. Apelin and APJ are highly expressed in various cardiovascular tissues, including the heart, kidney and vascular endothelial and smooth muscle cells. Although apelin exerts hypotensive effects via activation of endothelial nitric oxide synthase (eNOS), the ability of apelin to regulate blood pressure under pathological conditions is poorly understood. In the current study, NG-nitro-L-arginine methyl ester (L-NAME), a potent NOS inhibitor, was administered chronically, to induce peripheral vascular damage in mice. L-NAME-treated mice exhibited hypertension, increased vascular cell adhesion molecule-1 and plasminogen activator inhibitor-1 mRNA levels in the aorta and impaired vasodilatation associated with decreased aortic eNOS expression, consistent with endothelial damage. Three days following withdrawal of L-NAME treatment, the blood pressure response to apelin stimulation was assessed. Although apelin reduced blood pressure in non-treated mice, it was found to transiently elevate blood pressure in L-NAME-treated mice. These results indicate that apelin functions as a vasopressor peptide under pathological conditions, including vascular endothelial dysfunction in mice. PMID:23525196

  8. Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction

    Science.gov (United States)

    Catry, Emilie; Bindels, Laure B; Tailleux, Anne; Lestavel, Sophie; Neyrinck, Audrey M; Goossens, Jean-François; Lobysheva, Irina; Plovier, Hubert; Essaghir, Ahmed; Demoulin, Jean-Baptiste; Bouzin, Caroline; Pachikian, Barbara D; Cani, Patrice D; Staels, Bart; Dessy, Chantal; Delzenne, Nathalie M

    2018-01-01

    Objective To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction. Design We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe−/−) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed. Results ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe−/− mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation. Conclusions We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases. PMID:28377388

  9. Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction.

    Science.gov (United States)

    Catry, Emilie; Bindels, Laure B; Tailleux, Anne; Lestavel, Sophie; Neyrinck, Audrey M; Goossens, Jean-François; Lobysheva, Irina; Plovier, Hubert; Essaghir, Ahmed; Demoulin, Jean-Baptiste; Bouzin, Caroline; Pachikian, Barbara D; Cani, Patrice D; Staels, Bart; Dessy, Chantal; Delzenne, Nathalie M

    2018-02-01

    To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction. We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe -/- ) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed. ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe -/- mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation. We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  10. HIV-infected persons with type 2 diabetes show evidence of endothelial dysfunction and increased inflammation

    DEFF Research Database (Denmark)

    Hove-Skovsgaard, Malene; Gaardbo, Julie Christine; Kolte, Lilian

    2017-01-01

    BACKGROUND: Increased incidence of cardiovascular diseases (CVD) in both HIV infection and type 2 diabetes (T2D) compared to the general population has been described. Little is known about the combined effect of HIV infection and T2D on inflammation and endothelial function, both of which may...... contribute to elevated risk of CVD. METHODS: Cross-sectional study including 50 HIV-infected persons on combination anti-retroviral therapy (cART), with HIV RNA persons (n = 22 with T2D (HIV-T2D+) and n = 28.......001), which was mainly driven by a close correlation in HIV + T2D+ (rs = 0.63, p = 0.001). CONCLUSION: Elevated inflammation and evidence of endothelial dysfunction was found in HIV-infected persons with T2D. The effect on inflammation was mainly driven by T2D, while both HIV infection and T2D may contribute...

  11. Impact of Unsaturated Fatty Acids on Cytokine-Driven Endothelial Cell Dysfunction.

    Science.gov (United States)

    Trommer, Simon; Leimert, Anja; Bucher, Michael; Schumann, Julia

    2017-12-16

    Polyunsaturated fatty acids (PUFA) are reported to exert prophylactic and acute therapeutic effects in diseases linked to endothelial dysfunction. In the present study, the consequences of a PUFA enrichment of endothelial cells (cell line TIME) on cell viability, expression of the cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein 1 (MCP-1), synthesis of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular adhesion molecule 1 (VCAM-1), and production of the coagulation factors plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), and tissue factor (TF) was analyzed in parallel. PUFA of both the n3 and the n6 family were investigated in a physiologically relevant concentration of 15 µM, and experiments were performed in both the presence and the absence of the pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Supplementation of the culture medium with particular fatty acids was found to have a promoting effect on cellular production of the cytokines IL-6, IL-8, GM-CSF, and MCP-1. Further on, PUFA treatment in the absence of a stimulant diminished the percentage of endothelial cells positive for ICAM-1, and adversely affected the stimulation-induced upregulation of VCAM-1. Cell viability and production of coagulation factors were not or only marginally affected by supplemented fatty acids. Altogether, the data indicate that PUFA of either family are only partially able to counterbalance the destructive consequences of an endothelial dysfunction.

  12. Microvascular endothelial dysfunction is associated with albuminuria and CKD in older adults.

    Science.gov (United States)

    Seliger, Stephen L; Salimi, Shabnam; Pierre, Valerie; Giffuni, Jamie; Katzel, Leslie; Parsa, Afshin

    2016-07-13

    Impairment in glomerular endothelial function likely plays a major role in the development of albuminuria and CKD progression. Glomerular endothelial dysfunction may reflect systemic microvascular dysfunction, accounting in part for the greater cardiovascular risk in patients with albuminuria. Prior studies of vascular function in CKD have focused on conduit artery function or those with ESRD, and have not examined microvascular endothelial function with albuminuria. We conducted a cross-sectional study among older hypertensive male veterans with stage 1-4 CKD, and hypertensive controls without CKD. Microvascular function was quantified by two distinct Laser-Doppler flowmetry (LDF) measures: peak responses to 1) post-occlusive reactive hyperemia (PORH) and 2) thermal hyperemia (TH), measured on forearm skin. Associations of each LDF measure with albuminuria, eGFR, and CKD status were estimated using correlation coefficients and multiple linear regression, accounting for potential confounders. Among 66 participants (mean age 69.2 years), 36 had CKD (mean eGFR 46.1 cc/min/1.73 m(2); 30.6 % with overt albuminuria). LDF responses to PORH and TH were 43 and 39 % significantly lower in multivariate analyses among those with macroalbuminuria compared to normoalbuminuria, (β= - 0.42, p = 0.009 and β= -0.37, p = 0.01, respectively). Those with CKD had a 23.9 % lower response to PORH compared to controls (p = 0.02 after adjustment). In contrast, TH responses did not differ between those with and without CKD. Microvascular endothelial function was strongly associated with greater albuminuria and CKD, independent of diabetes and blood pressure. These findings may explain in part the excess systemic cardiovascular risk associated with albuminuria and CKD.

  13. Association between endothelial dysfunction and otoneurological symptoms in children with sickle cell disease.

    Science.gov (United States)

    Rissatto-Lago, Mara Renata; Salles, Cristina; Campos de Pinho, Fernando Gesteira; Menezes Lyra, Isa; Terse-Ramos, Regina; Teixeira, Rozana; Ladeia, Ana Marice

    2017-06-01

    To evaluate the association between endothelial dysfunction and otoneurological symptoms and vaso-occlusive phenomena in children with sickle cell disease (SCD). Cross-sectional study with 54 children, aged between 6 and19 years of age, of whom 28 had genotype SS and 26 apparently healthy (AA genotype) whose parents or guardians, or the children themselves, filled out a questionnaire designed to assess their otoneurological symptoms. All the individuals were submitted assessment of endothelial function by flow-mediated dilation (FMD) percentage with reactive hyperemia of brachial artery Doppler. Otoneurological symptoms (tinnitus and/or vertigo) predominated in the SCD group (46.4 vs. 15.4%; p = 0.006). A negative correlation was observed between FMD percentage and time of evolution of vertigo SCD (r = -0.432; p = 0.022) and the linear regression analysis demonstrated that for every reduction in FMD percentage there was an increase in time of evolution of vertigo of 1.79 months (β = -1.79; p = 0.022). The positive correlation between episodes of painful crisis and time of evolution of vertigo (r = 0.3; p = 0.04). The presence of vascular endothelial damage in the labyrinthine artery in patients with SCD is capable of compromising the semicircular canals, shown by clinical expression of otoneurological symptoms, such as vertigo. In the present study, an association was observed between endothelial dysfunction with otoneurological symptoms and otoneurological symptoms and vaso-occlusive phenomena in SCD.

  14. Impact of Unsaturated Fatty Acids on Cytokine-Driven Endothelial Cell Dysfunction

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    Simon Trommer

    2017-12-01

    Full Text Available Polyunsaturated fatty acids (PUFA are reported to exert prophylactic and acute therapeutic effects in diseases linked to endothelial dysfunction. In the present study, the consequences of a PUFA enrichment of endothelial cells (cell line TIME on cell viability, expression of the cytokines interleukin-6 (IL-6, interleukin-8 (IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF, and monocyte chemoattractant protein 1 (MCP-1, synthesis of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1 and vascular adhesion molecule 1 (VCAM-1, and production of the coagulation factors plasminogen activator inhibitor-1 (PAI-1, von Willebrand factor (vWF, and tissue factor (TF was analyzed in parallel. PUFA of both the n3 and the n6 family were investigated in a physiologically relevant concentration of 15 µM, and experiments were performed in both the presence and the absence of the pro-inflammatory cytokines interleukin-1β (IL-1β, tumor necrosis factor-α (TNF-α, and interferon-γ (IFN-γ. Supplementation of the culture medium with particular fatty acids was found to have a promoting effect on cellular production of the cytokines IL-6, IL-8, GM-CSF, and MCP-1. Further on, PUFA treatment in the absence of a stimulant diminished the percentage of endothelial cells positive for ICAM-1, and adversely affected the stimulation-induced upregulation of VCAM-1. Cell viability and production of coagulation factors were not or only marginally affected by supplemented fatty acids. Altogether, the data indicate that PUFA of either family are only partially able to counterbalance the destructive consequences of an endothelial dysfunction.

  15. Mechanisms of endothelial dysfunction in resistance arteries from patients with end-stage renal disease.

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    Leanid Luksha

    Full Text Available The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS, prerequisites for myoendothelial gap junctions (MEGJ, and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications.

  16. Lipoteichoic acid from Staphylococcus aureus induces lung endothelial cell barrier dysfunction: role of reactive oxygen and nitrogen species.

    Science.gov (United States)

    Pai, Amy Barton; Patel, Heena; Prokopienko, Alexander J; Alsaffar, Hiba; Gertzberg, Nancy; Neumann, Paul; Punjabi, Anjoli; Johnson, Arnold

    2012-01-01

    Tunneled central venous catheters (TCVCs) are used for dialysis access in 82% of new hemodialysis patients and are rapidly colonized with Gram-positive organism (e.g. Staphylococcus aureus) biofilm, a source of recurrent infections and chronic inflammation. Lipoteichoic acid (LTA), a cell wall ribitol polymer from Gram-positive organisms, mediates inflammation through the Toll-like receptor 2 (TLR2). The effect of LTA on lung endothelial permeability is not known. We tested the hypothesis that LTA from Staphylococcus aureus induces alterations in the permeability of pulmonary microvessel endothelial monolayers (PMEM) that result from activation of TLR2 and are mediated by reactive oxygen/nitrogen species (RONS). The permeability of PMEM was assessed by the clearance rate of Evans blue-labeled albumin, the activation of the TLR2 pathway was assessed by Western blot, and the generation of RONS was measured by the fluorescence of oxidized dihydroethidium and a dichlorofluorescein derivative. Treatment with LTA or the TLR2 agonist Pam((3))CSK((4)) induced significant increases in albumin permeability, IκBα phosphorylation, IRAK1 degradation, RONS generation, and endothelial nitric oxide synthase (eNOS) activation (as measured by the p-eNOS(ser1177):p-eNOS(thr495) ratio). The effects on permeability and RONS were effectively prevented by co-administration of the superoxide scavenger Tiron, the peroxynitrite scavenger Urate, or the eNOS inhibitor L-NAME and these effects as well as eNOS activation were reduced or prevented by pretreatment with an IRAK1/4 inhibitor. The results indicate that the activation of TLR2 and the generation of ROS/RNS mediates LTA-induced barrier dysfunction in PMEM.

  17. Association between endothelial dysfunction, epicardial fat and subclinical atherosclerosis during menopause.

    Science.gov (United States)

    Cabrera-Rego, Julio Oscar; Navarro-Despaigne, Daisy; Staroushik-Morel, Liudmila; Díaz-Reyes, Karel; Lima-Martínez, Marcos M; Iacobellis, Gianluca

    Menopausal transition is critical for the development of early, subclinical vascular damage. Multiple factors, such as atherosclerosis, increased epicardial fat, and endothelial dysfunction can play a role. Hence, the objective of this study was the comparison of epicardial adipose tissue and carotid intima media thickness in order to establish the best predictor of carotid stiffness in middle-aged women with endothelial dysfunction. A total of 43 healthy women aged 40-59 years old with endothelial dysfunction previously demonstrated by flow mediated dilation were recruited to have anthropometric, biochemical, hormonal and ultrasound determinations of carotid intima media thickness and epicardial fat thickness. Carotid arterial stiffness parameters (local pulse wave velocity [4.7±0.7 vs 4.8±0.5 vs 5.6±0.5m/s, respectively, p<0.001], pressure strain elastic modulus [55.2±13.4 vs 59.2±11.8 vs 81.9±15.6kPa, respectively, p<0.001], arterial stiffness index β [4.4±1.4 vs 5.0±1.1 vs 6.4±1.3, respectively, p<0.001]) and epicardial fat thickness (2.98±1.4 vs 3.28±1.9 vs 4.70±1.0mm, respectively, p=0.007) showed a significant and proportional increase in the group of late post-menopausal women when compared to early post-menopausal and pre-menopausal groups, respectively. Among body fat markers, epicardial fat was the strongest predictor of local pulse wave velocity, independent of age. In menopausal women with endothelial dysfunction, menopausal transition is associated with increased carotid arterial stiffness and epicardial fat thickness, independent of age. Ultrasound measured epicardial fat was a better independent predictor of arterial stiffness than carotid intima media thickness in these women. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Aqueous extracts of Tribulus terrestris protects against oxidized low-density lipoprotein-induced endothelial dysfunction.

    Science.gov (United States)

    Jiang, Yue-hua; Yang, Chuan-hua; Li, Wei; Wu, Sai; Meng, Xian-qing; Li, Dong-na

    2016-03-01

    To investigate the role of aqueous extracts of Tribulus terrestris (TT) against oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) dysfunction in vitro. HUVECs were pre-incubated for 60 min with TT (30 and 3 μg/mL respectively) or 10(-5) mol/L valsartan (as positive controls) and then the injured endothelium model was established by applying 100 μg/mL ox-LDL for 24 h. Cell viability of HUVECs was observed by real-time cell electronic sensing assay and apoptosis rate by Annexin V/PI staining. The cell migration assay was performed with a transwell insert system. Cytoskeleton remodeling was observed by immunofluorescence assay. The content of endothelial nitric oxide synthase (eNOS) was measured by enzyme-linked immunosorbent assay. Intracellular reactive oxygen species (ROS) generation was assessed by immunofluorescence and flow cytometer. Key genes associated with the metabolism of ox-LDL were chosen for quantitative real-time polymerase chain reaction to explore the possible mechanism of TT against oxidized LDL-induced endothelial dysfunction. TT suppressed ox-LDL-induced HUVEC proliferation and apoptosis rates significantly (41.1% and 43.5% after treatment for 3 and 38 h, respectively; P<0.05). It also prolonged the HUVEC survival time and postponed the cell's decaying stage (from the 69th h to over 100 h). According to the immunofluorescence and transwell insert system assay, TT improved the endothelial cytoskeletal network, and vinculin expression and increased cell migration. Additionally, TT regulated of the synthesis of endothelial nitric oxide synthase and generation of intracellular reactive oxygen species (P<0.05). Both 30 and 3 μg/mL TT demonstrated similar efficacy to valsartan. TT normalized the increased mRNA expression of PI3Kα and Socs3. It also decreased mRNA expression of Akt1, AMPKα1, JAK2, LepR and STAT3 induced by ox-LDL. The most notable changes were JAK2, LepR, PI3Kα, Socs3 and STAT3. TT

  19. c-Abl mediated tyrosine phosphorylation of paxillin regulates LPS-induced endothelial dysfunction and lung injury

    Science.gov (United States)

    Usatyuk, Peter V.; Lele, Abhishek; Harijith, Anantha; Gregorio, Carol C.; Garcia, Joe G. N.; Salgia, Ravi; Natarajan, Viswanathan

    2015-01-01

    Paxillin is phosphorylated at multiple residues; however, the role of tyrosine phosphorylation of paxillin in endothelial barrier dysfunction and acute lung injury (ALI) remains unclear. We used siRNA and site-specific nonphosphorylable mutants of paxillin to abrogate the function of paxillin to determine its role in lung endothelial permeability and ALI. In vitro, lipopolysaccharide (LPS) challenge of human lung microvascular endothelial cells (HLMVECs) resulted in enhanced tyrosine phosphorylation of paxillin at Y31 and Y118 with no significant change in Y181 and significant barrier dysfunction. Knockdown of paxillin with siRNA attenuated LPS-induced endothelial barrier dysfunction and destabilization of VE-cadherin. LPS-induced paxillin phosphorylation at Y31 and Y118 was mediated by c-Abl tyrosine kinase, but not by Src and focal adhesion kinase. c-Abl siRNA significantly reduced LPS-induced endothelial barrier dysfunction. Transfection of HLMVECs with paxillin Y31F, Y118F, and Y31/118F double mutants mitigated LPS-induced barrier dysfunction and VE-cadherin destabilization. In vivo, the c-Abl inhibitor AG957 attenuated LPS-induced pulmonary permeability in mice. Together, these results suggest that c-Abl mediated tyrosine phosphorylation of paxillin at Y31 and Y118 regulates LPS-mediated pulmonary vascular permeability and injury. PMID:25795725

  20. Endothelial and non-endothelial coronary blood flow reserve and left ventricular dysfunction in systemic hypertension

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    Aloísio Marchi Rocha

    2009-04-01

    Full Text Available OBJECTIVES: We evaluated the impairment of endothelium-dependent and endothelium-independent coronary blood flow reserve after administration of intracoronary acetylcholine and adenosine, and its association with hypertensive cardiac disease. INTRODUCTION: Coronary blood flow reserve reduction has been proposed as a mechanism for the progression of compensated left ventricular hypertrophy to ventricular dysfunction. METHODS: Eighteen hypertensive patients with normal epicardial coronary arteries on angiography were divided into two groups according to left ventricular fractional shortening (FS. Group 1 (FS >0.25: n=8, FS=0.29 ± 0.03; Group 2 (FS <0.25: n=10, FS= 0.17 ± 0.03. RESULTS: Baseline coronary blood flow was similar in both groups (Group 1: 80.15 ± 26.41 mL/min, Group 2: 100.09 ± 21.51 mL/min, p=NS. In response to adenosine, coronary blood flow increased to 265.1 ± 100.2 mL/min in Group 1 and to 300.8 ± 113.6 mL/min (p <0.05 in Group 2. Endothelium-independent coronary blood flow reserve was similar in both groups (Group 1: 3.31 ± 0.68 and Group 2: 2.97 ± 0.80, p=NS. In response to acetylcholine, coronary blood flow increased to 156.08 ± 36.79 mL/min in Group 1 and to 177.8 ± 83.6 mL/min in Group 2 (p <0.05. Endothelium-dependent coronary blood flow reserve was similar in the two groups (Group 1: 2.08 ± 0.74 and group Group 2: 1.76 ± 0.61, p=NS. Peak acetylcholine/peak adenosine coronary blood flow response (Group 1: 0.65 ± 0.27 and Group 2: 0.60 ± 0.17 and minimal coronary vascular resistance (Group 1: 0.48 ± 0.21 mmHg/mL/min and Group 2: 0.34 ± 0.12 mmHg/mL/min were similar in both groups (p= NS. Casual diastolic blood pressure and end-systolic left ventricular stress were independently associated with FS. CONCLUSIONS: In our hypertensive patients, endothelium-dependent and endothelium-independent coronary blood flow reserve vasodilator administrations had similar effects in patients with either normal or decreased left

  1. Magnetic ferroferric oxide nanoparticles induce vascular endothelial cell dysfunction and inflammation by disturbing autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Lu, E-mail: chaperones@163.com [College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001 (China); Wang, XueQin; Miao, YiMing; Chen, ZhiQiang; Qiang, PengFei; Cui, LiuQing; Jing, Hongjuan [College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001 (China); Guo, YuQi [Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052 (China)

    2016-03-05

    Highlights: • B-Fe{sub 3}O{sub 4}NPs did not induce cell apoptosis or necrosis in HUVECs within 24 h. • B-Fe{sub 3}O{sub 4}NPs induced HUVEC dysfunction and inflammation. • B-Fe{sub 3}O{sub 4}NPs induced enhanced autophagic activity and blockade of autophagy flux. • Suppression of autophagy dysfunction attenuated B-Fe{sub 3}O{sub 4}NP-induced HUVEC dysfunction. - Abstract: Despite the considerable use of magnetic ferroferric oxide nanoparticles (Fe{sub 3}O{sub 4}NPs) worldwide, their safety is still an important topic of debate. In the present study, we detected the toxicity and biological behavior of bare-Fe{sub 3}O{sub 4}NPs (B-Fe{sub 3}O{sub 4}NPs) on human umbilical vascular endothelial cells (HUVECs). Our results showed that B-Fe{sub 3}O{sub 4}NPs did not induce cell death within 24 h even at concentrations up to 400 μg/ml. The level of nitric oxide (NO) and the activity of endothelial NO synthase (eNOS) were decreased after exposure to B-Fe{sub 3}O{sub 4}NPs, whereas the levels of proinflammatory cytokines were elevated. Importantly, B-Fe{sub 3}O{sub 4}NPs increased the accumulation of autophagosomes and LC3-II in HUVECs through both autophagy induction and the blockade of autophagy flux. The levels of Beclin 1 and VPS34, but not phosphorylated mTOR, were increased in the B-Fe{sub 3}O{sub 4}NP-treated HUVECs. Suppression of autophagy induction or stimulation of autophagy flux, at least partially, attenuated the B-Fe{sub 3}O{sub 4}NP-induced HUVEC dysfunction. Additionally, enhanced autophagic activity might be linked to the B-Fe{sub 3}O{sub 4}NP-induced production of proinflammatory cytokines. Taken together, these results demonstrated that B-Fe{sub 3}O{sub 4}NPs disturb the process of autophagy in HUVECs, and eventually lead to endothelial dysfunction and inflammation.

  2. Effect of Lower Extremity Bypass Surgery on Inflammatory Reaction and Endothelial Dysfunction in Type 2 Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Pei-Hsuan Tsai

    2009-01-01

    Full Text Available Diabetes mellitus (DM is a metabolic disorder characterized by hyperglycemia and dyslipidemia. The abnormalities in nutrient metabolism and elevated inflammatory mediators resulting from DM lead to impairment of wound healing and vulnerability to infection and foot ulcers. Diabetic lower limb ischemia often leads to limb necrosis. Lower extremity bypass surgery (LEBS is indicated to prevent limb loss in patients with critical leg ischemia. This study investigated the alteration of inflammatory and endothelium dysfunction markers before and after LEBS in DM patients. Twenty one type 2 DM patients with LEBS were included. Blood was drawn before and at 1 day and 7 days after surgery in the patients. Plasma soluble cellular adhesion molecule levels and blood leukocyte integrin expressions were measured. Also, plasma concentrations of endothelin-1 and nitric oxide were analyzed to evaluate the vascular endothelial function. The results showed that there were no significant differences in plasma cellular adhesion molecules, endothelin-1 and nitric oxide levels, nor did any differences in leukocyte integrin expressions before and after the operation. These results suggest that the efficacy of LEBS on alleviating inflammatory reaction and improving endothelial function in DM patients was not obvious.

  3. CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CHRONIC COR PULMONALE BY ANGIOTENSIN II RECEPTORS ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    V. S. Zadionchenko

    2007-01-01

    Full Text Available Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II – candesartan (Atacand and losartan (Cosaar in patients with chronic cor pulmonale (CCP at different stages of disease.Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD, complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients – candesartan 4-8 mg daily, 20 patients – losartan 50-100 mg daily, 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI.Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p<0.01 for both groups. In the control group only 13.2% of von Willebrand factor reduction was seen.Conclusion. ARA II added to common therapy of COPD complicated by CCP improves functional state of endothelium restricting hyperproduction of nitric oxide and its toxic effects and slowing down apoptotic cell death.

  4. CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CHRONIC COR PULMONALE BY ANGIOTENSIN II RECEPTORS ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    V. S. Zadionchenko

    2015-12-01

    Full Text Available Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II – candesartan (Atacand and losartan (Cosaar in patients with chronic cor pulmonale (CCP at different stages of disease.Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD, complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients – candesartan 4-8 mg daily, 20 patients – losartan 50-100 mg daily, 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI.Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p<0.01 for both groups. In the control group only 13.2% of von Willebrand factor reduction was seen.Conclusion. ARA II added to common therapy of COPD complicated by CCP improves functional state of endothelium restricting hyperproduction of nitric oxide and its toxic effects and slowing down apoptotic cell death.

  5. Endothelial dysfunction and atherosclerosis in children with irreversible pulmonary hypertension due to congenital heart disease

    International Nuclear Information System (INIS)

    Çiftel, Murat; Şimşek, Ayse; Turan, Özlem; Kardelen, Firat; Akçurin, Gayaz; Ertuğ, Halil

    2012-01-01

    To assess endothelial dysfunction and the risk for coronary atherosclerosis in children with irreversible pulmonary hypertension due to congenital heart disease (CHD). The study included 18 cyanotic patients (the mean age was 12.28 ± 3.26 years) who developed irreversible pulmonary hypertension due to cyanotic and acyanotic CHDs, and 18 control patients (the mean age was 11.78 ± 3.00 years). Study groups were compared for flow-mediated dilatation (FMD), carotid intima media thickness (CIMT) and atherosclerotic risk factors. Compared to the control group, the mean FMD was significantly reduced in the cyanotic group (5.26 ± 2.42% and 9.48 ± 2.60%, respectively; P-value < 0.001). No significant difference was observed between the groups in CIMT (0.41 ± 0.08 mm and 0.39 ± 0.06 mm, respectively; P-value = 0.299). The levels of total cholesterol, low-density lipoprotein–cholesterol and very low-density lipoprotein–cholesterol were statistically significantly lower compared tothe control group (P-value = 0.001, 0.006 and 0.014, respectively), whereas no statistically significant difference was found in the levels of high-density lipoprotein–cholesterol and triglycerides (P-value = 0.113 and 0.975, respectively). Systemic endothelial dysfunction in children with irreversible pulmonary hypertension due to CHD was noted but there was no increased risk for atherosclerosis

  6. Cardioprotective effects of red wine and vodka in a model of endothelial dysfunction.

    Science.gov (United States)

    Lassaletta, Antonio D; Chu, Louis M; Elmadhun, Nassrene Y; Burgess, Thomas A; Feng, Jun; Robich, Michael P; Sellke, Frank W

    2012-12-01

    Moderate alcohol consumption is largely believed to be cardioprotective, while red wine is hypothesized to offer benefit in part due to the proangiogenic and antioxidant properties of polyphenols. We investigated the cardiovascular effects of both red wine and vodka in a swine model of endothelial dysfunction. Twenty-seven male Yorkshire swine fed a high-fat/cholesterol diet were divided into three groups and received either no alcohol (Control), red wine, or vodka. After 7 wk, myocardial perfusion was measured, and ventricular tissue was analyzed for microvascular reactivity and immunohistochemical studies. There were no differences in myocardial perfusion, in arteriolar or capillary density, or in VEGF expression among groups. Total protein oxidation as well as expression of superoxide dismutase-1 and -2 and NADPH oxidase was decreased in both treatment groups compared to controls. Endothelium-dependent microvessel relaxation, however, was significantly improved only in the red wine-supplemented group. Supplementation with both red wine and vodka decreased oxidative stress by several measures, implicating the effects of ethanol in reducing oxidative stress in the myocardium. However, it was only in the red wine-supplemented group that an improvement in microvessel function was observed. This suggests that a component of red wine, independent of ethanol, possibly a polyphenol such as resveratrol, may confer cardioprotection by normalizing endothelial dysfunction induced by an atherogenic diet. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Vascular Kinin B1 and B2 Receptors Determine Endothelial Dysfunction through Neuronal Nitric Oxide Synthase

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    Luciano Dos Santos A. Capettini

    2017-04-01

    Full Text Available B1- and B2-kinin receptors are G protein-coupled receptors that play an important role in the vascular function. Therefore, the present study was designed to evaluate the participation of kinin receptors in the acetylcholine (ACh-induced vascular relaxation, focusing on the protein-protein interaction involving kinin receptors with endothelial and neuronal nitric oxide synthases (eNOS and nNOS. Vascular reactivity, nitric oxide (NO· and reactive oxygen species (ROS generation, co-immunoprecipitation were assessed in thoracic aorta from male wild-type (WT, B1- (B1R−/−, B2- (B2R−/− knockout mice. Some vascular reactivity experiments were also performed in a double kinin receptors knockout mice (B1B2R−/−. For pharmacological studies, selective B1- and B2-kinin receptors antagonists, NOS inhibitors and superoxide dismutase (SOD mimetic were used. First, we show that B1- and B2-kinin receptors form heteromers with nNOS and eNOS in thoracic aorta. To investigate the functionality of these protein-protein interactions, we took advantage of pharmacological tools and knockout mice. Importantly, our results show that kinin receptors regulate ACh-induced relaxation via nNOS signaling in thoracic aorta with no changes in NO· donor-induced relaxation. Interestingly, B1B2R−/− presented similar level of vascular dysfunction as found in B1R−/− or B2R−/− mice. In accordance, aortic rings from B1R−/− or B2R−/− mice exhibit decreased NO· bioavailability and increased superoxide generation compared to WT mice, suggesting the involvement of excessive ROS generation in the endothelial dysfunction of B1R−/− and B2R−/− mice. Alongside, we show that impaired endothelial vasorelaxation induced by ACh in B1R−/− or B2R−/− mice was rescued by the SOD mimetic compound. Taken together, our findings show that B1- and B2-kinin receptors regulate the endothelium-dependent vasodilation of ACh through nNOS activity and indicate

  8. The Effects of Stress at Work and at Home on Inflammation and Endothelial Dysfunction

    Science.gov (United States)

    Non, Amy L.; Rimm, Eric B.; Kawachi, Ichiro; Rewak, Marissa A.; Kubzansky, Laura D.

    2014-01-01

    This study examined whether stress at work and at home may be related to dysregulation of inflammation and endothelial function, two important contributors to the development of cardiovascular disease. In order to explore potential biological mechanisms linking stress with cardiovascular health, we investigated cross-sectional associations between stress at work and at home with an inflammation score (n's range from 406–433) and with two endothelial biomarkers (intercellular and vascular adhesion molecules, sICAM-1 and sVCAM-1; n's range from 205–235) in a cohort of healthy US male health professionals. No associations were found between stress at work or at home and inflammation. Men with high or medium levels of stress at work had significantly higher levels of sVCAM-1 (13% increase) and marginally higher levels of sICAM-1 (9% increase), relative to those reporting low stress at work, independent of health behaviors. Men with high levels of stress at home had marginally higher levels of both sVCAM-1 and sICAM-1 than those with low stress at home. While lack of findings related to inflammation are somewhat surprising, if replicated in future studies, these findings may suggest that endothelial dysfunction is an important biological mechanism linking stress at work with cardiovascular health outcomes in men. PMID:24722508

  9. Does endothelial dysfunction correlate with endocrinal abnormalities in patients with polycystic ovary syndrome?

    Science.gov (United States)

    Dube, Rajani

    2016-01-01

    To study and critically analyze the published evidence on correlation of hormonal abnormalities and endothelial dysfunction (ED) in polycystic ovary syndrome (PCOS) through a systematic review. The databases including MEDLINE, PubMed, Up-To-Date, and Science Direct were searched using Medical subject handling terms and free text term keywords such as endocrine abnormalities in PCOS, ED assessment in PCOS, ED in combination with insulin resistance (IR), hyperandrogenism (HA), increased free testosterone, free androgen index (FAI), gonadotrophin levels, luteinizing hormone (LH), prolactin, estrogen, adipocytokines to search trials, and observational studies published from January 1987 to September 2015. Authors of original studies were contacted for additional data when necessary. PCOS increases the risk of cardiovascular disease in women. ED, which is a reliable indicator of cardiovascular risk in general population, is seen in most (but not all) women with PCOS. IR, seen in 70% patients with PCOS, is associated with ED in these women, but patients can have normal endothelial function even in the presence of IR. Free testosterone and FAI are consistently associated with ED, but endothelial function can be normal despite HA. Estradiol (not estrone) appears to be protective against ED though estrone is the predominant estrogen produced in PCOS. Increased levels of adipocytokines (visfatin) are promising in predicting ED and cardiovascular risk. However, more studies are required focusing on direct correlation of levels of prolactin, LH, estrone, and visfatin with ED in PCOS. PMID:27843797

  10. Two weeks taurine supplementation reverses endothelial dysfunction in young male type 1 diabetics.

    LENUS (Irish Health Repository)

    Moloney, Michael A

    2010-10-01

    Type 1 diabetics have a well-recognised risk of accelerated cardiovascular disease. Even in the absence of clinical signs there are detectable abnormalities of conduit vessel function. Our group has previously reported reversal of endothelial dysfunction in diabetics with pravastatin. In young asymptomatic smokers, taurine supplementation has a beneficial impact on macrovascular function, assessed by FMD, and shows an up-regulation of nitric oxide from monocyte-endothelial cell interactions. We hypothesise that taurine supplementation reverses early endothelial abnormalities in young male type 1 diabetics, as assessed by applanation tonometry, brachial artery ultrasound and laser Doppler fluximetry. Asymptomatic, male diabetics (n=9) were scanned prior to treatment and then randomised in a double-blind cross-over fashion to receive either 2 weeks placebo or taurine. Control patients (n=10) underwent a baseline scan. Assessed diabetics had detectable, statistically significant abnormalities when compared with controls, in both arterial stiffness (augmentation index) and brachial artery reactivity (FMD). Both of these parameters were returned to control levels with 2 weeks taurine supplementation. In conclusion, 2 weeks taurine supplementation reverses early, detectable conduit vessel abnormalities in young male diabetics. This may have important implications in the long-term treatment of diabetic patients and their subsequent progression towards atherosclerotic disease.

  11. Effect of cholecalciferol on local arterial stiffness and endothelial dysfunction in children with chronic kidney disease.

    Science.gov (United States)

    Aytaç, Mehmet Baha; Deveci, Murat; Bek, Kenan; Kayabey, Özlem; Ekinci, Zelal

    2016-02-01

    As cardiovascular factors are the leading cause of mortality in chronic kidney disease (CKD) and as vitamin D deficiency is prevalent in this population, we aimed to examine the effect of oral cholecalciferol on cardiac parameters and biomarkers for endothelial cell activation in children with CKD. Forty-one children with CKD and 24 healthy subjects free of any underlying cardiac or renal disease with low 25-hydroxyvitamin D3 (25OHD) levels were evaluated using echocardiography basally and following Stoss vitamin D supplementation. The local vascular stiffness and endothelial dysfunction markers were compared among the groups. Initial flow-mediated dilatation (FMD) measurements were lower and local arterial stiffness was significantly higher in patients. After vitamin D supplementation, these improved significantly in patients, while no significant change was observed for the healthy group. Homocysteine showed inverse correlation with baseline vitamin D level in CKD children and von Willebrand factor emerged as an independent risk factor for FMD impairment. Our interventional study revealed the favorable effects of high-dose cholecalciferol on cardiovascular and endothelial parameters, implying the importance of vitamin D supplementation in children with CKD.

  12. Effect of AST-120 on Endothelial Dysfunction in Adenine-Induced Uremic Rats

    Directory of Open Access Journals (Sweden)

    Yuko Inami

    2014-01-01

    Full Text Available Aim. Chronic kidney disease (CKD represents endothelial dysfunction. Monocyte adhesion is recognized as the initial step of arteriosclerosis. Indoxyl sulfate (IS is considered to be a risk factor for arteriosclerosis in CKD. Oral adsorbent AST-120 retards deterioration of renal function, reducing accumulation of IS. In the present study, we determined the monocyte adhesion in the adenine-induced uremic rats in vivo and effects of AST-120 on the adhesion molecules. Methods. Twenty-four rats were divided into control, control+AST-120, adenine, and adenine+AST-120 groups. The number of monocytes adherent to the endothelium of thoracic aorta by imaging the entire endothelial surface and the mRNA expressions of adhesion and atherosclerosis-related molecules were examined on day 49. The mRNA expressions of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells were also examined. Results. Adenine increased the number of adherent monocytes, and AST-120 suppressed the increase. The monocyte adhesion was related to serum creatinine and IS in sera. Overexpression of VCAM-1 and TGF-β1 mRNA in the arterial walls was observed in uremic rats. IS induced increase of the ICAM-1 and VCAM-1 mRNA expressions in vitro. Conclusion. It appears that uremic condition introduces the monocyte adhesion to arterial wall and AST-120 might inhibit increasing of the monocyte adherence with CKD progression.

  13. Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

    Science.gov (United States)

    Patt, Brian T.; Jarjoura, David; Haddad, Diane N.; Sen, Chandan K.; Roy, Sashwati; Flavahan, Nicholas A.; Khayat, Rami N.

    2010-01-01

    Rationale: Obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease. We hypothesized that patients with OSA and no cardiovascular disease have oxidant-related microcirculatory endothelial dysfunction. Objectives: To evaluate the microcirculation in OSA. Methods: This study included seven patients with OSA and seven age- and weight-matched control subjects (mean age, 38 yr; mean body mass index, 32.5 kg/m2). All participants were free of cardiovascular risk factors. Participants received measurement of brachial artery flow-mediated dilation and forearm subcutaneous biopsy. Patients underwent repeated tests 12 weeks after treatment. Microcirculatory endothelial cells were isolated, and immunohistochemistry staining for peroxynitrite in the microcirculation was performed. Measurements and Main Results: Flow-mediated dilation was lower in patients than in control subjects at baseline (mean ± SEM: 5.7 ± 0.5 vs. 9.5 ± 0.6; P = 0.02) and increased after treatment (5.7–7.3; change, 1.7 ± 0.6; P = 0.04). Microcirculatory peroxynitrite deposit was higher in patients compared with control subjects (44.0 ± 1.6 vs. 21.8 ± 1.9 stain density units; P 4.0 to 30.5 stain density units (change, −13.5 ± 2.9; P = 0.009). In patients, transcription of endothelial nitric oxide synthase decreased from 5.2 to −1.3 after treatment (change, 6.5 ± 2.5; P = 0.05), and transcription of superoxide dismutase1 decreased from −4.0 to −12.3 after treatment (change, −8.3 ± 2.1; P = 0.01). These changes persisted after adjustment for weight and underlying severity of OSA. Conclusions: This is the first direct evaluation of the microcirculation in OSA. Patients with OSA with low cardiovascular risk status had increased oxidant production in the microcirculation and endothelial dysfunction, both of which improved with treatment. Endothelial nitric oxide synthase transcription decreased with treatment. PMID:20656942

  14. Impairment of IKCa channels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy.

    Science.gov (United States)

    Gokina, Natalia I; Bonev, Adrian D; Phillips, Julie; Gokin, Alexander P; Veilleux, Kelsey; Oppenheimer, Karen; Goloman, Gabriela

    2015-08-15

    Diabetes in rat pregnancy is associated with impaired vasodilation of the maternal uteroplacental vasculature. In the present study, we explored the role of endothelial cell (EC) Ca(2+)-activated K(+) channels of small conductance (SKCa channels) and intermediate conductance (IKCa channels) in diabetes-induced uterine vascular dysfunction. Diabetes was induced by injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with citrate buffer. Changes in smooth muscle cell intracellular Ca(2+) concentration, membrane potential, and vasodilation induced by SKCa/IKCa channel activators were studied in uteroplacental arteries of control and diabetic rats. The impact of diabetes on SKCa- and IKCa-mediated currents was explored in freshly dissociated ECs. NS309 evoked a potent vasodilation that was effectively inhibited by TRAM-34 but not by apamin. NS309-induced smooth muscle cell intracellular Ca(2+) concentration, membrane potential, and dilator responses were significantly diminished by diabetes; N-cyclohexyl-N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine (CyPPA)-evoked responses were not affected. Ca(2+)-activated ion currents in ECs were insensitive to paxilline, markedly inhibited by charybdotoxin (ChTX), and diminished by apamin. NS309-induced EC currents were generated mostly due to activation of ChTX-sensitive channels. Maternal diabetes resulted in a significant reduction in ChTX-sensitive currents with no effect on apamin-sensitive or CyPPA-induced currents. We concluded that IKCa channels play a prevalent role over SKCa channels in the generation of endothelial K(+) currents and vasodilation of uteroplacental arteries. Impaired function of IKCa channels importantly contributes to diabetes-induced uterine endothelial dysfunction. Therapeutic restoration of IKCa channel function may be a novel strategy for improvement of maternal uteroplacental blood flow in

  15. Endothelial cells in dengue hemorrhagic fever.

    Science.gov (United States)

    Srikiatkhachorn, Anon; Kelley, James F

    2014-09-01

    Therapies to prevent or reverse endothelial dysfunction and vascular leak found in dengue hemorrhagic fever (DHF) have not been identified. In this review we summarize dengue viruses and the spectrum of human disease and highlight evidence of endothelial cell dysfunction in DHF based on studies in patients and mouse and tissue culture models. Evidence suggests that both virus antigen and host immune response, can cause endothelial cell dysfunction and weaken endothelial barrier integrity. We suggest possible therapeutic interventions and highlight how therapies targeting altered endothelial function might be evaluated in animal models and in patients with DHF. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Vascular insulin response is preserved in non-diabetic patients with coronary artery disease, despite endothelial dysfunction

    DEFF Research Database (Denmark)

    Ihlemann, Nikolaj; Rask-Madsen, Christian; Køber, Lars

    2004-01-01

    BACKGROUND--Patients with coronary artery disease (CAD) are often insulin resistant, a state that predisposes to increased atherosclerosis. Recently, it was suggested that a "vascular insulin resistance" could explain this association, causing endothelial dysfunction and hence atherosclerosis. We...... nitroprusside (SNP) elicited endothelium-dependent and -independent vasodilation and were repeated during intra-arterial insulin infusion. RESULTS--Patients were insulin resistant as determined by HOMA index. Insulin infusion resulted in high physiological levels of insulin in the forearm without systemic...... response is intact in non-diabetic CAD patients in spite of insulin resistance and endothelial dysfunction....

  17. Analysis of Ghrelin and Asymmetric Dimethylarginine (ADMA as Endothelial Dysfunction Marker Among Obese Men

    Directory of Open Access Journals (Sweden)

    Lia Meliani

    2012-08-01

    Full Text Available BACKGROUND: Ghrelin has many biological activities such as regulating energy homeostasis and recent studies have shown its effects in the cardiovascular system. Ghrelin concentration decreases in obese man that indicates relatioship between ghrelin and energy homeostasis. Ghrelin also improves endothelial function by increasing the bioavaibility of nitric oxide (NO. The bioavaibility of NO is also influenced by ADMA. ADMA is an endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS, which is significantly elevated during endothelial dysfuction. This study aimed to evaluate the relationship of ADMA and ghrelin with central obesity based on waist circumference and to evaluate the relationship of total ghrelin and ADMA in centrally obese men. METHODS: Total ghrelin and ADMA were measured in 20 non-obese men (waist circumference (WC 78.85±4.40 cm and 60 centrally obese men (WC 97.54±5.94 cm. Anthropometric measurements (height, weight, BM, waist circumference and blood pressure were also recorded. Statistic were carried out by the Spearman and Pearson bivariate correlation analysis and independent sample T test. RESULTS: ADMA concentrations were significantly higher in centrally obese men than in normal weight controls (p-value 0.05. Ghrelin total concentrations were significantly lower in centrally obese men with metabolic syndrome than in normal weight controls (p-value <0.05. No significant correlation existed between total ghrelin and ADMA. CONCLUSIONS: No correlation existed between ADMA and total ghrelin. The pathway of ghrelin in altering vascular function may not involve ADMA. KEYWORDS: ghrelin, ADMA, endothelial dysfunction, obese.

  18. Perirenal Fat Promotes Renal Arterial Endothelial Dysfunction in Obese Swine through Tumor Necrosis Factor-α.

    Science.gov (United States)

    Ma, Shuangtao; Zhu, Xiang-Yang; Eirin, Alfonso; Woollard, John R; Jordan, Kyra L; Tang, Hui; Lerman, Amir; Lerman, Lilach O

    2016-04-01

    Perirenal fat is associated with poor blood pressure control and chronic kidney disease but the underlying mechanisms remain elusive. We tested the hypothesis that perirenal fat impairs renal arterial endothelial function in pigs with obesity-metabolic derangements. We studied 14 domestic pigs after 16 weeks of a high fat/high fructose diet (obesity-metabolic derangement group) or standard chow (lean group). Renal blood flow, glomerular filtration rate and visceral fat volumes were studied in vivo by computerized tomography. Renal arterial endothelial function was also studied ex vivo in organ baths. Pigs with obesity-metabolic derangements demonstrated increased body weight, blood pressure, cholesterol and intra-abdominal fat compared to lean pigs and perirenal fat volume was significantly larger. Renal blood flow and glomerular filtration rate were markedly elevated while urinary protein level was preserved. Ex vivo acetylcholine induced, endothelium dependent vasodilation of renal artery rings was substantially impaired in pigs with obesity-metabolic derangements compared to lean pigs. Endothelial function was further blunted in obesity-metabolic derangement and lean arterial rings by incubation with perirenal fat harvested from pigs with obesity-metabolic derangements but not from lean pigs. It was restored by inhibiting tumor necrosis factor-α. Perirenal fat from pigs with obesity-metabolic derangements also showed increased pro-inflammatory macrophage infiltration and tumor necrosis factor-α expression. In pigs with obesity-metabolic derangements perirenal fat directly causes renal artery endothelial dysfunction, which is partly mediated by tumor necrosis factor-α. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  19. Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction

    Science.gov (United States)

    Weiss, Norbert; Zhang, Ying-Yi; Heydrick, Stanley; Bierl, Charlene; Loscalzo, Joseph

    2001-01-01

    Homocyst(e)ine (Hcy) inhibits the expression of the antioxidant enzyme cellular glutathione peroxidase (GPx-1) in vitro and in vivo, which can lead to an increase in reactive oxygen species that inactivate NO and promote endothelial dysfunction. In this study, we tested the hypothesis that overexpression of GPx-1 can restore the normal endothelial phenotype in hyperhomocyst(e)inemic states. Heterozygous cystathionine β-synthase-deficient (CBS(−/+)) mice and their wild-type littermates (CBS(+/+)) were crossbred with mice that overexpress GPx-1 [GPx-1(tg+) mice]. GPx-1 activity was 28% lower in CBS(−/+)/GPx-1(tg−) compared with CBS(+/+)/GPx-1(tg−) mice (P < 0.05), and CBS(−/+) and CBS(+/+) mice overexpressing GPx-1 had 1.5-fold higher GPx-1 activity compared with GPx-1 nontransgenic mice (P < 0.05). Mesenteric arterioles of CBS(−/+)/GPx-1(tg−) mice showed vasoconstriction to superfusion with β-methacholine and bradykinin (P < 0.001 vs. all other groups), whereas nonhyperhomocyst(e)inemic mice [CBS(+/+)/GPx-1(tg−) and CBS(+/+)/GPx-1(tg+) mice] demonstrated dose-dependent vasodilation in response to both agonists. Overexpression of GPx-1 in hyperhomocyst(e)inemic mice restored the normal endothelium-dependent vasodilator response. Bovine aortic endothelial cells (BAEC) were transiently transfected with GPx-1 and incubated with dl-homocysteine (HcyH) or l-cysteine. HcyH incubation decreased GPx-1 activity in sham-transfected BAEC (P < 0.005) but not in GPx-1-transfected cells. Nitric oxide release from BAEC was significantly decreased by HcyH but not cysteine, and GPx-1 overexpression attenuated this decrease. These findings demonstrate that overexpression of GPx-1 can compensate for the adverse effects of Hcy on endothelial function and suggest that the adverse vascular effects of Hcy are at least partly mediated by oxidative inactivation of NO. PMID:11606774

  20. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

    2013-11-15

    Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential

  1. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

    International Nuclear Information System (INIS)

    Sharma, Bhupesh; Sharma, P.M.

    2013-01-01

    Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in

  2. Deletion of T-type calcium channels Cav3.1 or Cav3.2 attenuates endothelial dysfunction in aging mice

    DEFF Research Database (Denmark)

    Thuesen, Anne D; Andersen, Kenneth; Lyngsø, Kristina S

    2018-01-01

    Impairment of endothelial function with aging is accompanied by reduced nitric oxide (NO) production. T-type Cav3.1 channels augment nitric oxide and co-localize with eNOS. Therefore, the hypothesis was that T-type channels contribute to the endothelial dysfunction of aging. Endothelial function ...

  3. Periodontitis is associated with endothelial dysfunction in a general population: a cross-sectional study.

    Directory of Open Access Journals (Sweden)

    Birte Holtfreter

    Full Text Available A large body of evidence underlines an association between periodontal disease and cardiovascular disease. In contrast, data on its relation with endothelial dysfunction as a marker of early subclinical atherosclerosis is inconclusive and limited to patient-cohort studies. We therefore investigated the association between periodontal disease and flow-mediated dilation of the brachial artery (FMD as a measure of endothelial dysfunction in a general population, and also addressed a possible mediation via inflammation. The study population comprised 1,234 subjects (50.5% men aged 25-85 years from the 5-year follow-up of the Study of Health in Pomerania, a population-based cohort study. Clinical attachment loss (CAL and pocket probing depth (PPD as measures of periodontal disease were assessed half-mouth at four sites per tooth. Subjects were classified according to the periodontitis case definition proposed by Tonetti and Claffey (2005. Measurements of FMD and nitroglycerin-mediated dilation (NMD were performed using standardized ultrasound techniques. High-sensitive C-reactive protein, fibrinogen and leukocyte count were measured. Fully adjusted multivariate linear regression analyses revealed significant associations of the percentage of sites with PPD ≥ 6 mm with FMD (p(trend=0.048, with subjects within the highest category having a 0.74% higher FMD compared to subjects within the lowest category (p<0.05. Consistently, FMD values increased significantly across categories of the percentage of sites with CAL ≥ 6 mm (p(trend=0.01 and the periodontitis case definition (p(trend=0.006. Restrictions to subjects without antihypertensive or statin medication or current non-smokers confirmed previous results. Systemic inflammation did not seem to mediate the relation. Both PPD and CAL were not consistently associated with NMD. In contrast to previous studies, high levels of periodontal disease were significantly associated with high FMD values. This

  4. Effects of spinach nitrate on insulin resistance, endothelial dysfunction markers and inflammation in mice with high-fat and high-fructose consumption

    Directory of Open Access Journals (Sweden)

    Ting Li

    2016-09-01

    Full Text Available Background: Insulin resistance, which is associated with an increased risk of cardiovascular morbidity and mortality, has become a leading nutrition problem. Inorganic nitrate enriched in spinach has been demonstrated to reverse the pathological features of insulin resistance and endothelial dysfunction. However, the effects of a direct intake of nitrate-enriched spinach on insulin resistance and endothelial dysfunction have not been studied. Objective: To investigate the effects of spinach nitrate on insulin resistance, lipid metabolism, endothelial function, and inflammation in mice fed with a high-fat and high-fructose diet. Design: A diet intervention of spinach with or without nitrate was performed in mice. A high-fat and high-fructose diet was used to cause insulin resistance, endothelial dysfunction, and inflammation in mice. The impacts of spinach nitrate on lipid profile, insulin resistance, markers of endothelial function, and inflammation were determined in mice. Results: Spinach nitrate improved the vascular endothelial function of the mice with high-fat and high-fructose consumption, as evidenced by the elevated plasma nitrite level, increased serum nitric oxide (NO level and decreased serum ET-1 level after spinach nitrate intervention. Spinach nitrate also reduced serum triglycerides, total cholesterol, and low-density lipoprotein-cholesterol levels and elevated serum high-density lipoprotein-cholesterol levels in the mice fed with a high-fat and high-fructose diet. Mice receiving spinach with 60 mg/kg of nitrate (1.02±0.34 showed a significantly low homeostasis model assessment-insulin resistance index as compared with the model mice (2.05±0.58, which is indicating that spinach nitrate could effectively improve the insulin resistance. In addition, spinach nitrate remarkably decreased the elevated serum C-reactive protein, tumor necrosis factor α, and interleukin-6 levels induced by a high-fat and high-fructose diet

  5. l-arginine and l-NMMA for assessing cerebral endothelial dysfunction in ischaemic cerebrovascular disease

    DEFF Research Database (Denmark)

    Karlsson, William K; Sørensen, Caspar G; Kruuse, Christina

    2017-01-01

    Endothelial dysfunction (ED), in particular cerebral ED, may be an essential biomarker for ischaemic cerebrovascular disease. However, there is no consensus on methods to best estimate cerebral ED. In this systematic review, we evaluate the use of l-arginine and NG -monomethyl-l-arginine (l......-NMMA) for assessment of cerebral ED. A systematic search of PubMed, EMBASE and the Cochrane Library was done. We included studies investigating cerebrovascular response to l-arginine or l-NMMA in human subjects with vascular risk factors or ischaemic cerebrovascular disease. Seven studies (315 subjects) were eligible...... according to inclusion and exclusion criteria. Studies investigated the effect of age (n=2), type 2 diabetes mellitus (DM) (n=1), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (n=1), leukoaraiosis (n=1), and prior ischaemic stroke or transient ischaemic...

  6. Gut hormones and endothelial dysfunction in patients with obesity and diabetes.

    Science.gov (United States)

    Iantorno, M; Campia, U; Di Daniele, N; Nistico, S; Forleo, G B; Cardillo, C; Tesauro, M

    2014-01-01

    Overweight and obesity are the fifth leading risk for global deaths and its prevalence has doubled since 1980. At least 2.8 million adults, worldwide, die each year as a result of being overweight or obese. The deleterious effects of obesity are tightly related to diabetes, as they are often clinically present in combination to confer increased cardiovascular mortality. Thus, patients with diabetes and obesity are known to develop accelerated atherosclerosis characterized by a dysfunctional endothelium and decreased nitric oxide bioavailability. Recent clinical studies support, indeed, the use of incretin-based antidiabetic therapies for vascular protection. Thus, attention has been focusing on gut hormones and their role, not only in the regulation of appetite but also in vascular health. Intervention directed at modulating these molecules has the potential to decrease mortality of patients with diabetes and obesity. This review will cover part of the ongoing research to understand the role of gut hormones on endothelial function and vascular health.

  7. High density lipoproteins as indicators of endothelial dysfunction in children with diadetes type I

    Directory of Open Access Journals (Sweden)

    Lobanova S.M.

    2011-12-01

    Full Text Available The aim of the investigation was to study the level of blood high density lipoproteins (HDL in the groups of children with different course of diadetes type I in order to find out the dependence of course and complications of diabetes on that level. Materials and methods: Blood high density lipoprotein (HDL levels were investigated in children and adolescents with diadetes type I, depending on the duration of diadetes type I, age, stage of sexual development, the stage of diabetic nephropathy and levels of plasma endothelin-1 (E-1. Results: Decrease in HDL level with increasing duration of diadetes type I in prepubertate patients, higher indices of HDL cholesterol were determined in girls, especially with impaired puberty. HDL cholesterol was higher in diabetic nephropathy at the stage of proteinuria and high level of blood endothelin-1. Conclusion: The revealed changes were considered to cause deregulation of vascular endothelium as a manifestation of the initial stages of endothelial dysfunction

  8. Role of endothelial dysfunction in the pathogenesis of diabetic retinopathy in patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    I. V. Vorobyeva

    2014-07-01

    Full Text Available The reason for the progressive vision reduction at diabetes mellitus (DM is diabetic retinopathy (DR. When type 2 diabetes combined with hypertension (Ht, it increases the risk of vision loss by 25 times. In the pathogenesis of DR is important to endothelial dysfunction and a variety of biochemical processes (an excess of intracellular sorbitol, non-enzymatic glycation of proteins, oxidative stress. there is a decrease in generation vasodilating factors, nitric oxide, with a simultaneous increase of endothelin, which causes vasoconstriction. Key processes underlying the development of DR, such as increased vascular permeability, edema, neovasculariza- tion, inflammation and associated with the effects of kallikrein-kinin system. In the pathogenesis of DR can be involved independent intraocular renin-angiotensin system, which is an important mediator of angiogenesis and increased vascular permeability. Damage to the endothelium of retinal vessels leads to ischemia of the retina. there is growth and development of newly formed blood vessels, which may provoke recurrent bleeding.

  9. Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction

    DEFF Research Database (Denmark)

    Saad, Mohamed I.; Abdelkhalek, Taha M.; Saleh, Moustafa M.

    2015-01-01

    Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected...... understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes...... to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully...

  10. Endothelial Dysfunction Plays a Key Role in Increasing Cardiovascular Risk in Type 2 Diabetes The Hoorn Study

    NARCIS (Netherlands)

    van Sloten, T.T.; Henry, R.M.A.; Dekker, J.M.; Nijpels, G.; Unger, T.; Schram, M.T.; Stehouwer, C.D.A.

    2014-01-01

    In the pathogenesis of cardiovascular events, interaction between risk factors has seldom been identified. However, endothelial dysfunction on the one hand and type 2 diabetes mellitus, impaired glucose metabolism (IGM), and insulin resistance on the other may act synergistically (ie, interact) in

  11. Extracellular but not cytosolic superoxide dismutase protects against oxidant-mediated endothelial dysfunction

    Directory of Open Access Journals (Sweden)

    Erin L. Foresman

    2013-01-01

    Full Text Available Superoxide (O2•− contributes to the development of cardiovascular disease. Generation of O2•− occurs in both the intracellular and extracellular compartments. We hypothesized that the gene transfer of cytosolic superoxide dismutase (SOD1 or extracellular SOD (SOD3 to blood vessels would differentially protect against O2•−-mediated endothelial-dependent dysfunction. Aortic ring segments from New Zealand rabbits were incubated with adenovirus (Ad containing the gene for Escherichia coli β-galactosidase, SOD1, or SOD3. Activity assays confirmed functional overexpression of both SOD3 and SOD1 isoforms in aorta 24 h following gene transfer. Histochemical staining for β-galactosidase showed gene transfer occurred in the endothelium and adventitia. Next, vessels were prepared for measurement of isometric tension in Kreb's buffer containing xanthine. After precontraction with phenylephrine, xanthine oxidase impaired relaxation to the endothelium-dependent dilator acetylcholine (ACh, max relaxation 33±4% with XO vs. 64±3% without XO, p<0.05, whereas relaxation to the endothelium-independent dilator sodium nitroprusside was unaffected. In the presence of XO, maximal relaxation to ACh was improved in vessels incubated with AdSOD3 (55±2%, p<0.05 vs. control but not AdSOD1 (34±4%. We conclude that adenoviral-mediated gene transfer of SOD3, but not SOD1, protects the aorta from xanthine/XO-mediated endothelial dysfunction. These data provide important insight into the location and enzymatic source of O2•− production in vascular disease.

  12. Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension.

    Science.gov (United States)

    Perros, Frédéric; Ranchoux, Benoît; Izikki, Mohamed; Bentebbal, Sana; Happé, Chris; Antigny, Fabrice; Jourdon, Philippe; Dorfmüller, Peter; Lecerf, Florence; Fadel, Elie; Simonneau, Gerald; Humbert, Marc; Bogaard, Harm Jan; Eddahibi, Saadia

    2015-02-24

    Endothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation. This study sought to test the hypothesis that nebivolol, a β1-antagonist and β2,3-agonist, may improve PAH and reverse the PAH-related phenotype of pulmonary ECs (P-EC). We compared the effects of nebivolol with metoprolol, a first-generation β1-selective β-blocker, on human cultured PAH and control P-EC proliferation, vasoactive and proinflammatory factor production, and crosstalk with PA smooth muscle cells. We assessed the effects of both β-blockers in precontracted PA rings. We also compared the effects of both β-blockers in experimental PAH. PAH P-ECs overexpressed the proinflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, fibroblast growth factor-2, and the potent vasoconstrictive agent endothelin-1 as compared with control cells. This pathological phenotype was corrected by nebivolol but not metoprolol in a dose-dependent fashion. We confirmed that PAH P-EC proliferate more than control cells and stimulate more PA smooth muscle cell mitosis, a growth abnormality that was normalized by nebivolol but not by metoprolol. Nebivolol but not metoprolol induced endothelium-dependent and nitric oxide-dependent relaxation of PA. Nebivolol was more potent than metoprolol in improving cardiac function, pulmonary vascular remodeling, and inflammation of rats with monocrotaline-induced pulmonary hypertension. Nebivolol could be a promising option for the management of PAH, improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function. Until clinical studies are undertaken, however, routine use of β-blockers in PAH cannot be recommended. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  13. Thrombomodulin as a New Marker of Endothelial Dysfunction in Chronic Kidney Disease in Children

    Directory of Open Access Journals (Sweden)

    Dorota Drożdż

    2018-01-01

    Full Text Available Endothelial dysfunction (ED and oxidative stress are potential new pathomechanisms of cardiovascular diseases in patients with chronic kidney disease (CKD. The aim of the study was to assess the association between endothelial dysfunction, oxidative stress biomarkers, and cardiovascular risk factors in children with CKD. Serum oxidized LDL (oxLDL, protein carbonyl group, urea, creatinine, cystatin C, thrombomodulin, asymmetric dimethylarginine (ADMA, von Willebrand factor, brain natriuretic peptide (BNP, lipids, high sensitivity C-reactive protein, intercellular adhesion molecule-1 levels, and albuminuria were measured. Anthropometric, ambulatory blood pressure (BP measurements and echocardiography were performed. The studied group consisted of 59 patients aged 0.7–18.6 (mean 11.1 years with stages 1 to 5 CKD. Thrombomodulin strongly correlated with creatinine (R=0.666; p<0.001, cystatin C (R=0.738; p<0.001, BNP (R=0.406; p=0.001, ADMA (R=0.353; p=0.01, oxLDL (R=0.340; p=0.009, 24-hour systolic (R=0.345; p=0.011 and mean (R=0.315; p<0.05 BP values, and left ventricular mass index (LVMI, R=0.293; p=0.024 and negatively with estimated glomerular filtration rate (R=−0.716; p<0.001. In children with CKD, TM strongly depended on kidney function parameters, oxLDL levels, and 24-hour systolic and mean BP values. Thrombomodulin seems to be a valuable marker of ED in CKD patients, correlating with CKD stage as well as oxidative stress, BP values, and LVMI.

  14. ENDOTHELIAL DYSFUNCTION IN STABLE ANGINA AND MYOCARDIAL INFARCTION COMBINED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    Directory of Open Access Journals (Sweden)

    M. A. Popova

    2015-01-01

    Full Text Available The research objective is to determine the state of endothelium-dependent and endothelium-independent vasodilatation in patients with coronary heart disease (CHD associated with chronic obstructive pulmonary disease (COPD.Material and methods. In the cross-sectional study included 122 patients with CHD associated with COPD: 68 people of them are patients with stable angina without acute coronary events in history and 54 patients with acute ST segment elevation myocardial infarction (STEMI. Comparison group comprised 53 patients with stable angina and 51 patients after STEMI without concomitant COPD. Patients were included if they met the following inclusion criteria: male, age <60 years, verified forms of CHD (stable angina, STEMI, documented with COPD without exacerbation and forced expiratory volume in 1 second > 30% in the groups with CHD and COPD. Arterial endothelial function was tested with high-resolution ultrasonography: brachial artery diameter was measured at rest, after flow increase (which causes endothelium-dependent dilatation, and after administration of sublingual nitroglycerin (an endothelium-independent dilator.Results. We found that endothelial dysfunction in patients with acute and chronic forms of CHD in combination with COPD are more pronounced than in isolated CHD.Conclusion. Expressed depression functional vascular reserve in patients with CHD associated with COPD, should be taken into account when conducting individualized therapy of these patients.

  15. The Role of Hypertriglyceridemia in the Development of Atherosclerosis and Endothelial Dysfunction

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    Saki Matsumoto

    2014-03-01

    Full Text Available A hereditary postprandial hypertriglyceridemic rabbit (PHT rabbit is a new dyslipidemic model showing remarkably high plasma triglycerides with only limited elevation of plasma total cholesterol. In PHT rabbits, plasma triglyceride was markedly elevated postprandially compared with healthy Japanese white (JW rabbits. In physiological experiments, the ring preparation of the thoracic aorta was suspended in an organ bath filled with modified Krebs-Henseleit solution, and the developed tension was recorded. Endothelial function was evaluated by acetylcholine-induced vasorelaxation in each preparation with intact endothelium. The acetylcholine-induced endothelium-dependent relaxation was diminished in PHT compared with JW rabbits, suggesting endothelial dysfunction in PHT rabbits. Histological examination was carried out in adipose tissue, liver and aorta. They were fixed in formaldehyde and embedded in paraffin. The tissues were sliced (4 μm and stained using hematoxylin-eosin solution. In the adipose tissue, the visceral fat accumulated, and the size of adipose cells was enlarged in PHT rabbits. The liver of the PHT rabbit was fatty and degenerated. In aorta, increased intimal thickness was observed, suggesting the progression of atherosclerosis in the PHT rabbit. This study suggests the important role of postprandial hypertriglyceridemia in atherosclerosis. By using PHT rabbits, the effects of hypertriglyceridemia on health and diseases could be evaluated precisely.

  16. Pulmonary endothelial dysfunction induced by unilateral as compared to bilateral thoracic irradiation in rats

    International Nuclear Information System (INIS)

    Ward, W.F.; Molteni, A.; Ts'Ao, C.H.; Solliday, N.H.

    1987-01-01

    Rats were sacrificed 2 months after a single dose of 10-30 Gy of 60 Co gamma rays delivered to either a right unilateral or a bilateral thoracic port. Four indices of lung endothelial function were measured: the activities of angiotensin-converting enzyme (ACE) and plasminogen activator (PLA) and the production of prostacyclin (PGI2) and thromboxane (TXA2). The number of macrophages recovered by bronchoalveolar lavage (BAL) and the degree of right ventricular hypertrophy (an index of pulmonary hypertension) also were determined. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. The response curves for right unilateral and bilateral thoracic irradiation were not significantly different. In contrast, bilateral irradiation was more toxic than unilateral, since rats exposed to the former exhibited decreased body weight, an increased incidence of pleural effusions, an increase in the number of macrophages recovered by BAL, and right ventricular hypertrophy. These data demonstrate that pulmonary endothelial dysfunction induced by hemithorax irradiation represents a direct response of the endothelium to radiation injury and is not secondary to other phenomena such as shunting of function to the shielded lung

  17. Endothelial dysfunction but not increased carotid intima-media thickness in young European women with endometriosis.

    Science.gov (United States)

    Santoro, Luca; D'Onofrio, Ferruccio; Campo, Sebastiano; Ferraro, Pietro Manuel; Tondi, Paolo; Campo, Vincenzo; Flex, Andrea; Gasbarrini, Antonio; Santoliquido, Angelo

    2012-05-01

    Atherosclerosis is a chronic and degenerative disease developing typically in the elderly; nonetheless, a condition of accelerated atherosclerosis can be observed precociously in the presence of some diseases. Endometriosis, a chronic benign gynecological disorder, shows some characteristics, such as oxidative stress, systemic inflammation and a pro-atherogenic lipid profile, which could increase the risk of developing accelerated atherosclerosis. The aim of our study was to evaluate markers of subclinical atherosclerosis in young European women with endometriosis. This cross-sectional study included 37 women with endometriosis and 31 control subjects. The presence of subclinical atherosclerosis was investigated by ultrasound evaluation of common carotid intima-media thickness (ccIMT) and flow-mediated dilation (FMD); in addition, serum levels of lipids, inflammatory and coagulation parameters, as well as markers of endothelial inflammation and activation, were determined. Women with endometriosis showed significantly lower values of FMD compared with controls [mean difference: -4.62, 95% confidence interval (CI): -6.52, -2.73; P women with endometriosis had significantly higher values of inter-cellular adhesion molecule 1 (P women with endometriosis have more subclinical atherosclerosis, resulting in a higher risk of developing cardiovascular disorders. Moreover, our findings demonstrate that endothelial dysfunction can occur in the absence of structural atherosclerotic changes; its evaluation might be helpful in young women with endometriosis.

  18. Perindopril Induces TSP-1 Expression in Hypertensive Patients with Endothelial Dysfunction in Chronic Treatment

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    Valentina Buda

    2017-02-01

    Full Text Available Thrombospondin-1 (TSP-1 is a potent endogenous inhibitor of both physiological and pathological angiogenesis, widely studied as a target in drug development for treating cancer. Several studies performed in the cardiovascular field on TSP-1 are contradictory, the role of TSP-1 in the physiopathology of cardiovascular disorders (CVDs being, for the moment, incompletely understood and may be due to the presence of several domains in its structure which can stimulate many cellular receptors. It has been reported to inhibit NO-mediated signaling and to act on the angiogenesis, tissue perfusion, endothelial cell proliferation, and homeostasis, so we aimed to quantify the effect Perindopril has on TSP-1 plasma levels in hypertensive patients with endothelial dysfunction in comparison with other antihypertensive drugs, such as beta blockers, calcium channel blockers, and diuretics, in a chronic treatment. As a conclusion, patients under treatment with Perindopril had increased plasma levels of TSP-1 compared with other hypertensive patients and with the control group. The results of this study confirms the pleiotropic properties of Perindopril: anti-proliferative, anti-inflammatory, with effects showed by quantifying a single biomarker: TSP-1.

  19. Increased Rho-kinase expression and activity and pulmonary endothelial dysfunction in smokers with normal lung function.

    Science.gov (United States)

    Duong-Quy, S; Dao, P; Hua-Huy, T; Guilluy, C; Pacaud, P; Dinh-Xuan, A T

    2011-02-01

    Endothelial dysfunction is one of the main consequences of the toxic effects of cigarette smoke on the vascular system. Increasing evidence suggests that the small G-protein RhoA and its downstream effectors, the Rho-kinases (ROCKs), are involved in systemic endothelial dysfunction induced by cigarette smoke. This study aimed to evaluate the role of the RhoA/ROCKs pathway in pulmonary artery endothelial function in current smokers with normal lung function. Lung tissues were obtained from nonsmokers and smokers who underwent lobectomy for lung carcinoma. Arterial relaxation in response to acetylcholine (ACh) was assessed in isolated pulmonary arterial rings. Protein expressions and activities of endothelial nitric oxide synthase (eNOS), ROCKs and the myosin phosphatase subunit 1 (MYPT-1) were sought. Relaxation in response to ACh was significantly lower in smokers as compared with nonsmokers (n = 8 in each group), consistent with reduced eNOS activity in the former compared with the latter. eNOS protein expression remained, however, the same in both groups. Expression of ROCKs, guanosine triphosphate-RhoA and phosphorylated MYPT-1 were significantly increased in smokers compared with controls. Pulmonary endothelial dysfunction is present in smokers whose lung function has not yet been impaired. Reduced activity of eNOS accounts at least in part for this endothelial dysfunction. Increased expression and activity of ROCKs accounts for another part through direct or indirect inhibition of the Rho-A/ROCKs pathway on nitric oxide synthesis and sustained pulmonary vasoconstriction through inhibition of myosin phosphatase.

  20. Kalirin and CHD7: novel endothelial dysfunction indicators in circulating extracellular vesicles from hypertensive patients with albuminuria

    Science.gov (United States)

    de la Cuesta, Fernando; Baldan-Martin, Montserrat; Moreno-Luna, Rafael; Alvarez-Llamas, Gloria; Gonzalez-Calero, Laura; Mourino-Alvarez, Laura; Sastre-Oliva, Tamara; López, Juan A.; Vázquez, Jesús; Ruiz-Hurtado, Gema; Segura, Julian; Vivanco, Fernando; Ruilope, Luis M.; Barderas, Maria G.

    2017-01-01

    Despite of the great advances in anti-hypertensive therapies, many patients under Renin-Angiotensin- System (RAS) suppression develop albuminuria, which is a clear indicator of therapeutic inefficiency. Hence, indicators of vascular function are needed to assess patients’ condition and help deciding future therapies. Proteomic analysis of circulating extracellular vesicles (EVs) showed two proteins, kalirin and chromodomain-helicase-DNA-binding protein 7 (CHD7), increased in albuminuric patients. A positive correlation of both with the expression of the endothelial activation marker E-selectin was found in EVs. In vitro analysis using TNFα-treated adult human endothelial cells proved their involvement in endothelial cell activation. Hence, we propose protein levels of kalirin and CHD7 in circulating EVs as novel endothelial dysfunction markers to monitor vascular condition in hypertensive patients with albuminuria. PMID:28152519

  1. Simultaneous ultrasound-assisted water extraction and β-cyclodextrin encapsulation of polyphenols from Mangifera indica stem bark in counteracting TNFα-induced endothelial dysfunction.

    Science.gov (United States)

    Mura, Marzia; Palmieri, Daniela; Garella, Davide; Di Stilo, Antonella; Perego, Patrizia; Cravotto, Giancarlo; Palombo, Domenico

    2015-01-01

    This study proposes an alternative technique to prevent heat degradation induced by classic procedures of bioactive compound extraction, comparing classical maceration/decoction in hot water of polyphenols from Mango (Mangifera indica L.) (MI) with ultrasound-assisted extraction (UAE) in a water solution of β-cyclodextrin (β-CD) at room temperature and testing their biological activity on TNFα-induced endothelial dysfunction. Both extracts counteracted TNFα effects on EAhy926 cells, down-modulating interleukin-6, interleukin-8, cyclooxygenase-2 and intracellular adhesion molecule-1, while increasing endothelial nitric oxide synthase levels. β-CD extract showed higher efficacy in improving endothelial function. These effects were abolished after pre-treatment with the oestrogen receptor inhibitor ICI1182,780. Moreover, the β-CD extract induced Akt activation and completely abolished the TNFα-induced p38MAPK phosphorylation. UAE and β-CD encapsulation provide an efficient extraction protocol that increases polyphenol bioavailability. Polyphenols from MI play a protective role on endothelial cells and may be further considered as oestrogen-like molecules with vascular protective properties.

  2. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis.

    Science.gov (United States)

    Kirkby, Nicholas S; Tesfai, Abel; Ahmetaj-Shala, Blerina; Gashaw, Hime H; Sampaio, Walkyria; Etelvino, Gisele; Leão, Nádia Miricéia; Santos, Robson A; Mitchell, Jane A

    2016-12-01

    Nonsteroidal antiinflammatory drugs, including ibuprofen, are among the most commonly used medications and produce their antiinflammatory effects by blocking cyclooxygenase (COX)-2. Their use is associated with increased risk of heart attacks caused by blocking COX-2 in the vasculature and/or kidney, with our recent work implicating the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), a cardiotoxic hormone whose effects can be prevented by l-arginine. The ibuprofen salt ibuprofen arginate (Spididol) was created to increase solubility but we suggest that it could also augment the NO pathway through codelivery of arginine. Here we investigated the idea that ibuprofen arginate can act to simultaneously inhibit COX-2 and preserve the NO pathway. Ibuprofen arginate functioned similarly to ibuprofen sodium for inhibition of mouse/human COX-2, but only ibuprofen arginate served as a substrate for NOS. Ibuprofen arginate but not ibuprofen sodium also reversed the inhibitory effects of ADMA and N G -nitro-l-arginine methyl ester on inducible NOS (macrophages) and endothelial NOS in vitro (aorta) and in vivo (blood pressure). These observations show that ibuprofen arginate provides, in one preparation, a COX-2 inhibitor and NOS substrate that could act to negate the harmful cardiovascular consequences mediated by blocking renal COX-2 and increased ADMA. While remarkably simple, our findings are potentially game-changing in the nonsteroidal antiinflammatory drug arena.-Kirkby, N. S., Tesfai, A., Ahmetaj-Shala, B., Gashaw, H. H., Sampaio, W., Etelvino, G., Leão, N. M., Santos, R. A., Mitchell, J. A. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis. © The Author(s).

  3. Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.

    Science.gov (United States)

    Menghini, Rossella; Campia, Umberto; Tesauro, Manfredi; Marino, Arianna; Rovella, Valentina; Rodia, Giuseppe; Schinzari, Francesca; Tolusso, Barbara; di Daniele, Nicola; Federici, Massimo; Zoli, Angelo; Ferraccioli, Gianfranco; Cardillo, Carmine

    2014-01-01

    To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA). Human aortic endothelial cells (HAECs) were treated with lipopolysaccharide (LPS), OxPAPC, and free fatty acids (FFA) at baseline and after incubation with the TLR4 antagonist eritoran (E5564). Cytokine expression was assessed by quantitative real-time PCR. In vivo endothelial function was assessed as brachial artery flow-mediated dilation (FMD) in RA patients with the wild type gene (aa) and with the Asp299Gly TLR4 polymorphic variant (ag). In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFα, CCL-2, VCAM and ICAM (P0.05). In 30 patients with RA (15 with the ag allele) undergoing measurement of FMD, no differences in FMD and plasma levels of IL-6, IL-8, VCAM, and ICAM were found between the aa and the ag phenotype (P>0.05 for all). TLR4 signaling in endothelial cells may be triggered by LPS and oxidized phospholipids, leading to endothelial activation and inflammation, which are inhibited by eritoran. Our in vivo investigation, however, does not support an association between the Asp299Gly TLR4 polymorphism and improved endothelium-dependent vasodilator function in patients with RA. Further study is needed to better understand the potential role of TLR4 on endothelial dysfunction in this and other patient populations.

  4. Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.

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    Rossella Menghini

    Full Text Available OBJECTIVE: To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA. METHODS: Human aortic endothelial cells (HAECs were treated with lipopolysaccharide (LPS, OxPAPC, and free fatty acids (FFA at baseline and after incubation with the TLR4 antagonist eritoran (E5564. Cytokine expression was assessed by quantitative real-time PCR. In vivo endothelial function was assessed as brachial artery flow-mediated dilation (FMD in RA patients with the wild type gene (aa and with the Asp299Gly TLR4 polymorphic variant (ag. RESULTS: In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFα, CCL-2, VCAM and ICAM (P0.05. In 30 patients with RA (15 with the ag allele undergoing measurement of FMD, no differences in FMD and plasma levels of IL-6, IL-8, VCAM, and ICAM were found between the aa and the ag phenotype (P>0.05 for all. CONCLUSIONS: TLR4 signaling in endothelial cells may be triggered by LPS and oxidized phospholipids, leading to endothelial activation and inflammation, which are inhibited by eritoran. Our in vivo investigation, however, does not support an association between the Asp299Gly TLR4 polymorphism and improved endothelium-dependent vasodilator function in patients with RA. Further study is needed to better understand the potential role of TLR4 on endothelial dysfunction in this and other patient populations.

  5. Persistent high fever for more than 10 days during acute phase is a risk factor for endothelial dysfunction in children with a history of Kawasaki disease.

    Science.gov (United States)

    Mori, Yasuhiko; Katayama, Hiroshi; Kishi, Kanta; Ozaki, Noriyasu; Shimizu, Tatsuo; Tamai, Hiroshi

    2016-07-01

    Endothelial dysfunction has previously been reported in children with a history of Kawasaki disease, but the determinants of endothelial function in Kawasaki disease patients are still unknown. In this study, we investigated endothelial function in Kawasaki disease patients and attempted to identify risk factors for persistent endothelial dysfunction. Using high-resolution ultrasound, we measured the percent flow-mediated dilatation, an arterial response to reactive hyperemia, to evaluate endothelial function in 67 patients with a history of Kawasaki disease and 28 age- and sex-matched control subjects. We divided the Kawasaki disease patients into a group with impaired endothelial function (the percent flow-mediated dilatation below -2 standard deviations of the control group) and a group with normal endothelial function (the percent flow-mediated dilatation more than -2 standard deviations of control). Logistic multiple regression analysis was performed to identify independent predictors of impaired endothelial function. In Kawasaki disease patients, the percent flow-mediated dilatation was significantly lower than in the control subjects (9.8±3.6%, compared with 13.1±3.4%, pKawasaki disease patients (3 patients with coronary artery lesions and 10 patients without coronary artery lesions), the percent flow-mediated dilatation was below -2 standard deviations of control. Logistic multiple regression analysis showed that a febrile period of longer than 10 days during the acute phase was the significant risk factor for endothelial dysfunction (odds ratio: 8.562; 95% confidence interval: 1.366-53.68). Presence of coronary artery lesions was not a determinant of endothelial dysfunction. Systemic endothelial dysfunction exists in children with a history of Kawasaki disease, and a febrile period of longer than 10 days during the acute phase is an independent predictor of endothelial dysfunction irrespective of coronary artery involvement. Copyright © 2015 Japanese

  6. Rosmarinic Acid Alleviates the Endothelial Dysfunction Induced by Hydrogen Peroxide in Rat Aortic Rings via Activation of AMPK

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    Hui Zhou

    2017-01-01

    Full Text Available Endothelial dysfunction is the key player in the development and progression of vascular events. Oxidative stress is involved in endothelial injury. Rosmarinic acid (RA is a natural polyphenol with antioxidative, antiapoptotic, and anti-inflammatory properties. The present study investigates the protective effect of RA on endothelial dysfunction induced by hydrogen peroxide (H2O2. Compared with endothelium-denuded aortic rings, the endothelium significantly alleviated the decrease of vasoconstrictive reactivity to PE and KCl induced by H2O2. H2O2 pretreatment significantly injured the vasodilative reactivity to ACh in endothelium-intact aortic rings in a concentration-dependent manner. RA individual pretreatment had no obvious effect on the vasoconstrictive reaction to PE and KCl, while its cotreatment obviously mitigated the endothelium-dependent relaxation impairments and the oxidative stress induced by H2O2. The RA cotreatment reversed the downregulation of AMPK and eNOS phosphorylation induced by H2O2 in HAEC cells. The pretreatment with the inhibitors of AMPK (compound C and eNOS (L-NAME wiped off RA’s beneficial effects. All these results demonstrated that RA attenuated the endothelial dysfunction induced by oxidative stress by activating the AMPK/eNOS pathway.

  7. Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure

    Science.gov (United States)

    Jablonski, Kristen L.; Racine, Matthew L.; Geolfos, Candace J.; Gates, Phillip E.; Chonchol, Michel; McQueen, Matthew B.; Seals, Douglas R.

    2013-01-01

    Objectives We determined the efficacy of dietary sodium restriction (DSR) for improving vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure (SBP; 130–159 mmHg) and the associated physiological mechanisms. Background Vascular endothelial dysfunction develops with advancing age and elevated SBP, contributing to increased cardiovascular risk. DSR lowers BP, but its effect on vascular endothelial function and mechanisms involved are unknown. Methods Seventeen subjects (11M/6F; 62±7 yrs, mean±S.D.) completed a randomized, crossover study of 4 weeks of both low and normal sodium intake. Vascular endothelial function (endothelium-dependent dilation; EDD), nitric oxide (NO)/tetrahydrobiopterin (BH4) bioavailability and oxidative stress-associated mechanisms were assessed following each condition. Results Urinary sodium excretion was reduced by ~50% (to 70±30 mmol/day), and conduit (brachial artery flow-mediated dilation [FMDBA]) and resistance (forearm blood flow responses to acetylcholine [FBFACh]) artery EDD were 68% and 42% (peak FBFACh) higher following the low sodium diet (psodium markedly enhanced NO- mediated EDD (greater ΔFBFACh with endothelial NO synthase [eNOS] inhibition) without changing eNOS expression/activation (Ser1177 phosphorylation), restored BH4 bioactivity (less ΔFMDBA with acute BH4), abolished tonic superoxide suppression of EDD (less ΔFMDBA and ΔFBFACh with ascorbic acid infusion), and increased circulating superoxide dismutase activity (p<0.05). These effects were independent of ΔSBP. Other subject characteristics/dietary factors and endothelium-independent dilation were unchanged. Conclusions DSR largely reverses both macro- and microvascular endothelial dysfunction by enhancing NO and BH4 bioavailability and reducing oxidative stress. Our findings support the emerging concept that DSR induces “vascular protection” beyond that attributable to its BP-lowering effects. PMID

  8. The role of tissue renin angiotensin aldosterone system in the development of endothelial dysfunction and arterial stiffness

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    Annayya R Aroor

    2013-10-01

    Full Text Available Epidemiological studies support the notion that arterial stiffness is an independent predictor of adverse cardiovascular events contributing significantly to systolic hypertension, impaired ventricular-arterial coupling and diastolic dysfunction, impairment in myocardial oxygen supply and demand, and progression of kidney disease. Although arterial stiffness is associated with aging, it is accelerated in the presence of obesity and diabetes. The prevalence of arterial stiffness parallels the increase of obesity that is occurring in epidemic proportions and is partly driven by a sedentary life style and consumption of a high fructose, high salt and high fat western diet. Although the underlying mechanisms and mediators of arterial stiffness are not well understood, accumulating evidence supports the role of insulin resistance and endothelial dysfunction. The local tissue renin angiotensin aldosterone system (RAAS in the vascular tissue and immune cells and perivascular adipose tissue is recognized as an important element involved in endothelial dysfunction which contributes significantly to arterial stiffness. Activation of vascular RAAS is seen in humans and animal models of obesity and diabetes, and associated with enhanced oxidative stress and inflammation in the vascular tissue. The cross talk between angiotensin and aldosterone underscores the importance of mineralocorticoid receptors in modulation of insulin resistance, decreased bioavailability of nitric oxide, endothelial dysfunction and arterial stiffness. In addition, both innate and adaptive immunity are involved in this local tissue activation of RAAS. In this review we will attempt to present a unifying mechanism of how environmental and immunological factors are involved in this local tissue RAAS activation, and the role of this process in the development of endothelial dysfunction and arterial stiffness and targeting tissue RAAS activation.

  9. Prognostic significance of endothelial dysfunctional markers of the first stage of chronic kidney disease

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    M. M. Mnuskina

    2014-01-01

    Full Text Available Non-adaptive remodeling of cardiovascular system and progressive kidney damage at chronic kidney disease (CKD is associated with the development of endothelial dysfunction (ED and apoptosis. The aim of this research was to study the changes of indicators of apoptosis and ED in patients with CKD 1 stage throughout 12 months. Complex biochemical, immunoferment and tool methods were applied at patient examinations. Arterial pressure of all observed patients was resolved on target values in 12 months. However, the indicators of endothelium-dependent vasodilation (EDV increased in 55 patients (1st group, and the peak of circulating blood volume in skin microvessels in 22 patients (2nd group wasn't changed: 134±4 % и 136±4 %, p>0.1. The level of the annexin A5 reduced from 3.5±0.47 to 1.27±0.31 ng/ml (p0.1 in 2nd group. Diurnal excretion of sodium chloride decreased from 6.8±0.57 g/d to 2.8±0.39 g/d (p<0.05 in patients of 1st group. Dynamics of these indicators was not marked in patients of 2nd group: accordingly from 7.39±0.63 g/d to 7.01±0.65 g/d. Diurnal excretion of sodium chloride reflected the salt intake in patients with CKD 1 stage is associated with disturbance of endothelial-dependent vasodilation and apoptosis.

  10. NOTCH4 signaling controls EFNB2-induced endothelial progenitor cell dysfunction in preeclampsia.

    Science.gov (United States)

    Liu, Xiaoxia; Luo, Qingqing; Zheng, Yanfang; Liu, Xiaoping; Hu, Ying; Liu, Weifang; Luo, Minglian; Zhao, Yin; Zou, Li

    2016-07-01

    Preeclampsia is a serious complication of pregnancy and is closely related to endothelial dysfunction, which can be repaired by endothelial progenitor cells (EPCs). The DLL4/NOTCH-EFNB2 (ephrinB2) cascade may be involved in the pathogenesis of preeclampsia by inhibiting the biological activity of EPCs. In addition, both NOTCH1 and NOTCH4, which are specific receptors for DLL4/NOTCH, play critical roles in the various steps of angiogenesis. However, it has not been determined which receptor (NOTCH1, NOTCH4, or both) is specific for the DLL4/NOTCH-EFNB2 cascade. Accordingly, we performed a series of investigations to evaluate it. EFNB2 expression was examined when NOTCH4 or NOTCH1 was downregulated, with or without DLL4 treatment. Then, the effects of NOTCH4 on EPC function were detected. Additionally, we analyzed NOTCH4 and EFNB2 expression in the EPCs from preeclampsia and normal pregnancies. Results showed that NOTCH4 downregulation led to decreased expression of EFNB2, which maintained the same level in the presence of DLL4/NOTCH activation. By contrast, NOTCH1 silencing resulted in a moderate increase in EFNB2 expression, which further increased in the presence of DLL4/NOTCH activation. The downregulation of NOTCH4 resulted in an increase of EPC biological activity, which was similar to EFNB2 silencing. NOTCH4 expression, consistent with the EFNB2 level, increased notably in preeclampsia EPCs compared with the controls. These findings suggest that NOTCH4, not NOTCH1, is the specific receptor for the DLL4/NOTCH-EFNB2 cascade. Blockade of this cascade may enhance the angiogenic property of EPCs, and act as a potential target to promote angiogenesis in patients with preeclampsia. © 2016 Society for Reproduction and Fertility.

  11. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

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    Murrin L Charles

    2011-03-01

    Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

  12. Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries.

    Science.gov (United States)

    Wiggers, G A; Peçanha, F M; Briones, A M; Pérez-Girón, J V; Miguel, M; Vassallo, D V; Cachofeiro, V; Alonso, M J; Salaices, M

    2008-09-01

    Increased cardiovascular risk after mercury exposure has been described, but the underlying mechanisms are not well explored. We analyzed the effects of chronic exposure to low mercury concentrations on endothelium-dependent responses in aorta and mesenteric resistance arteries (MRA). Wistar rats were treated with mercury chloride (1st dose 4.6 microg/kg, subsequent dose 0.07 microg.kg(-1).day(-1) im, 30 days) or vehicle. Blood levels at the end of treatment were 7.97 +/- 0.59 ng/ml. Mercury treatment: 1) did not affect systolic blood pressure; 2) increased phenylephrine-induced vasoconstriction; 3) reduced acetylcholine-induced vasodilatation; and 4) reduced in aorta and abolished in MRA the increased phenylephrine responses induced by either endothelium removal or the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 100 microM). Superoxide dismutase (SOD, 150 U/ml) and the NADPH oxidase inhibitor apocynin (0.3 mM) decreased the phenylephrine-induced contraction in aorta more in mercury-treated rats than controls. In MRA, SOD did not affect phenylephrine responses; however, when coincubated with l-NAME, the l-NAME effect on phenylephrine response was restored in mercury-treated rats. Both apocynin and SOD restored the impaired acetylcholine-induced vasodilatation in vessels from treated rats. Endothelial NOS expression did not change in aorta but was increased in MRA from mercury-treated rats. Vascular O2(-) production, plasmatic malondialdehyde levels, and total antioxidant status increased with the mercury treatment. In conclusion, chronic exposure to low concentrations of mercury promotes endothelial dysfunction as a result of the decreased NO bioavailability induced by increases in oxidative stress. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.

  13. Biomarkers of microvascular endothelial dysfunction predict incident dementia: a population-based prospective study.

    Science.gov (United States)

    Holm, H; Nägga, K; Nilsson, E D; Ricci, F; Melander, O; Hansson, O; Bachus, E; Magnusson, M; Fedorowski, A

    2017-07-01

    Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) with dementia and subtypes amongst community-dwelling older adults. A population-based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR-proANP, CT-proET-1 and MR-proADM. Three-hundred-and-seventy-three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis. Higher levels of MR-proANP were significantly associated with increased risk of all-cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07-1.36; P = 0.002, and 1.52; 1.21-1.89; P dementia increased across the quartiles of MR-proANP (p for linear trend = 0.004; Q4, 145-1681 pmol L -1 vs. Q1, 22-77 pmol L -1 : HR: 1.83; 95%CI: 1.23-2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14-6.46). Moreover, the two highest quartiles of CT-proET-1 predicted vascular dementia with a cut-off value at 68 pmol L -1 (Q3-Q4, 68-432 pmol L -1 vs. Q1-Q2,4-68 pmol L -1 ; HR: 1.94; 95%CI: 1.12-3.36). Elevated levels of MR-proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors. Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia. © 2017 The Association for the Publication of the

  14. The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells.

    Science.gov (United States)

    Han, Jingyan; Weisbrod, Robert M; Shao, Di; Watanabe, Yosuke; Yin, Xiaoyan; Bachschmid, Markus M; Seta, Francesca; Janssen-Heininger, Yvonne M W; Matsui, Reiko; Zang, Mengwei; Hamburg, Naomi M; Cohen, Richard A

    2016-10-01

    Oxidative stress is implicated in increased vascular permeability associated with metabolic disorders, but the underlying redox mechanism is poorly defined. S-glutathionylation, a stable adduct of glutathione with protein sulfhydryl, is a reversible oxidative modification of protein and is emerging as an important redox signaling paradigm in cardiovascular physiopathology. The present study determines the role of protein S-glutathionylation in metabolic stress-induced endothelial cell permeability. In endothelial cells isolated from patients with type-2 diabetes mellitus, protein S-glutathionylation level was increased. This change was also observed in aortic endothelium in ApoE deficient (ApoE -/- ) mice fed on Western diet. Metabolic stress-induced protein S-glutathionylation in human aortic endothelial cells (HAEC) was positively correlated with elevated endothelial cell permeability, as reflected by disassembly of cell-cell adherens junctions and cortical actin structures. These impairments were reversed by adenoviral overexpression of a specific de-glutathionylation enzyme, glutaredoxin-1 in cultured HAECs. Consistently, transgenic overexpression of human Glrx-1 in ApoE -/- mice fed the Western diet attenuated endothelial protein S-glutathionylation, actin cytoskeletal disorganization, and vascular permeability in the aorta. Mechanistically, glutathionylation and inactivation of Rac1, a small RhoGPase, were associated with endothelial hyperpermeability caused by metabolic stress. Glutathionylation of Rac1 on cysteine 81 and 157 located adjacent to guanine nucleotide binding site was required for the metabolic stress to inhibit Rac1 activity and promote endothelial hyperpermeability. Glutathionylation and inactivation of Rac1 in endothelial cells represent a novel redox mechanism of vascular barrier dysfunction associated with metabolic disorders. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Biomarkers of inflammation and endothelial dysfunction as predictors of pulse pressure and incident hypertension in type 1 diabetes

    DEFF Research Database (Denmark)

    Ferreira, Isabel; Hovind, Peter; Schalkwijk, Casper G

    2018-01-01

    AIMS/HYPOTHESIS: Vascular inflammation and endothelial dysfunction are thought to contribute to arterial stiffening and hypertension. This study aims to test this hypothesis with longitudinal data in the context of type 1 diabetes. METHODS: We investigated, in an inception cohort of 277 individuals...... with type 1 diabetes, the course, tracking and temporal inter-relationships of BP, specifically pulse pressure (a marker of arterial stiffening) and hypertension, and the following biomarkers of systemic and vascular inflammation/endothelial dysfunction: C-reactive protein (CRP), soluble intracellular...... adhesion molecule-1 (sICAM-1), soluble vascular cellular adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin). These biomarkers and other risk factors were measured at baseline and repeatedly up to 20 years after the onset of type 1 diabetes. Data were analysed with generalised estimating...

  16. Preservation of vascular DDAH activity contributes to the protection of captopril against endothelial dysfunction in hyperlipidemic rabbits.

    Science.gov (United States)

    Lin, Yuan; Feng, Mei; Lu, Chang-Wu; Lei, Yan-Ping; He, Zhi-Min; Xiong, Yan

    2017-03-05

    Endothelial dysfunction plays a pivotal role in the pathogenesis of atherosclerosis. Endogenous inhibitor of nitric oxide synthase (NOS) asymmetric dimethylarginine (ADMA) has been recognized as an independent risk factor of endothelial dysfunction and the biomarker of atherosclerosis. This study was to investigate whether endogenous ADMA and its metabolic enzyme dimethylarginine dimethylaminohydrolase (DDAH) were involved in mechanisms of captopril protection against endothelial dysfunction in high fat diet feeding rabbits. Half of model rabbits were treated with captopril (10mg/kg/d, i.g.) for 12w. Vascular morphology and serum lipid profiles were detected. Serum ADMA concentration were assayed by high performance liquid chromatography. Recombinant DDAH2 gene adenoviruses were ex vivo transferred to thoracic aortas of high fat diet feeding rabbits. Endothelium-dependent relaxation of aortas response to acetylcholine and DDAH activity were measured. Atherosclerosis was confirmed in high fat diet feeding rabbits by increased serum lipid profiles and morphologic changes of vascular wall. Serum ADMA levels were significantly increased in hyperlipidemic rabbits accompanied with impairment of endothelium-dependent relaxation and inhibition of DDAH activity in thoracic aortas. Captopril treatment not only decreased vascular intima thickening and serum ADMA concentration but also preserved vascular DDAH activity and endothelium-dependent relaxation in hyperlipidemic rabbits without influence on serum lipid profiles. Similar beneficial effects on endothelial function and DDAH activity could be achieved by DDAH2 gene transfection. These results indicated that captopril could protect against injuries of vascular morphology and endothelial function in hyperlipidemic rabbits, the mechanisms may be related to the preservation of DDAH activity and decrease of ADMA accumulation in vascular endothelium. Copyright © 2017. Published by Elsevier B.V.

  17. Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets.

    Science.gov (United States)

    Lee, Yun Jung; Choi, Deok Ho; Cho, Guk Hyun; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

    2012-08-06

    Arctium lappa L. (Asteraceae), burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL) seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD). EAL-I (100 mg·kg-1/day), EAL-II (200 mg·kg-1/day), and fluvastatin (3 mg·kg-1/day) groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh)-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP) and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP)-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation.

  18. Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets

    Directory of Open Access Journals (Sweden)

    Lee Yun

    2012-08-01

    Full Text Available Abstract Background Arctium lappa L. (Asteraceae, burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD. Method EAL-I (100 mg·kg−1/day, EAL-II (200 mg·kg−1/day, and fluvastatin (3 mg·kg−1/day groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Results Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM-1, vascular cell adhesion molecule (VCAM-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. Conclusion The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation.

  19. Effect of CPAP on New Endothelial Dysfunction Marker, Endocan, in People With Obstructive Sleep Apnea.

    Science.gov (United States)

    Altintas, Nejat; Mutlu, Levent Cem; Akkoyun, Dursun Cayan; Aydin, Murat; Bilir, Bulent; Yilmaz, Ahsen; Malhotra, Atul

    2016-04-01

    Obstructive sleep apnea (OSA) is associated with increased cardiovascular (CV) morbidity and mortality. Endocan is a surrogate endothelial dysfunction marker that may be associated with CV risk factors. In this study, we tested whether serum endocan is a biomarker for OSA. Serum endocan levels were measured at baseline in 40 patients with OSA and 40 healthy controls and after 3 months of continuous positive airway pressure (CPAP) treatment in the patients with OSA. All participants were evaluated by full polysomnography. Flow-mediated dilatation (FMD) and carotid intima media thickness (cIMT) were measured in all participants. Endocan levels were significantly higher in patients with OSA than in healthy controls. After adjusting confounders, endocan was a good predictor of OSA. Endocan levels correlated with OSA severity (measured by the apnea-hypopnea index [AHI]). After 3 months of CPAP treatment, endocan levels significantly decreased. Endocan levels were significantly and independently correlated with cIMT and FMD after multiple adjustments. The cIMT and FMD also had significant and independent correlation with AHI. Endocan might be a useful marker for the predisposition of patients with OSA to premature vascular disease. © The Author(s) 2015.

  20. Ultrasound and Biochemical Indices of Endothelial Dysfunction at Hemorrhagic Vasculitis in Children

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    Yu.V. Odynets

    2016-03-01

    Full Text Available 60 children with hemorrhagic vasculitis were examined in order to detect ultrasound and biochemical markers of endothelial dysfunction, depending on the degree of acti­vity and the form. Serum monocyte chemoattractant protein 1 (MCP-1 concentration was determined using enzyme-linked immunoassay, the content of nitric oxide by its stable metabolites — NO2, NO3 and S-nitrosothiol, von Willebrand factor — using aggregometry, intima-media complex thickness of the common carotid artery and endothelium-dependent dilation of the brachial artery were evaluated. Levels of von Willebrand factor and MCP-1 significantly increased, depending on the degree of hemorrhagic vasculitis activity. Statistical data show a significant decrease in the concentration of nitric oxide metabolites in the blood serum of children with mixed form and nephritic syndrome. Intima-media complex thickness of the common carotid artery was increased in children with severe hemorrhagic vasculitis, and in children with a mixed form with renal syndrome. We have detected a pathological reaction of endothelium-dependent dilation of the brachial artery regardless of the degree of activity and the form of hemorrhagic vasculitis, this fact evidences direct involvement of the endothelium in the pathological process.

  1. Visfatin versus Flow-Mediated Dilatation as a Marker of Endothelial Dysfunction in Pediatric Renal Transplant Recipients

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    Fatina Fadel

    2017-04-01

    CONCLUSION: Pediatric RTx recipients show lower serum Visfatin level and better FMD than those on regular hemodialysis, reflecting less endothelial dysfunction (ED and less cardiovascular risk. FMD in kidney transplant recipients tends to be less than normal subjects while visfatin level of the same group is similar to controls. Pediatric RTx appears to have a positive impact on the growth development of children with ESRD.

  2. Effect of Febuxostat on the Endothelial Dysfunction in Hemodialysis Patients: A Randomized, Placebo-Controlled, Double-Blinded Study.

    Science.gov (United States)

    Alshahawey, Mona; Shahin, Sara Mahmoud; Elsaid, Tamer Wahid; Sabri, Nagwa Ali

    2017-01-01

    Endothelial dysfunction is an important risk factor for cardiovascular diseases to occur in end-stage renal disease patients. Febuxostat, being a novel xanthine oxidase inhibitor, is apparently having a beneficial role in improving the endothelial dysfunction; however, data among hemodialysis patients are still limited. A prospective, placebo-controlled, block-randomized, double-blinded study was carried out to evaluate the effect of oral febuxostat on the endothelial dysfunction in hemodialysis patients. Fifty-seven eligible hemodialysis patients were randomly assigned to either the drug group (40 mg thrice weekly) or the placebo group. Serum Asymmetric dimethylarginine (ADMA), Serum uric acid (UA), and serum high sensitivity C-reactive protein (hsCRP) were measured at baseline and at the end of a 2-month study. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and the occurrence of pancytopenia were tested as safety parameters at baseline and at the end of study. Serum UA significantly decreased from 7.5 ± 0.8 to 5.1 ± 1.2 mg/dL in the febuxostat group, while it did not change significantly in the placebo group. Treatment with febuxostat resulted in a significant decrease in the serum ADMA level from 1.027 ± 0.116 to 0.944 ± 0.104 µmol/L and the serum hsCRP level from 12.5 ± 1.65 to 12.1 ± 1.70 mg/L. Testing of serum ALT, serum AST, and pancytopenia revealed no significant difference in both groups. Febuxostat appears to improve hyperuricemia and endothelial dysfunction and ameliorate inflammation in hemodialysis patients with no safety concerns. © 2017 S. Karger AG, Basel.

  3. Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Hovind, Peter

    2008-01-01

    OBJECTIVE: To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors...

  4. A possible link between endothelial dysfunction and insulin resistance in hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension

    DEFF Research Database (Denmark)

    Olsen, M H; Andersen, U B; Wachtell, K

    2000-01-01

    We wanted to investigate whether insulin resistance and time to steady state during isoglycemic clamp were associated with endothelial dysfunction, peripheral vascular remodeling and forearm blood flow (FBF) in patients with longstanding hypertension....

  5. Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia.

    Directory of Open Access Journals (Sweden)

    Rozana Santos Teixeira

    Full Text Available Hematological changes can drive damage of endothelial cells, which potentially lead to an early endothelial dysfunction in patients with sickle cell anemia (SCA. An association may exist between endothelial dysfunction and several clinical manifestations of SCA. The present study aims to evaluate the links between changes in endothelial function and clinical and laboratory parameters in children and adolescents with SCA.This study included 40 children and adolescents with stable SCA as well as 25 healthy children; aged 6-18 years. All study subjects were evaluated for endothelial function using Doppler ultrasonography. In addition, a number of laboratory assays were performed, including reticulocyte and leukocyte counts as well as measurement of circulating levels of total bilirubin, C-reactive protein (CRP, glucose, lipoproteins and peripheral oxyhemoglobin saturation. These parameters were also compared between SCA patients who were undertaking hydroxyurea (HU and those who were not.Flow-mediated vasodilation (FMD values were found to be reduced in SCA patients compared with those detected in healthy controls. SCA individuals with lower FMD values exhibited higher number of hospital admissions due to vaso-occlusive events. Additional analyses revealed that patients who had decreased FMD values exhibited higher odds of acute chest syndrome (ACS episodes. A preliminary analysis with limited number of individuals failed to demonstrate significant differences in FMD values between SCA individuals who were treated with HU and those who were not.Children and adolescents with SCA exhibit impaired endothelial function. Reductions in FMD values are associated with ACS. These findings underline the potential use of FMD as screening strategy of SCA patients with severe prognosis at early stages.

  6. [Biochemical markers of endothelial dysfunction in chronic obstructive pulmonary disease concurrent with hypertensive disease or coronary heart disease].

    Science.gov (United States)

    Akhmineeva, A Kh

    2014-01-01

    To evaluate the vascular endothelium in patients with cardiopulmonary disease, by studying the levels of endothelin-1 (ET-1) and C-type natriuretic peptide (CNP). Examinations were conducted in 212 dwellers of the Astrakhan Region, including 40 patients with chronic obstructive pulmonary disease (COPD) concurrent with hypertensive disease (HD), 40 patients with COPD concurrent with coronary heart disease (CHD), 27 somatically healthy individuals, 35 patients with Stage II HD, 35 patients with Functional Classes II and III CHD, and 35 patients with moderate and severe COPD. The patients with COPD concurrent with HD and CHD were found to have endothelial dysfunction manifesting itself in the overproduction of ET-1 and CNP. The level of CNP was statistically significantly higher in the COPD + HD group than in the HD and COPD groups whereas in the COPD + HD group the level of ET-1 remained comparable to that in the COPD and HD groups. This indicates that CNP is a more sensitive indirect marker of endothelial dysfunction and that nitric oxide deficiency is aggravated in the concurrence of COPD and HD as compared to a mononosological entity (HD, COPD). The concurrence of COPD and CHD is more unfavorable for the development and severity of endothelial dysfunction, which may lead to mutual aggravation syndrome, the rapider progression of the diseases, and the increased frequency of complications.

  7. Endothelial dysfunction in high fructose containing diet fed rats: Increased nitric oxide and decreased endothelin-1 levels in liver tissue

    Directory of Open Access Journals (Sweden)

    Zeki Arı

    2010-09-01

    Full Text Available Objectives: Dietary high fructose consumption which is closely associated with endothelial dysfunction via insulin re-sistance has recently increased in developed countries. Insulin resistance has a promoter effect on many metabolic disorders such as syndrome X, polycystic ovary syndrome, Type 2 diabetes mellitus etc. Our aim in this study is to understand the impact of increased fructose intake on metabolisms of glucose, insulin and endothelial dysfunction by measuring nitric oxide (NO and endothelin-1 (ET-1 levels in hepatic tissue which is crucial in fructose metabolism.Materials and Methods: We designed an animal study to understand increased fructose intake on hepatic endothe-lium. Twenty adult male albino rats were divided into two groups; the study group (group 1, n=10 received isocaloric fructose enriched diet (fructose-fed rats, containing 18.3% protein, 60.3% fructose and 5.2% fat while the control group received purified regular chow (group 2, n=10 for 2 weeks. After feeding period, blood and hepatic tissue samples were collected and glucose, insulin, NO and ET-1 levels were analysed.Results: We found increased fasting glucose and insulin levels and impaired glucose tolerance in fructose fed rats. Higher NO and lower ET–1 levels were also detected in hepatic tissue samples of the group 1.Conclusion: Increased fructose consumption has deleterious effects on glucose tolerance, insulin resistance and may cause to endothelial dysfunction.

  8. TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension.

    Science.gov (United States)

    Ma, Ming-Ming; Gao, Min; Guo, Kai-Min; Wang, Mi; Li, Xiang-Yu; Zeng, Xue-Lin; Sun, Lu; Lv, Xiao-Fei; Du, Yan-Hua; Wang, Guan-Lei; Zhou, Jia-Guo; Guan, Yong-Yuan

    2017-05-01

    Ca 2+ -activated Cl - channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism. Reverse transcription-polymerase chain reaction, Western blotting, coimmunoprecipitation, confocal imaging, patch-clamp recordings, and TMEM16A endothelial-specific transgenic and knockout mice were used. We found that TMEM16A was expressed abundantly and functioned as a Ca 2+ -activated Cl - channel in endothelial cells. Angiotensin II induced endothelial dysfunction with an increase in TMEM16A expression. The knockout of endothelial-specific TMEM16A significantly lowered the blood pressure and ameliorated endothelial dysfunction in angiotensin II-induced hypertension, whereas the overexpression of endothelial-specific TMEM16A resulted in the opposite effects. These results were related to the increased reactive oxygen species production, Nox2-containing NADPH oxidase activation, and Nox2 and p22phox protein expression that were facilitated by TMEM16A on angiotensin II-induced hypertensive challenge. Moreover, TMEM16A directly bound with Nox2 and reduced the degradation of Nox2 through the proteasome-dependent degradation pathway. Therefore, TMEM16A is a positive regulator of endothelial reactive oxygen species generation via Nox2-containing NADPH oxidase, which induces endothelial dysfunction and hypertension. Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated diseases. © 2017 American Heart Association, Inc.

  9. A possible link between endothelial dysfunction and insulin resistance in hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension

    DEFF Research Database (Denmark)

    Olsen, M H; Andersen, U B; Wachtell, K

    2000-01-01

    We wanted to investigate whether insulin resistance and time to steady state during isoglycemic clamp were associated with endothelial dysfunction, peripheral vascular remodeling and forearm blood flow (FBF) in patients with longstanding hypertension.......We wanted to investigate whether insulin resistance and time to steady state during isoglycemic clamp were associated with endothelial dysfunction, peripheral vascular remodeling and forearm blood flow (FBF) in patients with longstanding hypertension....

  10. Transplantation of endothelial progenitor cells ameliorates vascular dysfunction and portal hypertension in carbon tetrachloride-induced rat liver cirrhotic model.

    Science.gov (United States)

    Sakamoto, Masaharu; Nakamura, Toru; Torimura, Takuji; Iwamoto, Hideki; Masuda, Hiroshi; Koga, Hironori; Abe, Mitsuhiko; Hashimoto, Osamu; Ueno, Takato; Sata, Michio

    2013-01-01

    In cirrhosis, sinusoidal endothelial cell injury results in increased endothelin-1 (ET-1) and decreased nitric oxide synthase (NOS) activity, leading to portal hypertension. However, the effects of transplanted endothelial progenitor cells (EPCs) on the cirrhotic liver have not yet been clarified. We investigated whether EPC transplantation reduces portal hypertension. Cirrhotic rats were created by the administration of carbon tetrachloride (CCl(4) ) twice weekly for 10 weeks. From week 7, rat bone marrow-derived EPCs were injected via the tail vein in this model once a week for 4 weeks. Endothelial NOS (eNOS), vascular endothelial growth factor (VEGF) and caveolin expressions were examined by Western blots. Hepatic tissue ET-1 was measured by a radioimmunoassay (RIA). Portal venous pressure, mean aortic pressure, and hepatic blood flow were measured. Endothelial progenitor cell transplantation reduced liver fibrosis, α-smooth muscle actin-positive cells, caveolin expression, ET-1 concentration and portal venous pressure. EPC transplantation increased hepatic blood flow, protein levels of eNOS and VEGF. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC-transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Transplantation of EPCs ameliorates vascular dysfunction and portal hypertension, suggesting this treatment may provide a new approach in the therapy of portal hypertension with liver cirrhosis. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  11. Lectin-like oxidized low-density lipoprotein receptor-1 promotes endothelial dysfunction in LDL receptor knockout background.

    Science.gov (United States)

    Hofmann, Anja; Brunssen, Coy; Poitz, David M; Langbein, Heike; Strasser, Ruth H; Henle, Thomas; Ravens, Ursula; Morawietz, Henning

    2017-11-01

    Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date. Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr -/- ) mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph. WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr -/- mice (Eff max : 56.7 ± 23.0%) compared to WT (Eff max : 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Eff max : 76.7 ± 12.9%, P < 0.05) and Ldlr -/- mice (Eff max : 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr -/- mice were detectable when comparing all genotypes. Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Endothelial dysfunction in hyperandrogenic polycystic ovary syndrome is not explained by either obesity or ectopic fat deposition.

    Science.gov (United States)

    Sprung, Victoria S; Jones, Helen; Pugh, Christopher J A; Aziz, Nabil F; Daousi, Christina; Kemp, Graham J; Green, Daniel J; Cable, N Timothy; Cuthbertson, Daniel J

    2014-01-01

    PCOS (polycystic ovary syndrome) is associated with IR (insulin resistance), increased visceral fat and NAFLD (non-alcoholic fatty liver disease) all of which may contribute to endothelial dysfunction, an early marker of CVD (cardiovascular disease) risk. Our objective was to examine the relationships between endothelial dysfunction in PCOS, the volume of AT (adipose tissue) compartments and the size of intracellular TAG (triacylglycerol) pools in liver and skeletal muscle. A total of 19 women with PCOS (means±S.D.; 26±6 years, 36±5 kg/m2) and 16 control women (31±8 years, 30±6 kg/m2) were recruited. Endothelial function was assessed in the brachial artery using FMD (flow-mediated dilation). VAT (visceral AT) and abdominal SAT (subcutaneous AT) volume were determined by whole body MRI, and liver and skeletal muscle TAG by 1H-MRS (proton magnetic resonance spectroscopy). Cardiorespiratory fitness and HOMA-IR (homoeostasis model assessment of IR) were also determined. Differences between groups were analysed using independent Student's t tests and ANCOVA (analysis of co-variance). FMD was impaired in PCOS by 4.6% [95% CI (confidence interval), 3.0-7.7; P<0.001], and this difference decreased only slightly to 4.2% (95% CI, 2.4-6.1; P<0.001) when FMD was adjusted for individual differences in visceral and SAT and HOMA-IR. This magnitude of impairment was also similar in lean and obese PCOS women. The results suggest that endothelial dysfunction in PCOS is not explained by body fat distribution or volume. FMD might be a useful independent prognostic tool to assess CVD risk in this population.

  13. Long-term smoking causes more advanced coronary endothelial dysfunction in middle-aged smokers compared to young smokers

    International Nuclear Information System (INIS)

    Naya, Masanao; Goto, Daisuke; Tsutsui, Hiroyuki; Morita, Koichi; Manabe, Osamu; Hirata, Kenji; Tamaki, Nagara; Yoshinaga, Keiichiro; Katoh, Chietsugu

    2011-01-01

    Smoking cessation has been shown to normalize the coronary endothelial dysfunction in healthy young smokers. However, its effect has not been explored in middle-aged smokers with a longer history of smoking. Therefore, we compared the effects of smoking cessation on coronary vasomotor response between both young and middle-aged smokers and identified the predictor for its improvement. This study investigated 14 young healthy smokers (age 25.2 ± 2.3 years), 13 middle-aged smokers (age 42.0 ± 6.5 years) and 10 non-smokers. Myocardial blood flow (MBF) was measured by using 15 O-water positron emission tomography (PET). At baseline, the ratio of MBF during the cold pressor test (CPT) to that at rest (MBF CPT/rest ), the index of coronary endothelial function, was significantly decreased in both young and middle-aged smokers compared to non-smokers (1.24 ± 0.20 and 1.10 ± 0.39 vs 1.53 ± 0.18, p CPT/rest at 1 month after smoking cessation significantly increased in young smokers, but not in middle-aged smokers. By multivariate analysis, baseline serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) was an independent predictor for the changes in MBF CPT/rest after smoking cessation (β = -0.45, p < 0.05). Coronary endothelial dysfunction was reversible by short-term smoking cessation in young smokers, but not in middle-aged smokers, which was associated with serum MDA-LDL levels. Long-term smoking exposure could lead to more advanced coronary endothelial dysfunction and atherosclerosis possibly via oxidative stress. (orig.)

  14. Generation and Feasibility Assessment of a New Vehicle for Cell-Based Therapy for Treating Corneal Endothelial Dysfunction.

    Directory of Open Access Journals (Sweden)

    Naoki Okumura

    Full Text Available The corneal endothelium maintains corneal transparency by its pump and barrier functions; consequently, its decompensation due to any pathological reason causes severe vision loss due to corneal haziness. Corneal transplantation is the only therapeutic choice for treating corneal endothelial dysfunction, but associated problems, such as a shortages of donor corneas, the difficulty of the surgical procedure, and graft failure, still need to be resolved. Regenerative medicine is attractive to researchers as a means of providing innovative therapies for corneal endothelial dysfunction, as it now does for other diseases. We previously demonstrated the successful regeneration of corneal endothelium in animal models by injecting cultured corneal endothelial cells (CECs in combination with a Rho kinase (ROCK inhibitor. The purpose of the present study was to optimize the vehicle for clinical use in cell-based therapy. Our screening of cell culture media revealed that RELAR medium promoted CEC adhesion. We then modified RELAR medium by removing hormones, growth factors, and potentially toxic materials to generate a cell therapy vehicle (CTV composed of amino acid, salts, glucose, and vitamins. Injection of CECs in CTV enabled efficient engraftment and regeneration of the corneal endothelium in the rabbit corneal endothelial dysfunction model, with restoration of a transparent cornea. The CECs retained >85% viability after a 24 hour preservation as a cell suspension in CTV at 4°C and maintained their potency to regenerate the corneal endothelium in vivo. The vehicle developed here is clinically applicable for cell-based therapy aimed at treating the corneal endothelium. Our strategy involves the generation of vehicle from a culture medium appropriate for a given cell type by removing materials that are not favorable for clinical use.

  15. Combination therapy with losartan and L-carnitine protects against endothelial dysfunction of streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Sleem, Mostafa; Taye, Ashraf; El-Moselhy, Mohamed A; Mangoura, Safwat A

    2014-12-05

    Endothelial dysfunction is a critical factor during the initiation of diabetic cardiovascular complications and angiotensin II appears to play a pivotal role in this setting. The present study aimed to investigate whether the combination therapy with losartan and the nutritional supplement, L-carnitine can provide an additional protection against diabetes-associated endothelial dysfunction and elucidate the possible mechanism(s) underlying this effect. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg) in rat. Effects of losartan (20 mg/kg, orally, 3 months) and L-carnitine (200 mg/kg, orally, 3 months) on tumor necrosis factor (TNF)-α, oxidative stress parameters, endothelial nitric oxide synthase expression (eNOS), and vascular function were evaluated. Our results showed a marked increase in aortic superoxide anion (O2(-)) production and serum malondialdehyde (MDA) level alongside attenuating antioxidant enzyme capacities in diabetic rats. This was associated with a significant increase in anigiotensin II type 1 receptor gene expression and TNF-α serum level of diabetic rats alongside reducing aortic eNOS gene expression and nitric oxide (NO) bioavailability. The single or combined administration of losartan and L-carnitine significantly inhibited these changes. Additionally, the vascular endothelium-dependent relaxation with acetylcholine (ACh) in aortic diabetic rat was significantly ameliorated by the single and combined administration of losartan or L-carnitine. Noteworthy, the combination therapy exhibited a more profound response over the monotherapy. Collectively, our results demonstrate that the combined therapy of losartan and L-carnitine affords additive beneficial effects against diabetes-associated endothelial dysfunction, possibly via normalizing the dysregulated eNOS and reducing the inflammation and oxidative stress in diabetic rats. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. CD36 mediates endothelial dysfunction downstream of circulating factors induced by O3 exposure.

    Science.gov (United States)

    Robertson, Sarah; Colombo, Elizabeth S; Lucas, Selita N; Hall, Pamela R; Febbraio, Maria; Paffett, Michael L; Campen, Matthew J

    2013-08-01

    Inhaled pollutants induce the release of vasoactive factors into the systemic circulation, but little information is available regarding the nature of these factors or their receptors. The pattern recognition receptor CD36 interacts with many damage-related circulating molecules, leading to activation of endothelial cells and promoting vascular inflammation; therefore, we hypothesized that CD36 plays a pivotal role in mediating cross talk between inhaled ozone (O3)-induced circulating factors and systemic vascular dysfunction. O3 exposure (1 ppm × 4h) induced lung inflammation in wild-type (WT) mice, which was absent in the CD36 deficient (CD36(-/-)) mice. Acetylcholine (ACh)-evoked vasorelaxation was impaired in isolated aortas from O3-exposed WT mice but not in vessels from CD36(-/-) mice. To delineate whether vascular impairments were caused by lung inflammation or CD36-mediated generation of circulating factors, naïve aortas were treated with diluted serum from control or O3-exposed WT mice, which recapitulated the impairments of vasorelaxation observed after inhalation exposures. Aortas from CD36(-/-) mice were insensitive to the effects of O3-induced circulating factors, with robust vasorelaxation responses in the presence of serum from O3-exposed WT mice. Lung inflammation was not a requirement for production of circulating vasoactive factors, as serum from O3-exposed CD36(-/-) mice could inhibit vasorelaxation in naïve WT aortas. These results suggest that O3 inhalation induces the release of circulating bioactive factors capable of impairing vasorelaxation to ACh via a CD36-dependent signaling mechanism. Although lung inflammatory and systemic vascular effects were both dependent on CD36, the presence of circulating factors appears to be independent of CD36 and inflammatory responses.

  17. Omeprazole impairs vascular redox biology and causes xanthine oxidoreductase-mediated endothelial dysfunction

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    Lucas C. Pinheiro

    2016-10-01

    Full Text Available Proton pump inhibitors (PPIs are widely used drugs that may increase the cardiovascular risk by mechanisms not entirely known. While PPIs increase asymmetric dimethylarginine (ADMA levels and inhibit nitric oxide production, it is unknown whether impaired vascular redox biology resulting of increased xanthine oxidoreductase (XOR activity mediates PPIs-induced endothelial dysfunction (ED. We examined whether increased XOR activity impairs vascular redox biology and causes ED in rats treated with omeprazole. We also examined whether omeprazole aggravates the ED found in hypertension. Treatment with omeprazole reduced endothelium-dependent aortic responses to acetylcholine without causing hypertension. However, omeprazole did not aggravate two-kidney, one-clip (2K1C hypertension, nor hypertension-induced ED. Omeprazole and 2K1C increased vascular oxidative stress as assessed with dihydroethidium (DHE, which reacts with superoxide, and by the lucigenin chemiluminescence assay. The selective XOR inhibitor febuxostat blunted both effects induced by omeprazole. Treatment with omeprazole increased plasma ADMA concentrations, XOR activity and systemic markers of oxidative stress. Incubation of aortic rings with ADMA increased XOR activity, DHE fluorescence and lucigenin chemiluminescence signals, and febuxostat blunted these effects. Providing functional evidence that omeprazole causes ED by XOR-mediated mechanisms, we found that febuxostat blunted the ED caused by omeprazole treatment. This study shows that treatment with omeprazole impairs the vascular redox biology by XOR-mediated mechanisms leading to ED. While omeprazole did not further impair hypertension-induced ED, further studies in less severe animal models are warranted. Our findings may have major relevance, particularly to patients with cardiovascular diseases taking PPIs.

  18. Reverse-D-4F Increases the Number of Endothelial Progenitor Cells and Improves Endothelial Progenitor Cell Dysfunctions in High Fat Diet Mice.

    Science.gov (United States)

    Nana, Yang; Peng, Jiao; Jianlin, Zhang; Xiangjian, Zhang; Shutong, Yao; Enxin, Zhan; Bin, Li; Chuanlong, Zong; Hua, Tian; Yanhong, Si; Yunsai, Du; Shucun, Qin; Hui, Wang

    2015-01-01

    Although high density lipoprotein (HDL) improves the functions of endothelial progenitor cells (EPCs), the effect of HDL ApoAI mimetic peptide reverse-D-4F (Rev-D4F) on EPC mobilization and repair of EPC dysfunctions remains to be studied. In this study, we investigated the effects of Rev-D4F on peripheral blood cell subpopulations in C57 mice treated with a high fat diet and the mechanism of Rev-D4F in improving the function of EPCs impaired by tumor necrosis factor-α (TNF-α). The high fat diet significantly decreased the number of EPCs, EPC migratory functions, and the percentage of lymphocytes in the white blood cells. However, it significantly increased the number of white blood cells, the percentage of monocytes in the white blood cells, and the level of vascular endothelial growth factor (VEGF) and TNF-α in the plasma. Rev-D4F clearly inhibited the effect of the high fat diet on the quantification of peripheral blood cell subpopulations and cytokine levels, and increased stromal cell derived factor 1α (SDF-1α) in the plasma. We provided in vitro evidence that TNF-α impaired EPC proliferation, migration, and tube formation through inactive AKT and eNOS, which was restored by Rev-D4F treatment. In contrast, both the PI3-kinase (PI3K) inhibitor (LY294002) and AKT inhibitor (perifosine) obviously inhibited the restoration of Rev-4F on EPCs impaired by TNF-α. Our results suggested that Rev-D4F increases the quantity of endothelial progenitor cells through increasing the SDF-1α levels and decreasing the TNF-α level of peripheral blood in high fat diet-induced C57BL/6J mice, and restores TNF-α induced dysfunctions of EPCs partly through stimulating the PI3K/AKT signal pathway.

  19. Gender differences in the risk factors for endothelial dysfunction in Chinese hypertensive patients: homocysteine is an independent risk factor in females.

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    Cheng Cao

    Full Text Available Endothelial dysfunction plays a key role in the pathogenesis of cardiovascular disease. However, the gender-related differences in risk factors for endothelial dysfunction are controversial. We investigated the gender differences in the risk factor profiles for endothelial dysfunction in Chinese hypertensive patients.Vascular endothelial functions in 213 hypertensive patients were measured by digital reactive hyperemia peripheral arterial tonometry (RH-PAT. Peripheral blood samples were collected, and the self-reported smoking and alcohol consumption status, age, body mass index, heart rate, blood pressure and drug administrations were recorded.RH-PAT indexes were attenuated in both male and female hypertensive patients [1.60 (1.38-2.02 vs. 1.63 (1.44-1.98]. Multivariate logistic regression analysis identified plasma creatinine (p < 0.001, total cholesterol (p = 0.001, homocysteine (p = 0.002 and smoking (p < 0.001 as the independent factors correlated with gender (male. Multivariate linear regression analysis further identified homocysteine as the factor that is significantly and independently correlated with the decrease in the RH-PAT indexes in female patients (odds ratio: -0.166, 95% confidence interval: -0.292 to -0.040, p = 0.01. However, none of these four factors were correlated with the RH-PAT indexes in male patients.There are gender-related differences in the risk factors for endothelial dysfunction in Chinese hypertensive patients. Homocysteine is an independent factor for endothelial dysfunction in female hypertensive patients.

  20. Glutathione regulation of redox-sensitive signals in tumor necrosis factor-α-induced vascular endothelial dysfunction

    International Nuclear Information System (INIS)

    Tsou, T.-C.; Yeh, S.C.; Tsai, F.-Y.; Chen, J.-W.; Chiang, H.-C.

    2007-01-01

    We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-α)-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-α induces various biological effects on vascular cells, TNF-α dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-α concentrations, we adopted the lower TNF-α (0.2 ng/ml) to rule out the possible involvement of other TNF-α-induced biological effects. Inhibition of glutathione synthesis by L-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-α-induced adhesion molecule expression and monocyte-endothelial monolayer binding. BSO attenuated the TNF-α-induced nuclear factor-kappaB (NF-κB) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-α. Inhibition of ERK, JNK, or NF-κB attenuates TNF-α-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-α induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-κB in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-α. Although AP-1 activation by the lower TNF-α was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-α-induced adhesion molecule expression

  1. Markers of endothelial dysfunction and inflammation in type 1 diabetic patients with or without diabetic nephropathy followed for 10 years

    DEFF Research Database (Denmark)

    Astrup, Anne Sofie; Tarnow, Lise; Pietraszek, Lotte

    2008-01-01

    associated with all-cause mortality and cardiovascular morbidity and mortality in patients with nephropathy after multivariate adjustment. These data suggest that the high risk of cardiovascular disease in type 1 diabetes may be explained in part by inflammatory activity. Mean Z score of endothelial......OBJECTIVE: We evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in glomerular filtration rate (GFR) in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: We prospectively followed...... 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with persistent normoalbuminuria. Biomarkers were measured at baseline. RESULTS: We constructed two Z scores: the mean inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (s...

  2. Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes

    DEFF Research Database (Denmark)

    Kjaer, Andreas; Meyer, Christian; Nielsen, Flemming S

    2003-01-01

    (CPT) with that of dipyridamole, a pharmacologic vasodilator, on coronary blood flow (CBF) measured by PET in NIDDM patients and healthy volunteers. In addition, we studied the effect of acute angiotensin-converting enzyme (ACE) inhibition on the flow response. METHODS: Ten NIDDM patients and 10......Much evidence suggests endothelial dysfunction to be present in non-insulin-dependent diabetes mellitus (NIDDM) and to be important for the development of myocardial ischemia. Endothelial function in the coronary vessels may be studied in various ways. We compared the effect of cold pressor testing...... control subjects participated. Myocardial perfusion was determined at baseline, during CPT, and after dipyridamole infusion by PET using intravenous (13)N-ammonia. RESULTS: Resting CBF was similar in NIDDM patients and in control subjects. CPT increased CBF by 20% in the control group, whereas no increase...

  3. CLINICAL IMPORTANCE OF ENDOTHELIAL DYSFUNCTION AND INSULIN RESISTANCE SYNDROME IN PATIENTS WITH GOUT ASSOCIATED WITH ARTERIAL HYPERTENSION

    Directory of Open Access Journals (Sweden)

    N. N. Kushnarenko

    2015-09-01

    Full Text Available Aim. To study the endothelium status and determine the correlation between endothelial dysfunction and glucose metabolism in men with gout associated with arterial hypertension (HT.Material and methods. Patients (n=175, all are males with gout were enrolled into the study. Ambulatory blood pressure monitoring (ABPM was performed in all patients. Endothelial function was studied in tests with reactive hyperemia (endothelium-dependent reaction and nitroglycerin (endothelium independent reaction in brachial artery by ultrasonic Doppler examination. The level of nitrite-nitrate and endothelin-1 in blood serum was determined by ELISA technique. Fasting blood glucose and oral glucose tolerance tests were performed as well as fasting insulin blood level was determined by immunoenzyme method. Insulin-resistance index (HOMA-IR was calculated. Patients with HOMA- IR>2.77 were considered as insulin-resistant.Results. Patients with gout demonstrated endothelial deterioration associated with activation of nitroxid producing function, elevation in endothelin-1 serum level (1.36 fmol/ml [0.91; 2.32 fmol/ml] vs 0.19 fmol/ml [0.16; 0.27 fmol/ml] in controls, p<0.05 and impairments of endothelium-dependent vasodilation (6.4% [3.3; 7.3%] vs 17.8% [12.7; 23.9%] in controls, p<0.05. The revealed changes were the most marked in patients with gout associated with HT. The correlation between some endothelial dysfunction in- dices and glucose metabolism was observed.Conclusion. ABPM, brachial artery endothelium-dependent vasodilation and glucose metabolism status should be studied in patients with gout. Complex treatment of cardiovascular diseases in patients with gout should include ω-3 polyunsaturated fatty acids, angiotensin receptor antagonists should be used for antihypertensive therapy.

  4. Obligatory Role of Intraluminal O2− in Acute Endothelin-1 and Angiotensin II Signaling to Mediate Endothelial Dysfunction and MAPK Activation in Guinea-Pig Hearts

    Directory of Open Access Journals (Sweden)

    Emilia Wojtera

    2014-10-01

    Full Text Available We hypothesized that, due to a cross-talk between cytoplasmic O2−-sources and intraluminally expressed xanthine oxidase (XO, intraluminal O2− is instrumental in mediating intraluminal (endothelial dysfunction and cytosolic (p38 and ERK1/2 MAPKs phosphorylation manifestations of vascular oxidative stress induced by endothelin-1 (ET-1 and angiotensin II (AT-II. Isolated guinea-pig hearts were subjected to 10-min agonist perfusion causing a burst of an intraluminal O2−. ET-1 antagonist, tezosentan, attenuated AT-II-mediated O2−, indicating its partial ET-1 mediation. ET-1 and Ang-T (AT-II + tezosentan triggered intraluminal O2−, endothelial dysfunction, MAPKs and p47phox phosphorylation, and NADPH oxidase (Nox and XO activation. These effects were: (i prevented by blocking PKC (chelerythrine, Nox (apocynin, mitochondrial ATP-dependent K+ channel (5-HD, complex II (TTFA, and XO (allopurinol; (ii mimicked by the activation of Nox (NADH; and mitochondria (diazoxide, 3-NPA and (iii the effects by NADH were prevented by 5-HD, TTFA and chelerythrine, and those by diazoxide and 3-NPA by apocynin and chelerythrine, suggesting that the agonists coactivate Nox and mitochondria, which further amplify their activity via PKC. The effects by ET-1, Ang-T, NADH, diazoxide, and 3-NPA were opposed by blocking intraluminal O2− (SOD and XO, and were mimicked by XO activation (hypoxanthine. Apocynin, TTFA, chelerythrine, and SOD opposed the effects by hypoxanthine. In conclusion, oxidative stress by agonists involves cellular inside-out and outside-in signaling in which Nox-mitochondria-PKC system and XO mutually maintain their activities via the intraluminal O2−.

  5. CD36 and Fyn kinase mediate malaria-induced lung endothelial barrier dysfunction in mice infected with Plasmodium berghei.

    Directory of Open Access Journals (Sweden)

    Ifeanyi U Anidi

    Full Text Available Severe malaria can trigger acute lung injury characterized by pulmonary edema resulting from increased endothelial permeability. However, the mechanism through which lung fluid conductance is altered during malaria remains unclear. To define the role that the scavenger receptor CD36 may play in mediating this response, C57BL/6J (WT and CD36-/- mice were infected with P. berghei ANKA and monitored for changes in pulmonary endothelial barrier function employing an isolated perfused lung system. WT lungs demonstrated a >10-fold increase in two measures of paracellular fluid conductance and a decrease in the albumin reflection coefficient (σalb compared to control lungs indicating a loss of barrier function. In contrast, malaria-infected CD36-/- mice had near normal fluid conductance but a similar reduction in σalb. In WT mice, lung sequestered iRBCs demonstrated production of reactive oxygen species (ROS. To determine whether knockout of CD36 could protect against ROS-induced endothelial barrier dysfunction, mouse lung microvascular endothelial monolayers (MLMVEC from WT and CD36-/- mice were exposed to H2O2. Unlike WT monolayers, which showed dose-dependent decreases in transendothelial electrical resistance (TER from H2O2 indicating loss of barrier function, CD36-/- MLMVEC demonstrated dose-dependent increases in TER. The differences between responses in WT and CD36-/- endothelial cells correlated with important differences in the intracellular compartmentalization of the CD36-associated Fyn kinase. Malaria infection increased total lung Fyn levels in CD36-/- lungs compared to WT, but this increase was due to elevated production of the inactive form of Fyn further suggesting a dysregulation of Fyn-mediated signaling. The importance of Fyn in CD36-dependent endothelial signaling was confirmed using in vitro Fyn knockdown as well as Fyn-/- mice, which were also protected from H2O2- and malaria-induced lung endothelial leak, respectively. Our

  6. Late gestational hypoxia and a postnatal high salt diet programs endothelial dysfunction and arterial stiffness in adult mouse offspring.

    Science.gov (United States)

    Walton, Sarah L; Singh, Reetu R; Tan, Tiffany; Paravicini, Tamara M; Moritz, Karen M

    2016-03-01

    Gestational hypoxia and high dietary salt intake have both been associated with impaired vascular function in adulthood. Using a mouse model of prenatal hypoxia, we examined whether a chronic high salt diet had an additive effect in promoting vascular dysfunction in offspring. Pregnant CD1 dams were placed in a hypoxic chamber (12% O2) or housed under normal conditions (21% O2) from embryonic day 14.5 until birth. Gestational hypoxia resulted in a reduced body weight for both male and female offspring at birth. This restriction in body weight persisted until weaning, after which the animals underwent catch-up growth. At 10 weeks of age, a subset of offspring was placed on a high salt diet (5% NaCl). Pressurized myography of mesenteric resistance arteries at 12 months of age showed that both male and female offspring exposed to maternal hypoxia had significantly impaired endothelial function, as demonstrated by impaired vasodilatation to ACh but not sodium nitroprusside. Endothelial dysfunction caused by prenatal hypoxia was not exacerbated by postnatal consumption of a high salt diet. Prenatal hypoxia increased microvascular stiffness in male offspring. The combination of prenatal hypoxia and a postnatal high salt diet caused a leftward shift in the stress-strain relationship in both sexes. Histopathological analysis of aortic sections revealed a loss of elastin integrity and increased collagen, consistent with increased vascular stiffness. These results demonstrate that prenatal hypoxia programs endothelial dysfunction in both sexes. A chronic high salt diet in postnatal life had an additive deleterious effect on vascular mechanics and structural characteristics in both sexes. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  7. Effects of Complementary Creatine Monohydrate and Physical Training on Inflammatory and Endothelial Dysfunction Markers Among Heart Failure Patients.

    Science.gov (United States)

    Hemati, Farajollah; Rahmani, Asghar; Asadollahi, Khairollah; Soleimannejad, Koroush; Khalighi, Zahra

    2016-03-01

    Previous studies have reported endothelial dysfunction and inflammatory cytokine in heart failure patients (HF). The purpose of this study was to determine the effects of creatine monohydrate and exercise on inflammatory and endothelial dysfunction markers among HF patients. One hundred patients were prospectively randomized into two groups: Intervention group which received 5 grams/day creatine monohydrate and exercised for 8 weeks; and control group which did not receive any interventions. Interleukine-6 (IL-6), high sensitivity C reactive protein (hs-CRP), P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured at the start and end of the study for both groups. In total, 100 patients including 50 controls and 50 intervention group (54% male, mean EF of 34.2 ± 10.5% and 52% male, mean EF of 35.6 ± 12.7%, respectively) were analyzed. The serum levels of hs-CRP and IL-6 increased at the end of the study in the control group compared to the baseline, (7.5 ± 1.5 mg/L vs. 6.9 ± 1.3 mg/L, P markers decreased at the end of the study in the intervention group (6.3 ± 1.6 mg/L vs.7.5 ± 1.5 mg/L, P markers decreased in the intervention group, at the end of study (49.7 ± 1.9 ng/l vs. 51.4 ± 2.1 ng/l, P 0.05). Combination of creatine monohydrate and exercise attenuated inflammation and endothelial dysfunction markers among heart failure patients.

  8. Endothelial Dysfunction After ST-segment Elevation Myocardial Infarction and Long-term Outcome: A Study With Reactive Hyperemia Peripheral Artery Tonometry.

    Science.gov (United States)

    Kandhai-Ragunath, Jasveen J; Doggen, Carine J M; Jørstad, Harald T; Doelman, Cees; de Wagenaar, Bjorn; IJzerman, Maarten J; Peters, Ron J G; von Birgelen, Clemens

    2016-07-01

    Long-term data on the relationship between endothelial dysfunction after ST-segment elevation myocardial infarction and future adverse clinical events are scarce. The aim of this study was to noninvasively assess whether endothelial dysfunction 4 weeks to 6 weeks after primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction predicts future clinical events. This prospective cohort study was performed in 70 patients of the RESPONSE randomized trial, who underwent noninvasive assessment of endothelial function 4 weeks to 6 weeks after primary percutaneous coronary intervention. Endothelial function was measured by the reactive hyperemia peripheral artery tonometry method; an index<1.67 identified endothelial dysfunction. The reactive hyperemia peripheral artery tonometry index measured on average 1.90±0.58. A total of 35 (50%) patients had endothelial dysfunction and 35 (50%) patients had normal endothelial function. Periprocedural "complications" (eg, cardiogenic shock, total atrioventricular block) were more common in patients with endothelial dysfunction than in those without (25.7% vs 2.9%; P<.01). During 4.0±1.7 years of follow-up, 20 (28.6%) patients had major adverse cardiovascular events: events occurred in 9 (25.7%) patients with endothelial dysfunction and in 11 (31.5%) patients with normal endothelial function (P=.52). There was an association between the prevalence of diabetes mellitus at baseline and the occurrence of major adverse cardiovascular events during follow-up (univariate analysis: hazard ratio=2.8; 95% confidence interval, 1.0-7.8; P<.05), and even in multivariate analyses the risk appeared to be increased, although not significantly (multivariate analysis: hazard ratio=2.5; 95% confidence interval, 0.8-7.5). In this series of patients who survived an ST-segment elevation myocardial infarction, endothelial dysfunction, as assessed by reactive hyperemia peripheral artery tonometry 4 weeks to 6 weeks

  9. ENDOTHELIAL DYSFUNCTION AND “OXIDATIVE STRESS” BY THE NONNSTABLE COURSE OF ISCHEMIC HEART DISEASE

    Directory of Open Access Journals (Sweden)

    A. E. Kratnov

    2014-07-01

    Full Text Available Abstract. The purpose of study was to compare phagocytic indexes, free oxygen radicals generation, activity of antioxidative protection, cytokine levels and von Willebrand factor (vWF antigen in the patients with non–stable course of ischemic heart disease of. We examined 58 patients with ischemic heart disease: 31 with unstable angina and 27 with acute myocardial infarction. The methods of study included nitro–blue tetrasolium reduction test for neutrophiles and monocytes, detection of myeloperoxidase in phagocytes, assays of glutatione reductase in neutrophiles, as well as measurements of catalase, superoxide dismutase, malonic dialdehyde, circulating immune complexes, IL–6, TNFα and vWF factor antigen in blood. Upon admission to the hospital, the patients with unstable angina, as well as with acute myocardial infarction showed significantly higher levels of vWF, C–reactive protein, neutrophile myeloperoxidase and appropriate trends in circulating immune complexes, IL–6 and TNFα. In the patients admitted to the hospital with ischemic heart disease with repeated coronary events during the last year of follow–up, as well as in acute myocardial infarction, the levels of vWF antigen were found to be significantly increased. The raise of vWF was accompanied by increased levels of malonic dialdehyde, C3R–induced generation of free oxygen radicals in the neutrophils, and drop in glutatione reductase activity, thus reflecting an “oxidative stress” condition. These patients did also exhibit higher levels of C–reactive protein, circulating immune complexes, IL–6 and TNFα. According to regression analysis data, the levels of vWF antigen and C3R–induced activation free oxygen radicals in neutrophils are the indices that were most closely connected to ischemic heart failure disease within a year of observation. The results obtained point to the important role of “oxidative stress” in the development of endothelial dysfunction

  10. Complicated Onychomycosis in Patients with Metabolic Syndrome: Clinical Aspects of Deviation in the Laboratory Signs of Endothelial Dysfunction and Polyhypovitaminosis

    Directory of Open Access Journals (Sweden)

    O.N. Nadashkevich

    2015-08-01

    Full Text Available The study involved 93 patients aged 52 to 85 years with metabolic syndrome and concomitant complicated fungal nail infection. In all patients we have measured the levels of nitric oxide and endothelin-1. The content of B1, B2, PP, B6 and C vitamins in the blood, and urine excretion of derivatives before and during the treatment of patients with destructive onychomycosis were studied. It is noted that in the majority of patients (aged over 50 years with polyоnychomycosis and comorbid underlying metabolic syndrome has endothelial dysfunction and multivitamin deficiency that requires correction.

  11. YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis

    DEFF Research Database (Denmark)

    Rathcke, C N; Vestergaard, H

    2006-01-01

    Substantial evidence supports a role of chronic subclinical inflammation and activation of the innate immune system in the pathogenesis of insulin resistance and endothelial dysfunction and the development of type 2 diabetes (T2D) and atherosclerosis. Several proinflammatory cytokines, acute phase......-reactants and cell adhesion molecules play a pivotal role in this chronic subclinical inflammation but a comprehensive understanding of the interrelations of these molecules is still needed. YKL-40 is a new inflammatory marker with relation to acute and chronic inflammation as well as cancer. It is secreted in vitro...

  12. Myocardial Production of Plasminogen Activator Inhibitor-1 is Associated with Coronary Endothelial and Ventricular Dysfunction after Acute Myocardial Infarction.

    Science.gov (United States)

    Shimizu, Takuya; Uematsu, Manabu; Yoshizaki, Toru; Obata, Jun-Ei; Nakamura, Takamitsu; Fujioka, Daisuke; Watanabe, Kazuhiro; Watanabe, Yosuke; Kugiyama, Kiyotaka

    2016-05-02

    Although plasminogen activator inhibitor-1 (PAI-1) is abundantly expressed in infarcted myocardium, the pathogenic role of myocardial PAI-1 remains unknown. This study examined whether PAI-1 in the infarcted lesion contributes to coronary endothelial dysfunction and left ventricular (LV) dysfunction in patients with acute myocardial infarction (AMI). Plasma levels of PAI-1 activity and tissue-plasminogen activator (tPA) antigen were measured 2 weeks and 6 months after MI by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV) in 28 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD). Coronary blood flow responses in LAD to intracoronary infusion of acetylcholine (ACh) and left ventriculography were measured at the same time points: 2 weeks and 6 months after MI. The trans-myocardial gradient of PAI-1 from AO to AIV, reflecting production/release of PAI-1 in the infarcted lesion, was inversely correlated with the coronary blood flow response to ACh 6 months after MI (r=-0.43, p=0.02) and with the percentage change in LV regional motion in the LAD territory from 2 weeks to 6 months after MI (r=-0.38, p=0.04). The trans-myocardial gradient of tPA level showed no significant correlations. PAI-1 produced in the infarcted myocardium and released into the coronary circulation is associated with endothelial dysfunction in resistance vessels of the infarct-related coronary arteries and with progressive dysfunction of the infarcted region of the left ventricle in AMI survivors.

  13. Prevention of erectile dysfunction after radiotherapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    Izak Faiena

    2014-12-01

    Full Text Available With increasing scrutiny of prostate cancer (PCa diagnosis and treatment, much attention has been given to the morbidity caused by radical prostatectomy (RP and/or radiotherapy (RT. One of the most common side-effects of either treatment is erectile dysfunction (ED. [1] Approximately, 40% of patients will experience ED after RT for PCa. The post-RT ED causes significant patient dissatisfaction with cancer treatment as well as decrease in patient and partner psychosocial function. [2] To address this issue in patients undergoing RT, Pisansky et al. [3] conducted a prospective, randomized, double-blinded, placebo-controlled trial to assess the efficacy of a phosphodiesterase enzyme-5 inhibitor (PDE5i, tadalafil, as a preventive measure for patients undergoing RT for PCa and found no difference in erectile function between the control and treatment groups.

  14. Additive Effect of Non-Alcoholic Fatty Liver Disease on Metabolic Syndrome-Related Endothelial Dysfunction in Hypertensive Patients

    Directory of Open Access Journals (Sweden)

    Maria Perticone

    2016-03-01

    Full Text Available Metabolic syndrome (MS is characterized by an increased risk of incident diabetes and cardiovascular (CV events, identifying insulin resistance (IR and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA index. Vascular function, as forearm blood flow (FBF, was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS−NAFLD− and MS+NAFLD−. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD− and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD−, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives.

  15. Long-term smoking causes more advanced coronary endothelial dysfunction in middle-aged smokers compared to young smokers

    Energy Technology Data Exchange (ETDEWEB)

    Naya, Masanao; Goto, Daisuke; Tsutsui, Hiroyuki [Hokkaido University Graduate School of Medicine, Department of Cardiovascular Medicine, Sapporo (Japan); Morita, Koichi; Manabe, Osamu; Hirata, Kenji; Tamaki, Nagara [Hokkaido University Graduate School of Medicine, Department of Nuclear Medicine, Sapporo (Japan); Yoshinaga, Keiichiro [Hokkaido University Graduate School of Medicine, Department of Molecular Imaging, Sapporo (Japan); Katoh, Chietsugu [Hokkaido University Graduate School of Medicine, Department of Health Science, Sapporo (Japan)

    2011-03-15

    Smoking cessation has been shown to normalize the coronary endothelial dysfunction in healthy young smokers. However, its effect has not been explored in middle-aged smokers with a longer history of smoking. Therefore, we compared the effects of smoking cessation on coronary vasomotor response between both young and middle-aged smokers and identified the predictor for its improvement. This study investigated 14 young healthy smokers (age 25.2 {+-} 2.3 years), 13 middle-aged smokers (age 42.0 {+-} 6.5 years) and 10 non-smokers. Myocardial blood flow (MBF) was measured by using {sup 15}O-water positron emission tomography (PET). At baseline, the ratio of MBF during the cold pressor test (CPT) to that at rest (MBF{sub CPT/rest}), the index of coronary endothelial function, was significantly decreased in both young and middle-aged smokers compared to non-smokers (1.24 {+-} 0.20 and 1.10 {+-} 0.39 vs 1.53 {+-} 0.18, p < 0.05 and p < 0.001, respectively). The ratio of MBF during adenosine triphosphate infusion to that at rest was significantly decreased in middle-aged smokers compared to young smokers and non-smokers (3.34 {+-} 1.52 vs 4.43 {+-} 0.92 and 4.69 {+-} 1.25, p < 0.05, respectively). MBF{sub CPT/rest} at 1 month after smoking cessation significantly increased in young smokers, but not in middle-aged smokers. By multivariate analysis, baseline serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) was an independent predictor for the changes in MBF{sub CPT/rest} after smoking cessation ({beta} = -0.45, p < 0.05). Coronary endothelial dysfunction was reversible by short-term smoking cessation in young smokers, but not in middle-aged smokers, which was associated with serum MDA-LDL levels. Long-term smoking exposure could lead to more advanced coronary endothelial dysfunction and atherosclerosis possibly via oxidative stress. (orig.)

  16. Reduction of oxidative tissue injury and endothelial dysfunction by graduated reperfusion after cardioplegic arrest in isolated rat hearts.

    Science.gov (United States)

    Minor, T; Sturz, J; Klauke, H; Isselhard, W

    1995-03-01

    The aim of this study was to investigate whether or not a graduated resumption of the perfusion pressure after cardioplegic ischaemic arrest will reduce the impact of oxygen free radicals on myocardium and the cardiovasculature. Langendorff-perfused rat hearts were subjected to cardioplegia and subsequent 40 min of global ischaemia at 25 degrees C. Reperfusion was carried out either abruptly (AR) or gradually (i.e., perfusion pressure stepwise increased from 40 to 75 mmHg within 30 min -GR). GR resulted in a significant improvement of percentage recovery of left ventricular systolic pressure as compared to AR. A marked increase of thiobarbituric acid reactive substances (TBARS) was detected in the effluent during AR, accompanied by an impaired release of the endothelial vasodilator NO and diminished coronary flow rates compared to the baseline values. GR resulted in a significant reduction of TBARS in the effluent and promoted a better recovery of coronary flow as well as endothelial release of NO during the later phase of reperfusion. It is concluded that graduated reperfusion is beneficial in reducing free radical mediated peroxidative tissue injury and endothelial dysfunction upon reoxygenation.

  17. Effects of cyclic intermittent hypoxia on ET-1 responsiveness and endothelial dysfunction of pulmonary arteries in rats.

    Directory of Open Access Journals (Sweden)

    Zhuo Wang

    Full Text Available Obstructive sleep apnoea (OSA is a risk factor for cardiovascular disorders and in some cases is complication of pulmonary hypertension. We simulated OSA by exposing rats to cyclic intermittent hypoxia (CIH to investigate its effect on pulmonary vascular endothelial dysfunction. Sprague-Dawley Rats were exposed to CIH (FiO2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/wk for 3 wk, and the pulmonary arteries of normoxia and CIH treated rats were analyzed for expression of endothelin-1 (ET-1 and ET receptors by histological, immunohistochemical, RT-PCR and Western Blot analyses, as well as for contractility in response to ET-1. In the pulmonary arteries, ET-1 expression was increased, and ET-1 more potently elicited constriction of the pulmonary artery in CIH rats than in normoxic rats. Exposure to CIH induced marked endothelial cell damage associated with a functional decrease of endothelium-dependent vasodilatation in the pulmonary artery. Compared with normoxic rats, ETA receptor expression was increased in smooth muscle cells of the CIH rats, while the expression of ETB receptors was decreased in endothelial cells. These results demonstrated endothelium-dependent vasodilation was impaired and the vasoconstrictor responsiveness increased by CIH. The increased responsiveness to ET-1 induced by intermittent hypoxia in pulmonary arteries of rats was due to increased expression of ETA receptors predominantly, meanwhile, decreased expression of ETB receptors in the endothelium may also participate in it.

  18. L-Arginine and vitamin C attenuate pro-atherogenic effects of high-fat diet on biomarkers of endothelial dysfunction in rats.

    Science.gov (United States)

    Bogdański, Paweł; Suliburska, Joanna; Szulińska, Monika; Sikora, Marta; Walkowiak, Jarosław; Jakubowski, Hieronim

    2015-12-01

    High-fat diet (HFD) is known to cause endothelial dysfunction and contribute to atherosclerosis progression. The objective of this study was to evaluate the efficacy of L-arginine (L-Arg) and vitamin C supplementation as a potentially useful strategy for modulation of serum homocysteine (Hcy) levels, tumor necrosis factor alpha (TNF-α), oxidative stress, and insulin resistance induced by HFD in rats. Six weeks-old female and male Wistar rats were divided into five groups of twelve rats each and treated for six weeks with: group 1, standard diet; group 2, HFD; group 3, HFD supplemented with L-Arg (20g/kg diet); group 4, HFD supplemented with L-Arg (20g/kg diet) plus vitamin C (100mg/kg diet); group 5, HFD supplemented with vitamin C (100mg/kg diet). HFD significantly elevated TNF-α, reduced total antioxidant status (TAS), and increased insulin resistance (HOMA-IR). Significant increases of total cholesterol (TCH), LDL cholesterol (LDL), triglyceride (TG) and a decrease of HDL cholesterol (HDL) were observed in HFD rats. Supplementation with l-Arg prevented the decrease of TAS and the increases in HOMA-IR, LDL, and TG levels. Moreover, Hcy and TNF-α levels were reduced in L-Arg supplemented group. Supplementation with vitamin C significantly atenuated TAS decrease and lowered LDL levels. L-Arg plus vitamin C enhanced L-Arg effect on TAS and protected against TNF-α increase. Western blot analysis showed that l-Arg supplementation of HFD rats reduced the level of protein carbonyls. Taken together, these findings indicate that supplemental l-arginine and/or vitamin C, by their abilities to modulate biomarkers of HFD-induced endothelial dysfunction, are anti-atherogenic. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  19. Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced tumor necrosis factor-α expression.

    Science.gov (United States)

    Bollmann, Franziska; Wu, Zhixiong; Oelze, Matthias; Siuda, Daniel; Xia, Ning; Henke, Jenny; Daiber, Andreas; Li, Huige; Stumpo, Deborah J; Blackshear, Perry J; Kleinert, Hartmut; Pautz, Andrea

    2014-05-30

    Cardiovascular events are important co-morbidities in patients with chronic inflammatory diseases like rheumatoid arthritis. Tristetraprolin (TTP) regulates pro-inflammatory processes through mRNA destabilization and therefore TTP-deficient mice (TTP(-/-) mice) develop a chronic inflammation resembling human rheumatoid arthritis. We used this mouse model to evaluate molecular signaling pathways contributing to the enhanced atherosclerotic risk in chronic inflammatory diseases. In the aorta of TTP(-/-) mice we observed elevated mRNA expression of known TTP targets like tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1α, as well as of other pro-atherosclerotic mediators, like Calgranulin A, Cathepsin S, and Osteopontin. Independent of cholesterol levels TTP(-/-) mice showed a significant reduction of acetylcholine-induced, nitric oxide-mediated vasorelaxation. The endothelial dysfunction in TTP(-/-) mice was associated with increased levels of reactive oxygen and nitrogen species (RONS), indicating an enhanced nitric oxide inactivation by RONS in the TTP(-/-) animals. The altered RONS generation correlates with increased expression of NADPH oxidase 2 (Nox2) resulting from enhanced Nox2 mRNA stability. Although TNF-α is believed to be a central mediator of inflammation-driven atherosclerosis, genetic inactivation of TNF-α neither improved endothelial function nor normalized Nox2 expression or RONS production in TTP(-/-) animals. Systemic inflammation caused by TTP deficiency leads to endothelial dysfunction. This process is independent of cholesterol and not mediated by TNF-α solely. Thus, other mediators, which need to be identified, contribute to enhanced cardiovascular risk in chronic inflammatory diseases. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression*

    Science.gov (United States)

    Bollmann, Franziska; Wu, Zhixiong; Oelze, Matthias; Siuda, Daniel; Xia, Ning; Henke, Jenny; Daiber, Andreas; Li, Huige; Stumpo, Deborah J.; Blackshear, Perry J.; Kleinert, Hartmut; Pautz, Andrea

    2014-01-01

    Cardiovascular events are important co-morbidities in patients with chronic inflammatory diseases like rheumatoid arthritis. Tristetraprolin (TTP) regulates pro-inflammatory processes through mRNA destabilization and therefore TTP-deficient mice (TTP−/− mice) develop a chronic inflammation resembling human rheumatoid arthritis. We used this mouse model to evaluate molecular signaling pathways contributing to the enhanced atherosclerotic risk in chronic inflammatory diseases. In the aorta of TTP−/− mice we observed elevated mRNA expression of known TTP targets like tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1α, as well as of other pro-atherosclerotic mediators, like Calgranulin A, Cathepsin S, and Osteopontin. Independent of cholesterol levels TTP−/− mice showed a significant reduction of acetylcholine-induced, nitric oxide-mediated vasorelaxation. The endothelial dysfunction in TTP−/− mice was associated with increased levels of reactive oxygen and nitrogen species (RONS), indicating an enhanced nitric oxide inactivation by RONS in the TTP−/− animals. The altered RONS generation correlates with increased expression of NADPH oxidase 2 (Nox2) resulting from enhanced Nox2 mRNA stability. Although TNF-α is believed to be a central mediator of inflammation-driven atherosclerosis, genetic inactivation of TNF-α neither improved endothelial function nor normalized Nox2 expression or RONS production in TTP−/− animals. Systemic inflammation caused by TTP deficiency leads to endothelial dysfunction. This process is independent of cholesterol and not mediated by TNF-α solely. Thus, other mediators, which need to be identified, contribute to enhanced cardiovascular risk in chronic inflammatory diseases. PMID:24727475

  1. High-intensity interval exercise attenuates but does not eliminate endothelial dysfunction after a fast food meal.

    Science.gov (United States)

    Tucker, Wesley J; Sawyer, Brandon J; Jarrett, Catherine L; Bhammar, Dharini M; Ryder, Justin R; Angadi, Siddhartha S; Gaesser, Glenn A

    2018-02-01

    We investigated whether two different bouts of high-intensity interval exercise (HIIE) could attenuate postprandial endothelial dysfunction. Thirteen young (27 ± 1 yr), nonexercise-trained men underwent three randomized conditions: 1) four 4-min intervals at 85-95% of maximum heart rate separated by 3 min of active recovery (HIIE 4 × 4), 2) 16 1-min intervals at 85-95% of maximum heart rate separated by 1 min of active recovery (HIIE 16 × 1), and 3) sedentary control. HIIE was performed in the afternoon, ~18 h before the morning fast food meal (1,250 kcal, 63g of fat). Brachial artery flow-mediated dilation (FMD) was performed before HIIE ( baseline 1), during fasting before meal ingestion ( baseline 2), and 30 min, 2 h, and 4 h postprandial. Capillary glucose and triglycerides were assessed at fasting, 30 min, 1 h, 2 h, and 4 h (triglycerides only). Both HIIE protocols increased fasting FMD compared with control (HIIE 4 × 4: 6.1 ± 0.4%, HIIE 16 × 1: 6.3 ± 0.5%, and control: 5.1 ± 0.4%, P fast food meal can attenuate but not entirely eliminate postprandial decreases in FMD. This effect is not dependent on reductions in postprandial lipemia or glycemia. NEW & NOTEWORTHY Two similar high-intensity interval exercise (HIIE) protocols performed ∼18 h before ingestion of a high-energy fast food meal attenuated but did not entirely eliminate postprandial endothelial dysfunction in young men largely by improving fasting endothelial function. Both HIIE protocols produced essentially identical results, suggesting high reproducibility of HIIE effects.

  2. The results of correction of endothelial dysfunction in type 2 diabetes mellitus in patients with diabetic retinopathy and associated hypertension

    Directory of Open Access Journals (Sweden)

    L. K. Moshetova

    2013-01-01

    ischemic (Semaks therapy on clinical and functional and morphological parameters of the retina in patients with retinopathy in type 2 diabetes in combination with GB. NOx reduction in the tear fluid and serum was associated with decreased severity of clinical symptoms DR I and II, the resulting vascular endothelial dysfunction. This allows us to consider this as an effective therapeutic intervention aimed at preventing the onset and progression of retinopathy in the combined course of type 2 diabetes and hypertension.

  3. Factors correlated with improvement of endothelial dysfunction during rituximab therapy in patients with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Benucci M

    2013-03-01

    : 1.045–1.003; P = 0.025, IgM (OR 1.025; 95% CI: 1.045–1.004; P = 0.016, and interleukin (IL-8 (OR 0.487; 95% CI: 0.899–0.264; P = 0.021 were statistically associated with the improvement of FMD%, and that IL-8 (OR 0.717; 95% CI: 0.926–0.555; P = 0.018 was also statistically associated with improvement of ccIMT. The findings of the study confirm that RTX reduces the progression of accelerated atherosclerosis in patients with RA. They also show that improvement in CD19+ cells, IgM and GH after treatment are statistically associated with the improvement of FMD%, and that improvement in IL-8 levels after treatment is statistically associated with improved FMD% and with decrease in the ccIMT.Keywords: rituximab, rheumatoid arthritis, endothelial dysfunction 

  4. Pre-treatment with calcium prevents endothelial cell activation induced by multiple activators, necrotic trophoblastic debris or IL-6 or preeclamptic sera: possible relevance to the pathogenesis of preeclampsia.

    Science.gov (United States)

    Chen, Q; Zhang, Y; Tong, M; Wu, M; Snowise, S; Stone, P; Chamley, L W

    2013-12-01

    A hallmark of preeclampsia is endothelial cell dysfunction/activation in response to "toxins" from the placenta. Necrotic trophoblastic debris (NTD) is one possible placental toxin and others include inflammatory cytokines. Calcium supplementation appears to protect "at-risk" women from developing preeclampsia by an unknown mechanism. In this study we investigate whether the addition of high levels of calcium to endothelial cells prior to their exposure to the preeclampsia-associated activators could reduce the endothelial cell activation. NTD was harvested from 1st trimester placental explants. Endothelial cells were treated with varied concentrations of calcium prior to exposure to NTD, IL-6 or preeclamptic sera or low levels of calcium. Activation was monitored by quantifying endothelial cell-surface ICAM-1 by ELISA or U937 adhesion to endothelial cells. The activity of endothelial cell nitric oxide synthetase was blocked with L-NAME. Pre-treatment with increasing concentrations of calcium inhibited the activation of endothelial cells in response to NTD or IL-6 or preeclamptic sera. Inhibiting nitric oxide synthetase, using L-NAME, reduced the ability of high calcium levels to protect endothelial cell activation. Pre-treatment with calcium did not prevent endothelial cell activation induced by the reduction of the levels of calcium but additional calcium treatment did prevent endothelial cell activation induced by low calcium. Our results demonstrate calcium supplementation may prevent the activation of the endothelium in response to activators. These results may partially explain the benefits of calcium supplementation in the reduction of risk for developing preeclampsia and provide in vitro mechanistic support for the use of calcium supplementation in at-risk women. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults

    Science.gov (United States)

    Wilson, Carole L.; Gough, Peter J.; Chang, Cindy A.; Chan, Christina K.; Frey, Jeremy M.; Liu, Yonggang; Braun, Kathleen R.; Chin, Michael T.; Wight, Thomas N.; Raines, Elaine W.

    2013-01-01

    Global inactivation of the metalloproteinase ADAM17 during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of ADAM17-mediated processing of HB-EGF, as absence of soluble HB-EGF results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2-Cre transgenics to focus on the role of endothelial ADAM17 in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial ADAM17 appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf−/− valves, ADAM17-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-EGF. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that ADAM17 is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis. PMID:23354118

  6. Impaired blood rheology is associated with endothelial dysfunction in patients with coronary risk factors.

    Science.gov (United States)

    Yagi, Hideki; Sumino, Hiroyuki; Aoki, Tomoyuki; Tsunekawa, Katsuhiko; Araki, Osamu; Kimura, Takao; Nara, Makoto; Ogiwara, Takayuki; Murakami, Masami

    2016-01-01

    To investigate the relationship between blood rheology and endothelial function in patients with coronary risk factors, brachial arterial flow-mediated vasodilatation (FMD), an index of endothelial function and blood passage time (BPT), an index of blood rheology, and fasting blood cell count, glucose metabolism, and plasma fibrinogen, lipid, C-reactive protein, and whole blood viscosity levels were measured in 95 patients with coronary risk factors and 37 healthy controls. Brachial arterial FMD after reactive hyperemia was assessed by ultrasonography. BPT was assessed using the microchannel method. In healthy controls, BPT significantly correlated with FMD (r = - 0.325, p rheology using the microchannel method may be useful in evaluating brachial arterial endothelial function as a marker of atherosclerosis in these patients.

  7. Low-density lipoprotein modified by myeloperoxidase oxidants induces endothelial dysfunction

    DEFF Research Database (Denmark)

    Abdo, Adrian; Rayner, B.S.; van Reyk, D.M.

    2017-01-01

    Low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl) produced by myeloperoxidase (MPO) is present in atherosclerotic lesions, where it is implicated in the propagation of inflammation and acceleration of lesion development by multiple pathways, including the induction of endothelial...

  8. Urine albumin to creatinine ratio: A marker of early endothelial dysfunction in youth

    Science.gov (United States)

    The urine albumin-to-creatinine ratio (UACR) is a useful predictor of cardiovascular (CV) events in adults. Its relationship to vascular function in children is not clear. We investigated whether UACR was related to insulin resistance and endothelial function, a marker of subclinical atherosclerosis...

  9. Inhibition of Vascular c-Jun N-Terminal Kinase 2 Improves Obesity-Induced Endothelial Dysfunction After Roux-en-Y Gastric Bypass.

    Science.gov (United States)

    Doytcheva, Petia; Bächler, Thomas; Tarasco, Erika; Marzolla, Vincenzo; Engeli, Michael; Pellegrini, Giovanni; Stivala, Simona; Rohrer, Lucia; Tona, Francesco; Camici, Giovanni G; Vanhoutte, Paul M; Matter, Christian M; Lutz, Thomas A; Lüscher, Thomas F; Osto, Elena

    2017-11-14

    Roux-en-Y gastric bypass (RYGB) reduces obesity-associated comorbidities and cardiovascular mortality. RYGB improves endothelial dysfunction, reducing c-Jun N-terminal kinase (JNK) vascular phosphorylation. JNK activation links obesity with insulin resistance and endothelial dysfunction. Herein, we examined whether JNK1 or JNK2 mediates obesity-induced endothelial dysfunction and if pharmacological JNK inhibition can mimic RYGB vascular benefits. After 7 weeks of a high-fat high-cholesterol diet, obese rats underwent RYGB or sham surgery; sham-operated ad libitum-fed rats received, for 8 days, either the control peptide D-TAT or the JNK peptide inhibitor D-JNKi-1 (20 mg/kg per day subcutaneous). JNK peptide inhibitor D-JNKi-1 treatment improved endothelial vasorelaxation in response to insulin and glucagon-like peptide-1, as observed after RYGB. Obesity increased aortic phosphorylation of JNK2, but not of JNK1. RYGB and JNK peptide inhibitor D-JNKi-1 treatment blunted aortic JNK2 phosphorylation via activation of glucagon-like peptide-1-mediated signaling. The inhibitory phosphorylation of insulin receptor substrate-1 was reduced, whereas the protein kinase B/endothelial NO synthase pathway was increased and oxidative stress was decreased, resulting in improved vascular NO bioavailability. Decreased aortic JNK2 phosphorylation after RYGB rapidly improves obesity-induced endothelial dysfunction. Pharmacological JNK inhibition mimics the endothelial protective effects of RYGB. These findings highlight the therapeutic potential of novel strategies targeting vascular JNK2 against the severe cardiovascular disease associated with obesity. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  10. Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice

    Science.gov (United States)

    Winters, B.; Mo, Z.; Brooks-Asplund, E.; Kim, S.; Shoukas, A.; Li, D.; Nyhan, D.; Berkowitz, D. E.

    2000-01-01

    Obesity is a major health care problem and is associated with significant cardiovascular morbidity. Leptin, a neuroendocrine hormone released by adipose tissue, is important in modulating obesity by signaling satiety and increasing metabolism. Moreover, leptin receptors are expressed on vascular endothelial cells (ECs) and mediate angiogenesis. We hypothesized that leptin may also play an important role in vasoregulation. We investigated vasoregulatory mechanisms in the leptin-deficient obese (ob/ob) mouse model and determined the influence of leptin replacement on endothelial-dependent vasorelaxant responses. The direct effect of leptin on EC nitric oxide (NO) production was also tested by using 4, 5-diaminofluorescein-2 diacetate staining and measurement of nitrate and nitrite concentrations. Vasoconstrictor responses to phenylephrine, norepinephrine, and U-46619 were markedly enhanced in aortic rings from ob/ob mice and were modulated by NO synthase inhibition. Vasorelaxant responses to ACh were markedly attenuated in mesenteric microvessels from ob/ob mice. Leptin replacement resulted in significant weight loss and reversal of the impaired endothelial-dependent vasorelaxant responses observed in ob/ob mice. Preincubation of ECs with leptin enhanced the release of NO production. Thus leptin-deficient ob/ob mice demonstrate marked abnormalities in vasoregulation, including impaired endothelial-dependent vasodilation, which is reversed by leptin replacement. These findings may be partially explained by the direct effect of leptin on endothelial NO production. These vascular abnormalities are similar to those observed in obese, diabetic, leptin-resistant humans. The ob/ob mouse may, therefore, be an excellent new model for the study of the cardiovascular effects of obesity.

  11. Direct renin inhibition is not enough to prevent reactive oxygen species generation and vascular dysfunction in renovascular hypertension.

    Science.gov (United States)

    Martins-Oliveira, Alisson; Guimaraes, Danielle A; Ceron, Carla S; Rizzi, Elen; Oliveira, Diogo M M; Tirapelli, Carlos R; Casarini, Dulce E; Fernandes, Fernanda B; Pinheiro, Lucas C; Tanus-Santos, Jose E

    2018-02-15

    Renin-angiotensin system activation promotes oxidative stress and endothelial dysfunction. However, no previous study has examined the effects of the renin inhibitor aliskiren, either alone or combined with angiotensin II type 1 antagonists on alterations induced by two-kidney, one-clip (2K1C) hypertension. We compared the vascular effects of aliskiren (50mg/kg/day), losartan (10mg/kg/day), or both by gavage for 4 weeks in 2K1C and control rats. Treatment with losartan, aliskiren, or both exerted similar antihypertensive effects. Aliskiren lowered plasma Ang I concentrations in sham rats and in hypertensive rats treated with aliskiren or with both drugs. Aliskiren alone or combined with losartan decreased plasma angiotensin II concentrations measured by high performance liquid chromatography, whereas losartan alone had no effects. In contrast, losartan alone or combined with aliskiren abolished hypertension-induced increases in aortic angiotensin II concentrations, whereas aliskiren alone exerted no such effects. While hypertension enhanced aortic oxidative stress assessed by dihydroethidium fluorescence and by lucigenin chemiluminescence, losartan alone or combined with aliskiren, but not aliskiren alone, abolished this alteration. Hypertension impaired aortic relaxation induced by acetylcholine, and losartan alone or combined with aliskiren, but not aliskiren alone, reversed this alteration. Losartan alone or combined with aliskiren, but not aliskiren alone, increased plasma nitrite concentrations in 2K1C rats. These findings show that antihypertensive effects of aliskiren do not prevent hypertension-induced vascular oxidative stress and endothelial dysfunction. These findings contrast those found with losartan and suggest that renin inhibition is not enough to prevent hypertension-induced impaired redox biology and vascular dysfunction. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Habitual Coffee Consumption Does Not Correlate with Blood Pressure, Inflammation and Endothelial Dysfunction but Partially Correlates with Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Erizal Sugiono

    2013-04-01

    Full Text Available BACKGROUND: Coffee is the most widely consumed beverage in the world and has been known to have effects on cardiovascular system. Many researchers have examined the effects of coffee consumption on blood pressure (BP and risk of cardiovascular disease (CVD, but their results were inconsistent and still remain a subject of controversy. Oxidative stress, inflammation, and endothelial dysfunction have been known as risk factors of hypertension and CVD. Those factors are also known to be affected by coffee consumption. The aim of this study was to examine the relationship between the effects of habitual coffee consumption on BP and to examine the role of oxidative stress (F2 isoprostane, inflammation (high sensitive C-reactive protein (hsCRP and endothelial dysfunction (asymmetric dimethylarginine (ADMA. METHODS: This was a cross-sectional study in which 47 healthy, non-smoking men aged 30-60 years with varying coffee-drinking habits were enrolled. BP and blood/urine analysis of biomarkers were measured in the morning before activity. Coffee consumption was assessed using a questionnaire. The differences among variables were analyzed using ANOVA and the correlations between variables were analyzed using Kendall’s Tau correlation analysis. RESULTS: Habitual coffee consumption did not correlate with systolic/diastolic BP (r=-0.02; p=0.856 and r=0.15; p=0.230, respectively. Concentrations of ADMA and hsCRP were also not correlated with coffee consumption (r=0.03; p=0.764 and r=0.04; p=0.701, respectively. Coffee consumption only showed significant correlation with F2 isoprostane (r=0.34; p=0.004. CONCLUSIONS: BP was not affected by coffee consumption although coffee consumption has a significant correlation with F2 isoprostane. These findings suggest that correlation between coffee consumption and BP might be explained by other factors that were not included in this study. KEYWORDS: coffee, caffeine, cardiovascular disease, blood pressure, oxidative

  13. [Recent advances on pericytes in microvascular dysfunction and traditional Chinese medicine prevention].

    Science.gov (United States)

    Liu, Lei; Liu, Jian-Xun; Guo, Hao; Ren, Jian-Xun

    2017-08-01

    Pericytesis a kind of widespread vascular mural cells embedded within the vascular basement membrane of blood microvessels, constituting the barrier of capillaries and tissue spaces together with endothelial cells. Pericytes communicate with microvascular endothelial cells through cell connections or paracrine signals, playing an important role in important physiological processes such as blood flow, vascular permeability and vascular formation. Pericytes dysfunction may participate in some microvascular dysfunction, and also mediate pathological repair process, therefore pericytes attracted more and more attention. Traditional Chinese medicine suggests that microvascular dysfunction belongs to the collaterals disease; Qi stagnation and blood stasis in collaterals result in function imbalance of internal organs. Traditional Chinese medicine (TCM) has shown effects on pericytes in microvascular dysfunction, for example qi reinforcing blood-circulation activating medicines can reduce the damage of retinal pericytes in diabetic retinopathy. However, there are some limitations of research fields, inaccuracy of research techniques and methods, and lack of mechanism elaboration depth in the study of microvascular lesion pericytes. This paper reviewed the biological characteristics of pericytes and pericytes in microvascular dysfunction, as well as the intervention study of TCM on pericytes. The article aims to provide reference for the research of pericytes in microvascular dysfunction and the TCM study on pericytes. Copyright© by the Chinese Pharmaceutical Association.

  14. L-arginine and L-NMMA for Assessing Cerebral Endothelial Dysfunction in Ischemic Cerebrovascular Disease: A Systematic Review

    DEFF Research Database (Denmark)

    Karlsson, William Kristian; Sørensen, Caspar Godthaab; Kruuse, Christina

    2017-01-01

    Endothelial dysfunction (ED), in particular cerebral ED, may be an essential biomarker for ischaemic cerebrovascular disease. However, there is no consensus on methods to best estimate cerebral ED. In this systematic review, we evaluate the use of l-arginine and NG -monomethyl-l-arginine (l......-NMMA) for assessment of cerebral ED. A systematic search of PubMed, EMBASE and the Cochrane Library was done. We included studies investigating cerebrovascular response to l-arginine or l-NMMA in human subjects with vascular risk factors or ischaemic cerebrovascular disease. Seven studies (315 subjects) were eligible...... cerebrovascular disease. Inconsistencies in results were most likely due to variations in methods and included subject populations. In order to use cerebral ED as a prognostic marker, further studies are required to evaluate the association to cerebrovascular disease....

  15. Endothelial dysfunction in normoglycaemic first-degree relatives of type 2 diabetes mellitus complicated with hyperuricaemia.

    Science.gov (United States)

    Zhang, Junxia; Xiang, Lin; Zhang, Bilin; Cheng, Yangyang

    2017-03-01

    To reveal the effect of hyperuricaemia on endothelial function in normoglycaemic first-degree relatives of type 2 diabetes mellitus. In all, 40 first-degree relatives of type 2 diabetes mellitus with hyperuricaemia, 40 first-degree relatives of type 2 diabetes mellitus with normouricaemia and 35 healthy subjects without diabetic family history were recruited in this study. Anthropometric parameters as well as blood pressure, blood lipids, fasting blood glucose, fasting insulin, C-reactive protein, tumour necrosis factor-α and interleukin-6 were measured. Insulin resistance was assessed with homoeostasis model assessment index-insulin resistance index. To assess endothelial function, high-resolution ultrasonography was used for measuring flow- and nitroglycerine-mediated brachial artery vasodilation. When compared with control, flow-mediated dilation was lower in first-degree relatives with or without hyperuricaemia (both p type 2 diabetes mellitus (β = -0.677, p type 2 diabetes mellitus complicated with hyperuricaemia.

  16. Markers of inflammation and endothelial dysfunction are associated with incident cardiovascular disease, all-cause mortality, and progression of coronary calcification in type 2 diabetic patients with microalbuminuria

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Reinhard, Henrik; Hansen, Tine Willum

    2016-01-01

    BACKGROUND: We evaluated markers of inflammation and endothelial dysfunction and their associations with incident cardiovascular disease (CVD), all-cause mortality and progression of coronary artery calcium (CAC) in patients with type 2 diabetes (T2D) and microalbuminuria but without known corona...

  17. Alcohol and red wine consumption, but not fruit, vegetables, fish or dairy products, are associated with less endothelial dysfunction and less low-grade inflammation

    NARCIS (Netherlands)

    Bussel, van B.C.T.; Henry, R.M.A.; Schalkwijk, C.G.; Dekker, J.M.; Nijpels, G.; Feskens, E.J.M.; Stehouwer, C.D.A.

    2017-01-01

    Purpose: Endothelial dysfunction and low-grade inflammation are key phenomena in the pathobiology of cardiovascular disease (CVD). Their dietary modification might explain the observed reduction in CVD that has been associated with a healthy diet rich in fruit, vegetables and fish, low in dairy

  18. Body mass index is associated with microvascular endothelial dysfunction in patients with treated metabolic risk factors and suspected coronary artery disease

    NARCIS (Netherlands)

    D.J. Van Der Heijden (Dirk J.); M.A.H. van Leeuwen (Maarten); G.N. Janssens (Gladys N.); M.J. Lenzen (Mattie); P.M. van de Ven (Peter); E.C. Eringa (Etto ); N. van Royen (Niels)

    2017-01-01

    textabstractBackground--Obesity is key feature of the metabolic syndrome and is associated with high cardiovascular morbidity and mortality. Obesity is associated with macrovascular endothelial dysfunction, a determinant of outcome in patients with coronary artery disease. Here, we compared the

  19. Endovascular treatment of chronic cerebro spinal venous insufficiency in patients with multiple sclerosis modifies circulating markers of endothelial dysfunction and coagulation activation: a prospective study.

    Science.gov (United States)

    Napolitano, Mariasanta; Bruno, Aldo; Mastrangelo, Diego; De Vizia, Marcella; Bernardo, Benedetto; Rosa, Buonagura; De Lucia, Domenico

    2014-10-01

    We performed a monocentric observational prospective study to evaluate coagulation activation and endothelial dysfunction parameters in patients with multiple sclerosis undergoing endovascular treatment for cerebro-spinal-venous insufficiency. Between February 2011 and July 2012, 144 endovascular procedures in 110 patients with multiple sclerosis and chronical cerebro-spinal venous insufficiency were performed and they were prospectively analyzed. Each patient was included in the study according to previously published criteria, assessed by the investigators before enrollment. Endothelial dysfunction and coagulation activation parameters were determined before the procedure and during follow-up at 1, 3, 6, 9, 12, 15 and 18 months after treatment, respectively. After the endovascular procedure, patients were treated with standard therapies, with the addition of mesoglycan. Fifty-five percent of patients experienced a favorable outcome of multiple sclerosis within 1 month after treatment, 25% regressed in the following 3 months, 24.9% did not experience any benefit. In only 0.1% patients, acute recurrence was observed and it was treated with high-dose immunosuppressive therapy. No major complications were observed. Coagulation activation and endothelial dysfunction parameters were shown to be reduced at 1 month and stable up to 12-month follow-up, and they were furthermore associated with a good clinical outcome. Endovascular procedures performed by a qualified staff are well tolerated; they can be associated with other currently adopted treatments. Correlations between inflammation, coagulation activation and neurodegenerative disorders are here supported by the observed variations in plasma levels of markers of coagulation activation and endothelial dysfunction.

  20. INSTRUMENTAL AND DIAGNOSTIC CRITERIA OF HEMODYNAMIC DISORDERS AND ENDOTHELIAL DYSFUNCTION CORRECTION IN PREGNANTS WITH ARTERIAL HYPERTENSION

    OpenAIRE

    S. M. Heryak; I. Ye. Humenna

    2014-01-01

    Background. According to the WHO, hypertension is associated with 20-33 % of maternal death during pregnancy within extragenital pathology statistics. There are complications of the fetus and newborn associated with hypertension at 140/90 mm Hg and higher. Objective. A comparative analysis of antihypertensive therapy effectiveness in pregnants with arterial hypertension was performed using modern clinical and instrumental methods of endothelial function diagnostic, central and utero-placen...

  1. Endothelial dysfunction is associated with carotid plaque: a cross-sectional study from the population based Northern Manhattan Study

    Directory of Open Access Journals (Sweden)

    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.

  2. Correlation between Flicker-Induced Retinal Vessel Vasodilatation and Plasma Biomarkers of Endothelial Dysfunction in Hypertensive Patients.

    Science.gov (United States)

    Machalińska, Anna; Pius-Sadowska, Ewa; Babiak, Katarzyna; Sałacka, Anna; Safranow, Krzysztof; Kawa, Miłosz Piotr; Machaliński, Bogusław

    2018-01-01

    Hypertension (HT) strongly affects the vascular endothelium, resulting in chronic inflammatory disease. Dynamic vessel analysis (DVA) is a modern methodological approach to analyze vascular function in the retinal microcirculation. The aim of this study was to examine whether a defective retinal vessels response is associated with HT-induced endothelial dysfunction. Retinal vessel reactions to flicker stimulation were examined by DVA in both eyes of 37 hypertensive and 41 healthy control subjects. Plasma concentrations of C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha (TNFɑ) were measured using the enzyme-linked immunosorbent assay. Both arterial and vein responses to flicker stimulation were significantly decreased in patients with HT compared with the healthy controls (dilatation of the arteries was lower in the HT group by, on average, 1.31, p = 0.001 and dilatation of the veins was lower in the HT group by, on average, 1.32, p = 0.002) after independent adjustment for age, sex, body mass index, and pressure values. In the hypertensive group, there was a negative correlation between the arterial response to flicker stimulation and the plasma CRP concentration (Spearman's Rank-order Coefficient (Rs) = -0.29, p = 0.07). Similarly, the plasma TNFα concentrations negatively correlated with the arterial response to flicker stimulation (Rs = -0.39, p = 0.02). Our results indicate that DVA directly reflects the actual metabolic status of the retinal endothelium. DVA might be used as an early noninvasive screening tool to detect vascular dysregulation and pan-endothelial dysfunction in patients with HT.

  3. Development of endothelial dysfunction at an obliterating atherosclerosis of vessels of the lower extremities and markers of prediction of a course of a disease

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    S. S. Dunaevskaya

    2017-01-01

    Full Text Available In this review questions of development of endothelial dysfunction and its influence on progressing of a disease at an obliterating atherosclerosis of vessels of the lower extremities are considered. The role of selektin in adhesion of leukocytes on the endothelial cells leading to inflammatory reaction of a vascular wall is defined. In researches influence of the infectious agent on risk of development of a disease is noted. Decrease in dilatiruyushchy function of an endothelium happens due to deficiency of synthesis of nitrogen oxide. Development of an oxidizing stress and development of the fissile forms of oxygen exerts negative impact on an endothelium. The indicators associated with an atherosclerosis are inflammation mediators, markers of endothelial dysfunction and an angiogenesis, a lipide profile and factors of coagulation.

  4. Effects of zinc and manganese on advanced glycation end products (AGEs) formation and AGEs-mediated endothelial cell dysfunction.

    Science.gov (United States)

    Zhuang, Xiuyuan; Pang, Xiufeng; Zhang, Wen; Wu, Wenbin; Zhao, Jingjing; Yang, Huangjian; Qu, Weijing

    2012-01-16

    The present study investigated the effects of ZnCl₂ and MnCl₂ supplementations on advanced glycation end products (AGEs) formation and AGEs-mediated endothelial cell dysfunction. Fluorescence detection was used to monitor the Maillard reaction. Inductively coupled plasma optical emission spectroscopy was used to test cellular zinc and manganese levels. Real-time reverse transcription polymerase chain reaction and western blot were used to analyze the expression of endothelial nitric oxide synthase (eNOS), nuclear transcription factor kappa B (NF-κB), and receptor for AGEs (RAGE). Intracellular reactive oxygen species (ROS) and nitric oxide (NO) production, NOS activity were determined by fluorescent probe assay, superoxide dismutase (SOD) activity was determined by water soluble tetrazolium salt assay. MnCl₂ showed excellent inhibitory effect on AGEs formation. Primary cultured bovine aortic endothelial cells (BAECs) were exposed to AGEs for 30 min, followed by trace element treatments. Cell viability and the zinc levels declined due to AGEs exposure, which were improved with the supplementations of ZnCl₂ and MnCl₂. Furthermore, ZnCl₂ supplementation effectively enhanced intracellular NO production, elevated eNOS expression and enzymatic activity, and down-regulated NF-κB activation and RAGE expression. MnCl₂ dose-dependently impaired ROS formation, down-regulated NF-κB protein expression and nuclear translocation, as well as restored Mn-SOD enzymatic capability. Our findings suggested that trace elements relevant to diabetic, such as zinc and manganese played different roles in the formation of AGEs. Both the elements benefited the AGEs-injured BAECs through different mechanisms. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. [Influence of exam stress on the development of endothelial dysfunction and the formation of platelet-leukocyte coagregates].

    Science.gov (United States)

    Fefelova, E V; Tereshkov, P P; Plotnikova, O K; Stafeev, A N; Semenov, A V; Svistunova, N M; Ivanov, M O

    2015-01-01

    The aim of this work was to study the qualitative and quantitative composition of circulating endotheliocytes, P-selectin-associated leukocyte and platelet of coogregation blood levels of endothelin, interleukin-6 students on the background of exam stress. The research was made on the group conditionally healthy volunteers aged MT 18.3 ± 1 years that before participating in the study had a medical examination (n = 15). Blood sampling was made three times: 1--three months before the session (in a normal school day, two hours after training sessions), 2--for 25 ± 10 min before the exam, 3 - 15 ± 10 min after the exam. Approved the development of endothelial dysfunction in the background of exam stress, manifested by increased levels of circulating endothelial cells and endothelin. The total number of leukocyte and platelet of coogregation during the semester, before and after the exam has not changed, while there was an increase outlets, due to the expression of P-selectin on red blood cells before the exam and precipitous decline after the exam.

  6. Indoxyl Sulfate Impairs Endothelial Progenitor Cells and Might Contribute to Vascular Dysfunction in Patients with Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Cheng-Jui Lin

    2016-12-01

    Full Text Available Background/Aims: Indoxyl sulfate (IS is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease (CKD. We explored the effect of IS on human early endothelial progenitor cells (EPCs and analyzed the correlation between serum IS levels and parameters of vascular function, including endothelial function in a CKD-based cohort. Methods: A cross-sectional study with 128 stable CKD patients was conducted. Flow-mediated dilation (FMD, pulse wave velocity (PWV, ankle brachial index, serum IS and other biochemical parameters were measured and analyzed. In parallel, the activity of early EPCs was also evaluated after exposure to IS. Results: In human EPCs, a concentration-dependent inhibitory effect of IS on chemotactic motility and colony formation was observed. Additionally, serum IS levels were significantly correlated with CKD stages. The total IS (T-IS and free IS (F-IS were strongly associated with age, hypertension, cardiovascular disease, blood pressure, PWV, blood urea nitrogen, creatine and phosphate but negatively correlated with FMD, the estimated glomerular filtration rate (eGFR, hemoglobin, hematocrit, and calcium. A multivariate linear regression analysis also showed that FMD was significantly associated with IS after adjusting for other confounding factors. Conclusions: In humans, IS impairs early EPCs and was strongly correlated with vascular dysfunction. Thus, we speculate that this adverse effect of IS may partly result from the inhibition of early EPCs.

  7. Association of impaired endothelial glycocalyx with arterial stiffness, coronary microcirculatory dysfunction, and abnormal myocardial deformation in untreated hypertensives.

    Science.gov (United States)

    Ikonomidis, Ignatios; Voumvourakis, Astrinos; Makavos, George; Triantafyllidi, Helen; Pavlidis, George; Katogiannis, Konstantinos; Benas, Dimitris; Vlastos, Dimitris; Trivilou, Paraskevi; Varoudi, Maria; Parissis, John; Iliodromitis, Efstathios; Lekakis, John

    2018-03-02

    We investigated the association of endothelial glycocalyx damage with arterial stiffness, impairment of coronary microcirculatory function, and LV myocardial deformation in 320 untreated hypertensives and 160 controls. We measured perfused boundary region (PBR) of the sublingual microvessels, a marker inversely related with glycocalyx thickness, coronary flow reserve (CFR), and Global Longitudinal strain (GLS) by echocardiography, pulse wave velocity (PWV), and central systolic blood pressure (cSBP). Hypertensives had higher PBR, PWV cSBP, and lower CFR and GLS than controls (P < .05). In hypertensives, increased PBR was associated with increased cSBP, PWV, and decreased CFR and GLS after adjustment for age, sex, BMI, smoking LV mass, heart rate, hyperlipidemia, and office SBP (P < .05). PBR had an additive value to PWV, CFR, and office SBP for the prediction of abnormal GLS (x 2  = 2.4-3.8, P for change = .03). Endothelial glycocalyx is impaired in untreated hypertensives and is related to arterial stiffness, coronary, and myocardial dysfunction. ©2018 Wiley Periodicals, Inc.

  8. Circulating Endothelial Cells in Patients with Heart Failure and Left Ventricular Dysfunction

    Science.gov (United States)

    Martínez-Sales, Vicenta; Sánchez-Lázaro, Ignacio; Vila, Virtudes; Almenar, Luis; Contreras, Teresa; Reganon, Edelmiro

    2011-01-01

    Introduction and Aims: Acute and chronic heart failure may manifest different degrees of endothelial damage and angiogenesis. Circulating endothelial cells (CEC) have been identified as marker of vascular damage. The aim of our study was to evaluate the evolution of the CEC at different stages of patients with heart failure. We also investigated a potential correlation between CEC and markers of vascular damage and angiogenesis. Methods: We studied 32 heart failure patients at hospital admission (acute phase) and at revision after 3 months (stable phase) and 32 controls. Circulating markers of endothelial damage (CEC; von Willebrand factor, vWF and soluble E-selectin, sEsel) and angiogenesis (vascular endothelial growth factor, VEGF and thrombospondin-1) were quantified. Results: Levels of CEC, vWF, sEsel and VEGF are significantly higher in heart failure patients than in controls. Levels of CEC (36.9 ± 15.3 vs. 21.5 ± 10.0 cells/ml; p < 0.001), vWF (325 ± 101 vs. 231 ± 82%; p < 0.001) and VEGF (26.3 ± 15.2 vs. 21.9 ± 11.9 ng/ml; p < 0.001) are significantly higher in the acute phase than in the stable phase of heart failure. CEC levels correlate with vWF and VEGF. Results show than 100% of patients in acute phase and 37.5% in stable phase have levels of CEC higher than the 99th percentile of the distribution of controls (16 cells/ml). Therefore, increases in CEC represent a relative risk of 9.5 for heart failure patients suffering from acute phase. Conclusions: CEC, in addition to being elevated in heart failure, correlate with vWF levels, providing further support for CEC as markers of endothelial damage. Levels of CEC are associated with the acute phase of heart failure and could be used as a marker of the worsening in heart failure. PMID:21897001

  9. Interval exercise, but not endurance exercise, prevents endothelial ischemia-reperfusion injury in healthy subjects.

    Science.gov (United States)

    Seeger, Joost P H; Lenting, Charlotte J; Schreuder, Tim H A; Landman, Thijs R J; Cable, N Timothy; Hopman, Maria T E; Thijssen, Dick H J

    2015-02-15

    Endothelial ischemia-reperfusion (I/R) injury importantly contributes to the poor prognosis during ischemic (myocardial) events. Preconditioning, i.e., repeated exposure to short periods of ischemia, effectively reduces endothelial I/R injury. In the present study, we examined the hypothesis that exercise has preconditioning effects on endothelial I/R injury. Therefore, we studied whether an acute bout of endurance or interval exercise is able to protect against endothelial I/R injury. In 17 healthy young subjects, we examined changes in brachial artery endothelial function using flow-mediated dilation (FMD) before and after a bout of high-intensity interval exercise, moderate-intensity endurance exercise, or a control intervention. Subsequently, I/R injury was induced by inflation of a blood pressure cuff around the upper arm to 220 mmHg for 20 min and 20 min of reperfusion followed by another FMD measurement. Near-infrared spectrometry was used to examine local tissue oxygenation during exercise. No differences in brachial artery FMD were found at baseline for the three conditions. I/R induced a significant decline in FMD (7.1±2.3 to 4.3±2.3, Pexercise bout, no change in FMD was present after I/R (7.7±3.1 to 7.2±3.1, P=0.56), whereas the decrease in FMD after I/R could not be prevented by the endurance exercise bout (7.8±3.1 to 3.8±1.7, Pexercise, but not moderate-intensity endurance exercise, effectively prevents brachial artery endothelial I/R injury. This indicates the presence of a remote preconditioning effect of exercise, which is selectively present after short-term interval but not continuous exercise in healthy young subjects. Copyright © 2015 the American Physiological Society.

  10. Alcohol and red wine consumption, but not fruit, vegetables, fish or dairy products, are associated with less endothelial dysfunction and less low-grade inflammation: the Hoorn Study.

    Science.gov (United States)

    van Bussel, B C T; Henry, R M A; Schalkwijk, C G; Dekker, J M; Nijpels, G; Feskens, E J M; Stehouwer, C D A

    2017-03-27

    Endothelial dysfunction and low-grade inflammation are key phenomena in the pathobiology of cardiovascular disease (CVD). Their dietary modification might explain the observed reduction in CVD that has been associated with a healthy diet rich in fruit, vegetables and fish, low in dairy products and with moderate alcohol and red wine consumption. We investigated the associations between the above food groups and endothelial dysfunction and low-grade inflammation in a population-based cohort of Dutch elderly individuals. Diet was measured by food frequency questionnaire (n = 801; women = 399; age 68.5 ± 7.2 years). Endothelial dysfunction was determined (1) by combining von Willebrand factor, and soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, endothelial selectin and thrombomodulin, using Z-scores, into a biomarker score and (2) by flow-mediated vasodilation (FMD), and low-grade inflammation by combining C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumour necrosis factor α and sICAM-1 into a biomarker score, with smaller FMD and higher scores representing more dysfunction and inflammation, respectively. We used linear regression analyses to adjust associations for sex, age, energy, glucose metabolism, body mass index, smoking, prior CVD, educational level, physical activity and each of the other food groups. Moderate [β (95% CI) -0.13 (-0.33; 0.07)] and high [-0.22 (-0.45; -0.003)] alcohol consumption, and red wine [-0.16 (-0.30; -0.01)] consumption, but none of the other food groups, were associated with a lower endothelial dysfunction biomarker score and a greater FMD. The associations for FMD were, however, not statistically significant. Only red wine consumption was associated with a lower low-grade inflammation biomarker score [-0.18 (-0.33; -0.04)]. Alcohol and red wine consumption may favourably influence processes involved in atherothrombosis.

  11. Effects of the vasodilating beta-blocker nebivolol on smoking-induced endothelial dysfunction in young healthy volunteers

    Directory of Open Access Journals (Sweden)

    André C Schmidt

    2008-08-01

    Full Text Available André C Schmidt1, Burkhard Flick1, Elke Jahn2, Peter Bramlage31Charité – Universitätsmedizin Berlin, Institute for Clinical Pharmacology and Toxikology, Berlin, Germany; 2Berlin-Chemie AG, Clinical Research and Medical Information, Berlin, Germany; 3Institute for Clinical Pharmacology, Medical Faculty Carl Gustav Carus, TU Dresden, GermanyObjective: To assess the effect of nebivolol, a highly selective third generation β1-adrenoceptor antagonist with an endothelium-dependent vasodilatory action, on smoking-induced endothelial dysfunction.Research design and methods: This open-label study examined the effect of 14 daily doses of 5 mg nebivolol on forearm blood flow in 21 healthy, young, male, light smokers (≤5 cigarettes/day, measured by plethysmography on Days 1, 7, and 14. The primary endpoint was the difference in forearm blood flow after smoking one standard cigarette from baseline (Day 1 until treatment end on Day 14. Secondary outcomes included the difference in forearm blood flow between Day 1 and Day 7 compared with Day 14 before and after smoking, the effect of nebivolol on blood coagulation parameters, high-sensitive-C-reactive protein (hs-CRP, and the safety and tolerability of nebivolol.Results: Nebivolol for 14 days did not significantly affect forearm blood flow after smoking. On Day 7 of nebivolol treatment, forearm blood flow after smoking was significantly greater than blood flow before smoking (increase of 0.44 mL/min; p = 0.00656. Serum level of hs-CRP showed a marked decrease from Day 1 to Day 14. No changes in coagulation parameters were observed over the course of nebivolol treatment. Nebivolol was well tolerated throughout the study.Conclusions: The increase in forearm blood flow and the marked decrease in hs-CRP over 14 days of treatment suggest that nebivolol has a positive effect on endothelial function in light smokers, but larger studies are required to confirm these observations.Keywords: C-reactive protein

  12. Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn study

    NARCIS (Netherlands)

    Hecke, van M.V.; Dekker, J.M.; Nijpels, M.G.A.A.M.; Moll, A.C.; Heine, R.J.; Bouter, L.M.; Polak, B.C.P.; Stehouwer, C.D.A.

    2005-01-01

    AIMS/HYPOTHESIS: The exact pathogenesis of retinopathy in diabetic and non-diabetic individuals is incompletely understood, but may involve chronic low-grade inflammation and dysfunction of the vascular endothelium. The aim of this study was to investigate the association of inflammation and

  13. Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn study

    NARCIS (Netherlands)

    van Hecke, M.V.; Dekker, J.M.; Nijpels, M.G.A.A.M.; Moll, A.C.; Heine, R.J.; Bouter, L.M.; Polak, B.C.P.; Stehouwer, C.D.A.

    2005-01-01

    Aims/hypothesis: The exact pathogenesis of retinopathy in diabetic and non-diabetic individuals is incompletely understood, but may involve chronic low-grade inflammation and dysfunction of the vascular endothelium. The aim of this study was to investigate the association of inflammation and

  14. Immunohistochemical properties of the expression of endothelial nitric oxide synthase in placenta in its dysfunction in women with iron deficiency anemia

    Directory of Open Access Journals (Sweden)

    I. A. Ancheva

    2014-08-01

    Full Text Available Aim. The pertinence of the study is related to a large prevalence of dysfunction of the placenta in pregnant women suffering from anemia. To evaluate the immunohistochemical expression characteristics of endothelial NO-synthase (eNOS in the placenta during its dysfunction in women against the background of anemia 30 samples of placental tissue were studied with the use of immunohistochemical and micrometer methods. Materials and results. It was found that the expression of eNOS in patients with iron defi ciency anemia in the cytoplasm of syncytium of villi and fetal capillary endothelium as well as decidual vessels decreases, with the most pronounced changes in the expression of eNOS observed in the presence of the combination of placental dysfunction and iron defi ciency anemia in the form of paradoxical increase in expression. Conclusion. This indicates the necessity for correction of endothelial function in women with anemia during pregnancy.

  15. Aromatherapy alleviates endothelial dysfunction of medical staff after night-shift work: preliminary observations.

    Science.gov (United States)

    Shimada, Kenei; Fukuda, Shota; Maeda, Kumiko; Kawasaki, Toshihiro; Kono, Yasushi; Jissho, Satoshi; Taguchi, Haruyuki; Yoshiyama, Minoru; Yoshikawa, Junichi

    2011-02-01

    Night-shift work causes mental stress and lifestyle changes, and is recognized as a risk of cardiovascular diseases associated with impaired endothelial function. Aromatherapy is becoming popular as a complementary therapy that is beneficial for mental relaxation. The purpose of this study was to investigate the effect of aromatherapy on the endothelial function of medical staff after night-shift work. This study consisted of 19 healthy medical personnel (19 men, mean age 32 ± 7 years), including 11 physicians and 8 technicians. Aromatherapy was performed for 30 min by inhalation of the essential oil of lavender. Flow-mediated dilation (FMD) of the brachial artery was measured three times in each subject: on a regular workday, and after night-shift work before and immediately after aromatherapy. A control study was performed to assess the effect of a 30-min rest without aromatherapy. The mean value of sleep time during night-shift work was 3.3 ± 1.3 h. FMD after night-shift work was lower than on a regular workday (10.4 ± 1.8 vs. 12.5 ± 1.7%, Paromatherapy (11.8 ± 2.5%, P=0.02 vs. before aromatherapy). FMD was stable in the control study (10.1 ± 1.9 vs. 10.1 ± 2.2%, P=0.9). This study demonstrated that night-shift work impaired endothelial function in medical staff, an effect that was alleviated by short-term aromatherapy.

  16. Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Sandra Beer

    2008-12-01

    vascular complications. Plasma vWF, TFPI and s-TM levels were significantly increased compared with controls only in patients exhibiting vascular complications. Concentrations of t-PA and PAI-1 were significantly increased in the two groups of diabetics versus controls.Conclusion: In NIDDM, both endothelium-dependent and -independent microvascular skin reactivity are impaired, whether or not underlying vascular complications exist. It also appears that microvascular endothelial dysfunction is not necessarily associated in NIDDM with increased circulating levels of hemostatic markers of endothelial damage known to reflect a hypercoagulable state.Keywords: skin microcirculation, iontophoresis, pulse wave velocity, type 2 diabetes, hemostatic markers

  17. miR-143 is involved in endothelial cell dysfunction through suppression of glycolysis and correlated with atherosclerotic plaques formation.

    Science.gov (United States)

    Xu, R-H; Liu, B; Wu, J-D; Yan, Y-Y; Wang, J-N

    2016-10-01

    Atherosclerosis is recognized as a chronic inflammatory disease leading to hardening of the vessel wall and narrowing of arteries. Endothelial cells (ECs) exhibit highly active glycolysis, the dysfunction of which leads to accumulation of lipids in the arterial wall and formation of atherosclerotic plaque. qRT-PCR was performed to compare the deregulated miR-143 between atherosclerotic plaque and normal vessel tissues. The direct target of miR-143 was verified by Western blot and luciferase assay. The metabolic enzymes in atherosclerotic plaque and normal vessel tissues were measured. HUVECs were transfected with miR-143 precursor or control microRNAs, and glucose uptake, lactate production, intracellular ATP, and oxygen consumption were measured. In this study, we report a correlation between up-regulated miR-143, EC dysfunction, and atherosclerotic plaque formation. The glycolysis rate was significantly elevated in ECs, which show relatively low levels of miR-143. Importantly, miR-143 was upregulated in clinical atherosclerotic plaque samples compared with healthy arteries, suggesting that miR-143 might play important roles in the atherosclerotic plaque formation. Moreover, mRNA levels of key enzymes of glycolysis, such as HK2, LDHA, and PKM2 are significantly down-regulated in the atherosclerotic plaque samples. Overexpression of miR-143 in HUVECs suppresses glycolysis through direct targeting of HK2, leading to EC dysfunction. Restoration of HK2 expression rescues glycolysis in miR-143-overexpressing HUVECs. This study provides further insight into the metabolic mechanisms involved in atherosclerotic plaque formation due to microRNAs.

  18. COPART Risk Score, Endothelial Dysfunction, and Arterial Hypertension are Independent Risk Factors for Mortality in Claudicants.

    Science.gov (United States)

    Hackl, G; Jud, P; Avian, A; Gary, T; Deutschmann, H; Seinost, G; Brodmann, M; Hafner, F

    2016-08-01

    The COPART risk score consists of six variables to assess the prognosis of PAOD patients. The flow mediated dilation (FMD) quantifies endothelial function. The aim of this study was to evaluate the mortality prediction of these two variables in a long-term observation of claudicants. 184 consecutive claudicants were included in a prospective observational study over a median observation period of 7.9 (IQR 7.2-8.7) years. The endothelial function was assessed on the day of study inclusion using brachial FMD. Three groups were assigned according to the COPART risk score: low risk (LR), n = 72 (39%); medium risk (MR), n = 59 (32%); and high risk (HR), n = 53 (29%). Overall survival rates differed among COPART risk score groups (p 2.5, HR 2.6, 95% CI 1.4-4.9), and arterial hypertension (p = .039; HR 3.5, 95% CI 1.1-11.3). COPART risk score, FMD, and arterial hypertension are independent long-term mortality predictors in this group of claudicants. The best mortality assessment is provided by including all three predictors. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  19. Asymmetric dimethylarginine (ADMA) elevation and arginase up-regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans.

    Science.gov (United States)

    El Assar, Mariam; Angulo, Javier; Santos-Ruiz, Marta; Ruiz de Adana, Juan Carlos; Pindado, María Luz; Sánchez-Ferrer, Alberto; Hernández, Alberto; Rodríguez-Mañas, Leocadio

    2016-06-01

    The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity. Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)-mediated responses and subsequent endothelial dysfunction in IR, other mechanisms could compromise this pathway. In the present study, we assessed the role of asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of endothelium-dependent vasodilatation in human morbid obesity and in a non-obese rat model of IR. We show that both increased ADMA and up-regulated arginase are determinant factors in the alteration of the l-arginine/NO pathway associated with IR in both models and also that acute treatment of arteries with arginase inhibitor or with l-arginine significantly alleviate endothelial dysfunction. These results help to expand our knowledge regarding the mechanisms of endothelial dysfunction that are related to obesity and IR and establish potential therapeutic targets for intervention. Insulin resistance (IR) is determinant for endothelial dysfunction in human obesity. Although we have previously reported the involvement of mitochondrial superoxide and inflammation, other mechanisms could compromise NO-mediated responses in IR. We evaluated the role of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of l-arginine/NO-mediated vasodilatation in human morbid obesity and in a non-obese rat model of IR. Bradykinin-induced vasodilatation was evaluated in microarteries derived from insulin-resistant morbidly obese (IR-MO) and non-insulin-resistant MO (NIR-MO) subjects. Defective endothelial vasodilatation in IR-MO was improved by l-arginine supplementation. Increased levels of ADMA were detected in serum and adipose tissue from IR-MO. Serum ADMA positively correlated with IR score and negatively with pD2 for bradykinin. Gene

  20. Asymmetric dimethylarginine (ADMA) elevation and arginase up‐regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans

    Science.gov (United States)

    El Assar, Mariam; Angulo, Javier; Santos‐Ruiz, Marta; Ruiz de Adana, Juan Carlos; Pindado, María Luz; Sánchez‐Ferrer, Alberto; Hernández, Alberto

    2016-01-01

    Key points The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity.Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)‐mediated responses and subsequent endothelial dysfunction in IR, other mechanisms could compromise this pathway.In the present study, we assessed the role of asymmetric dimethylarginine (ADMA) and arginase with respect to IR‐induced impairment of endothelium‐dependent vasodilatation in human morbid obesity and in a non‐obese rat model of IR.We show that both increased ADMA and up‐regulated arginase are determinant factors in the alteration of the l‐arginine/NO pathway associated with IR in both models and also that acute treatment of arteries with arginase inhibitor or with l‐arginine significantly alleviate endothelial dysfunction.These results help to expand our knowledge regarding the mechanisms of endothelial dysfunction that are related to obesity and IR and establish potential therapeutic targets for intervention. Abstract Insulin resistance (IR) is determinant for endothelial dysfunction in human obesity. Although we have previously reported the involvement of mitochondrial superoxide and inflammation, other mechanisms could compromise NO‐mediated responses in IR. We evaluated the role of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) and arginase with respect to IR‐induced impairment of l‐arginine/NO‐mediated vasodilatation in human morbid obesity and in a non‐obese rat model of IR. Bradykinin‐induced vasodilatation was evaluated in microarteries derived from insulin‐resistant morbidly obese (IR‐MO) and non‐insulin‐resistant MO (NIR‐MO) subjects. Defective endothelial vasodilatation in IR‐MO was improved by l‐arginine supplementation. Increased levels of ADMA were detected in serum and adipose tissue from IR‐MO. Serum ADMA positively correlated with

  1. Polyphenol fraction of extra virgin olive oil protects against endothelial dysfunction induced by high glucose and free fatty acids through modulation of nitric oxide and endothelin-1

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    Carolina Emilia Storniolo

    2014-01-01

    Full Text Available Epidemiological and clinical studies have reported that olive oil reduces the incidence of cardiovascular disease. However, the mechanisms involved in this beneficial effect have not been delineated. The endothelium plays an important role in blood pressure regulation through the release of potent vasodilator and vasoconstrictor agents such as nitric oxide (NO and endothelin-1 (ET-1, respectively, events that are disrupted in type 2 diabetes. Extra virgin olive oil contains polyphenols, compounds that exert a biological action on endothelial function. This study analyzes the effects of olive oil polyphenols on endothelial dysfunction using an in vitro model that simulates the conditions of type 2 diabetes. Our findings show that high glucose and linoleic and oleic acids decrease endothelial NO synthase phosphorylation, and consequently intracellular NO levels, and increase ET-1 synthesis by ECV304 cells. These effects may be related to the stimulation of reactive oxygen species production in these experimental conditions. Hydroxytyrosol and the polyphenol extract from extra virgin olive oil partially reversed the above events. Moreover, we observed that high glucose and free fatty acids reduced NO and increased ET-1 levels induced by acetylcholine through the modulation of intracellular calcium concentrations and endothelial NO synthase phosphorylation, events also reverted by hydroxytyrosol and polyphenol extract. Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids.

  2. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration

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    Detaille, D; Vial, G; Borel, A-L; Cottet-Rouselle, C; Hallakou-Bozec, S; Bolze, S; Fouqueray, P; Fontaine, E

    2016-01-01

    Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of ?-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which ...

  3. Prolactin as a predictor of endothelial dysfunction and arterial stiffness progression in menopause.

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    Georgiopoulos, G; Lambrinoudaki, I; Athanasouli, F; Armeni, E; Koliviras, A; Augoulea, A; Rizos, D; Papamichael, C; Protogerou, A; Stellos, K; Stamatelopoulos, K

    2017-08-01

    Postmenopausal women are at increased risk for progression of arteriosclerosis and hypertension. Recent cross-sectional evidence suggests that high normal circulating prolactin levels may accelerate vascular ageing in menopause. Postmenopausal women (n=201) were consecutively recruited from a Menopause Clinic and re-evaluated in at least one follow-up visit within the next 3 years. Baseline circulating prolactin levels were measured while both baseline and follow-up vascular and biochemical measurements were performed. Endothelial function was assessed by flow-mediated dilation (FMD), aortic stiffness by pulse-wave velocity (PWV) and arterial wave reflections by applanation tonometry. Baseline prolactin significantly correlated with lower FMD at follow-up (P=0.005). After multivariable adjustment for age, follow-up time, blood pressure (BP), body mass index, smoking and medication, this correlation remained significant (P=0.003). In addition, baseline circulating prolactin levels were independently associated with changes in mean BP (β=0.131, P=0.021), peripheral diastolic BP (β=0.169, P=0.004) and new-onset hypertension (OR=1.235, P=0.001). Owing to significant interaction between baseline prolactin and age for changes in PWV over time (P=0.036), a subgroup analysis based on median age was performed. This analysis revealed that in women younger than 55 years, prolactin was an independent predictor of changes in PWV over time (P=0.008). In conclusion, high normal circulating prolactin levels predict changes in haemodynamic indices and worsening endothelial function in healthy postmenopausal women. Particularly in young postmenopausal women, prolactin predicts accelerated arterial stiffening.

  4. Effects of Basal Insulin Analog and Metformin on Glycaemia Control and Weight as Risk Factors for Endothelial Dysfunction

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    Belma Aščić – Buturović

    2008-11-01

    Full Text Available Obese patients with type 2 diabetes and impaired glucose tolerance are at increased risk of development of cardiovascular diseases. Endothelial dysfunction may be a reason for development of atherosclerosis and cardiovascular diseases. Lifestyle modification, increased physical activity, weight reduction, energy restricted diet and good glycaemia control can be useful for the endothelial function improvement and may decrease the risk of cardiovascular diseases. The aim of this study was to evaluate the effects of basal insulin analog and metformin on glycaemia control and weight as risk factors of endothelial dysfunction. Total of 15 patients (9 male and 6 female with type 2 diabetes were studied. The patients were monitored over six months period. Glycated hemoglobin (HbA1c, fasting plasma glucose (FPG, postprandial plasma glucose (PPG, and body mass index (BMI were observed. Mean age of the subjects was 53,4 ± 6,27 years. Mean diabetes duration was 3,71 ± 1,89 years. At the end of the study mean body mass index decreased from 27,5 ± 1,45 kg/m2 to 25,7 ±1,22 kg/m2. In this study we included diabetic patients with fasting glycaemia over 7 mmol/ dm3, postmeal glycaemia over 7,8 mmol/dm3 and glycated hemoglobin over 7%. Prior to the study, the patients were treated with premix insulin divided in two daily doses and metformin after the lunch, which did not result in sufficient regulation of glycaemia. We started treatment with one daily insulin basal analog and three daily doses of metformin and monitored the above mentioned parameters. We advised patients to change their lifestyle, to practice energy restricted diet and to increase their daily physical activity. Insulin doses were titrated separately for each patient (0,7-1 IU/kg. Weight reduction was recorded after the study. Mean fasting glycaemia decreased from 8,6±0,49 mmol/dm3 to 7,04±0,19 mmol/dm3 (p < 0,05. Mean postmeal glycaemia decreased from 9,74 ± 0,79 mmol/dm3 to 7,6 ± 0

  5. EFFECTS OF Β-ADRENOBLOCKERS ON MYOCARDIAL REMODELING, IMMUNO-INFLAMMATORY REACTIONS AND ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH ISCHEMIC HEART DISEASE AND CHRONIC HEART FAILURE

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    A. N. Zakirova

    2015-12-01

    Full Text Available Aim. To assess the effect of β-adrenoblockers (BAB on myocardial remodeling, immuno-inflammatory reactions and endothelial dysfunction in patients with ischemic heart disease and chronic heart failure (CHF.Material and methods. 84 patients with ischemic CHF of II-IV functional class were involved in the study. They were randomized in two groups. The first group was presented with 43 patients receiving carvedilol in addition to standard therapy for 24 weeks; the second group was presented with 41patients receiving metoprolol. Echocardiography, 6-minute walk test were applied. Blood levels of primary and secondary lipid peroxidation (LP products, cytokines, endothelin-1 (ET-1, intercellular adhesive molecule (VCAM-1 were determined.Results. Both of BAB improved the clinical condition and physical working ability of patients with CHF. Carvedilol in comparison with metoprolol was more effective in myocardial remodeling prevention, inhibition of pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α, interleukins (IL-1β IL-6] and LP. Besides carvedilol increased in endothelium-dependent vasodilatation and reduced in ET-1 and VCAM-1 levels.Conclusion. Long-term carvedilol treatment has anti-inflammatory, antioxidant and endothelium-protective effects as well as improves haemodynamics. 

  6. Gugulipid causes hypercholesterolemia leading to endothelial dysfunction, increased atherosclerosis, and premature death by ischemic heart disease in male mice.

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    Andrea Leiva

    Full Text Available For proper cholesterol metabolism, normal expression and function of scavenger receptor class B type I (SR-BI, a high-density lipoprotein (HDL receptor, is required. Among the factors that regulate overall cholesterol homeostasis and HDL metabolism, the nuclear farnesoid X receptor plays an important role. Guggulsterone, a bioactive compound present in the natural product gugulipid, is an antagonist of this receptor. This natural product is widely used globally as a natural lipid-lowering agent, although its anti-atherogenic cardiovascular benefit in animal models or humans is unknown. The aim of this study was to determine the effects of gugulipid on cholesterol homeostasis and development of mild and severe atherosclerosis in male mice. For this purpose, we evaluated the impact of gugulipid treatment on liver histology, plasma lipoprotein cholesterol, endothelial function, and development of atherosclerosis and/or ischemic heart disease in wild-type mice; apolipoprotein E knockout mice, a model of atherosclerosis without ischemic complications; and SR-B1 knockout and atherogenic-diet-fed apolipoprotein E hypomorphic (SR-BI KO/ApoER61h/h mice, a model of lethal ischemic heart disease due to severe atherosclerosis. Gugulipid administration was associated with histological abnormalities in liver, increased alanine aminotransferase levels, lower hepatic SR-BI content, hypercholesterolemia due to increased HDL cholesterol levels, endothelial dysfunction, enhanced atherosclerosis, and accelerated death in animals with severe ischemic heart disease. In conclusion, our data show important adverse effects of gugulipid intake on HDL metabolism and atherosclerosis in male mice, suggesting potential and unknown deleterious effects on cardiovascular health in humans. In addition, these findings reemphasize the need for rigorous preclinical and clinical studies to provide guidance on the consumption of natural products and regulation of their use in the

  7. l-arginine and l-NMMA for assessing cerebral endothelial dysfunction in ischaemic cerebrovascular disease: A systematic review.

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    Karlsson, William K; Sørensen, Caspar G; Kruuse, Christina

    2017-01-01

    Endothelial dysfunction (ED), in particular cerebral ED, may be an essential biomarker for ischaemic cerebrovascular disease. However, there is no consensus on methods to best estimate cerebral ED. In this systematic review, we evaluate the use of l-arginine and N G -monomethyl-l-arginine (l-NMMA) for assessment of cerebral ED. A systematic search of PubMed, EMBASE and the Cochrane Library was done. We included studies investigating cerebrovascular response to l-arginine or l-NMMA in human subjects with vascular risk factors or ischaemic cerebrovascular disease. Seven studies (315 subjects) were eligible according to inclusion and exclusion criteria. Studies investigated the effect of age (n=2), type 2 diabetes mellitus (DM) (n=1), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (n=1), leukoaraiosis (n=1), and prior ischaemic stroke or transient ischaemic attack (TIA) (n=2) on cerebral ED. Most studies applied transcranial Doppler to quantify cerebral ED. Endothelium-dependent vasodilatation (EDV) induced by l-arginine was impaired in elderly and subjects with leukoaraiosis, but enhanced in CADASIL patients. Studies including subjects with prior ischaemic stroke or TIA reported both enhanced and impaired EDV to l-arginine. Responses to l-NMMA deviated between subjects with type 2 DM and the elderly. We found only few studies investigating cerebral endothelial responses to l-arginine and l-NMMA in subjects with vascular risk factors or ischaemic cerebrovascular disease. Inconsistencies in results were most likely due to variations in methods and included subject populations. In order to use cerebral ED as a prognostic marker, further studies are required to evaluate the association to cerebrovascular disease. © 2016 John Wiley & Sons Australia, Ltd.

  8. Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice.

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    Kina-Tanada, Mika; Sakanashi, Mayuko; Tanimoto, Akihide; Kaname, Tadashi; Matsuzaki, Toshihiro; Noguchi, Katsuhiko; Uchida, Taro; Nakasone, Junko; Kozuka, Chisayo; Ishida, Masayoshi; Kubota, Haruaki; Taira, Yuji; Totsuka, Yuichi; Kina, Shin-Ichiro; Sunakawa, Hajime; Omura, Junichi; Satoh, Kimio; Shimokawa, Hiroaki; Yanagihara, Nobuyuki; Maeda, Shiro; Ohya, Yusuke; Matsushita, Masayuki; Masuzaki, Hiroaki; Arasaki, Akira; Tsutsui, Masato

    2017-06-01

    Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

  9. Association of inflammation and endothelial dysfunction with metabolic syndrome, prediabetes and diabetes in adults from Inner Mongolia, China

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    Kelly Tanika N

    2011-10-01

    Full Text Available Abstract Background We examined the association of biomarkers of inflammation and endothelial dysfunction with diabetes and metabolic syndrome (MetS in persons from Inner Mongolia. Methods A cross-sectional study was conducted among 2,536 people aged 20 years and older from Inner Mongolia, China. Overnight fasting blood samples were obtained to measure plasma concentrations of high sensitivity C-reactive protein (hsCRP, soluble inter-cellular adhesion molecule-1 (sICAM-1, sE-selectin, angiotensin II, high density lipoprotein cholesterol, triglycerides, and blood glucose. Waist circumference and blood pressure were measured by trained staff. MetS was defined according to the modified ATP III definition for Asians. Elevated level of the biomarker was defined as values in the upper tertile of the distribution. Participants were categorized into one of four groups based on the presence or absence of metabolic and glycemic abnormalities: 1 free of prediabetes, diabetes and MetS (reference group, 2 prediabetes or diabetes only, 3 MetS without prediabetes or diabetes, and 4 MetS plus prediabetes or diabetes. The multivariable models are adjusted for age, gender, smoking, drinking, family history of hypertension, and body mass index. Results Among study participants, 18.5% had prediabetes, 3.6% had diabetes, and 27.4% of the entire study population had 3 or more components of the MetS. Elevated hsCRP was associated with an increased odds of prediabetes or diabetes only, MetS without prediabetes or diabetes, and MetS plus prediabetes or diabetes with multivariable adjusted odds ratios (95% confidence intervals of 2.3 (1.7-3.1, 3.0 (2.4-3.8, and 5.8 (4.5-7.5, respectively. Elevated sICAM-1 was associated with increased odds (95% CI of prediabetes or diabetes only (2.1, 1.6-2.9 and MetS plus prediabetes or diabetes (4.2, 3.2-5.3 but was not associated with MetS alone. Elevated sE-selectin was associated with a modestly increased risk of MetS (OR 1.7, 95

  10. Ethinylestradiol30μg-drospirenone and metformin: could this combination improve endothelial dysfunction in polycystic ovary syndrome?

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    Ilie Ioana

    2012-06-01

    Full Text Available Abstract Background We are hereby investigating for the first time the effect of the association ethinylestradiol30μg-drospirenone 3mg (DRP/EE30μg plus metformin and weight loss on endothelial status and C-reactive protein (hsCRP levels in polycystic ovary syndrome (PCOS. Methods 25 young women with PCOS (mean age 22.76 ± 0.83 years, body mass index (BMI: 28.44 ± 6.23 who completed the study were prospectively evaluated. The oral contraceptive- DRP/EE30μg (21 days/month and metformin (1700 mg daily were administered for 6 months to the PCOS group. Additionally, the 15 overweight and obese patients (BMI > 25 kg/m2 were instructed in a diet of no more than 1500 cal daily. Primary outcome measures were surrogate markers of cardiovascular disease and included endothelial function, i.e. flow-mediated dilatation (FMD on the brachial artery and endothelin-1 levels, as well as hsCRP concentrations, body composition (measured by whole-body dual-energy X-ray-absorptiometry and insulin resistance. Variables were assessed at baseline, as well as after our medical intervention. Results The combination between DRP/EE30μg plus metformin combined with weight loss triggered a significant improvement in the FMD values (FMD-PCOSbasal 3.48 ± 1.00 vs FMD-PCOS6 months7.43 ± 1.04, p = 0.033, as well as body composition and insulin insensitivity (p 6months – PCOSbasal difference. Conclusion A 6-month course of metformin- DRP/EE30μg (associated with weight loss improves the endothelial dysfunction in PCOS and shows neutral effects on hsCRP concentrations as an inflammation marker. These data demand for reevaluation of the medical therapy in PCOS, particularly in women with additional metabolic and cardiovascular risk factors (ClinicalTrials.gov Identifier: NCT01459445.

  11. Current strategies for preventing renal dysfunction in patients with heart failure: a heart failure stage approach

    Science.gov (United States)

    Issa, Victor Sarli; Andrade, Lúcia; Bocchi, Edimar Alcides

    2013-01-01

    Renal dysfunction is common during episodes of acute decompensated heart failure, and historical data indicate that the mean creatinine level at admission has risen in recent decades. Different mechanisms underlying this change over time have been proposed, such as demographic changes, hemodynamic and neurohumoral derangements and medical interventions. In this setting, various strategies have been proposed for the prevention of renal dysfunction with heterogeneous results. In the present article, we review and discuss the main aspects of renal dysfunction prevention according to the different stages of heart failure. PMID:23644863

  12. Relationship of endothelial dysfunction and kidney functional state in patients with systemic sclerosis

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    A M Basova

    2009-01-01

    Full Text Available Objective. To study vasoregulatory function of vascular wall in pts with systemic sclerosis (SS and chronic scleroderma-related renal disease (SRD and determine relationship with main measures of kidney functional state. Material and methods. 25 pts with SS (24 female with mean age 46,4±10,7 years and mean disease duration 7,5±4,7 years were included. 24 pts (96% had diffuse form and 17 pts (68% – generalized stage of SS. 22 pts (88% had chronic course of the disease with typical damage of vessels, heart, lungs and skin. SRD was revealed in 17 pts (68%. Sonographic method of Celermejer D. et al. (1992 was used for assessment of vascular endothelial function. 15 healthy persons without SS were included in control group. Results. Most prominent changes of brachial artery reactivity with insufficient vasodilatation and paradoxical vasoconstriction to reactive hyperemia were revealed in most pts with moderate and severe SRD. Conclusion. These changes of endothelium dependent and endothelium independent parameters in pts with SRD pointed to irreversible probably scleroderma-related vascular wall damage.

  13. Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction: Novel Targets for Treatment.

    Science.gov (United States)

    Schinzari, Francesca; Tesauro, Manfredi; Cardillo, Carmine

    2017-06-01

    The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.

  14. Pro-Coagulant Endothelial Dysfunction Results from EHEC Shiga toxins and Host Damage-Associated Molecular Patterns

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    Chad L Mayer

    2015-04-01

    Full Text Available Hemolytic uremic syndrome (HUS from enterohemorrhagic E.coli infection (EHEC is a leading cause of kidney failure in otherwise healthy U.S. children. The bacterial Shiga toxins (Stx induce the characteristic coagulopathy of HUS, but the cell and organ damage during infection likely also releases inflammatory damage-associated molecular patterns (DAMPs that may exacerbate injury in concert with the toxins. To examine this, aortic and renal glomerular cell anticoagulant and barrier functions were studied after in vitro challenge with Stx1, Stx2 and DAMPs. There was significant loss of surface anticoagulant protein C pathway molecules, increased expression of prothrombotic PAR1 and reduced protein C activation capability by 15-27%. Histones nearly completely prevented activated protein C protection of endothelial cells from thrombin-induced permeability. In mice, lethal Stx2 challenge elevated plasma HMGB1 (day 2, 321±118%; p<0.01 and extracellular histones (day 3, 158±62%; p<0.01. Mice colonized with Stx2-expressing Citrobacter rodentium developed increased HMGB1 (day 5, 155±55%; p<0.01 and histones (day 3, 378±188%; p<0.01. Anti-histone antibody reduced both DAMPs to baseline, but was not sufficient to improve survival outcome or kidney function. Together, these data suggest a potential role for both Stx and DAMPs in producing endothelial injury and a prothrombotic environment.

  15. F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling

    Science.gov (United States)

    Heemskerk, Niels; Schimmel, Lilian; Oort, Chantal; van Rijssel, Jos; Yin, Taofei; Ma, Bin; van Unen, Jakobus; Pitter, Bettina; Huveneers, Stephan; Goedhart, Joachim; Wu, Yi; Montanez, Eloi; Woodfin, Abigail; van Buul, Jaap D.

    2016-01-01

    During immune surveillance and inflammation, leukocytes exit the vasculature through transient openings in the endothelium without causing plasma leakage. However, the exact mechanisms behind this intriguing phenomenon are still unknown. Here we report that maintenance of endothelial barrier integrity during leukocyte diapedesis requires local endothelial RhoA cycling. Endothelial RhoA depletion in vitro or Rho inhibition in vivo provokes neutrophil-induced vascular leakage that manifests during the physical movement of neutrophils through the endothelial layer. Local RhoA activation initiates the formation of contractile F-actin structures that surround emigrating neutrophils. These structures that surround neutrophil-induced endothelial pores prevent plasma leakage through actomyosin-based pore confinement. Mechanistically, we found that the initiation of RhoA activity involves ICAM-1 and the Rho GEFs Ect2 and LARG. In addition, regulation of actomyosin-based endothelial pore confinement involves ROCK2b, but not ROCK1. Thus, endothelial cells assemble RhoA-controlled contractile F-actin structures around endothelial pores that prevent vascular leakage during leukocyte extravasation. PMID:26814335

  16. Endothelial dysfunction in rats with ligature-induced periodontitis: Participation of nitric oxide and cycloxygenase-2-derived products.

    Science.gov (United States)

    Campi, Paula; Herrera, Bruno Schneider; de Jesus, Flavia Neto; Napolitano, Mauro; Teixeira, Simone Aparecida; Maia-Dantas, Aline; Spolidorio, Luis Carlos; Akamine, Eliana Hiromi; Mayer, Marcia Pinto Alves; de Carvalho, Maria Helena Catelli; Costa, Soraia Katia Pereira; Muscara, Marcelo Nicolas

    2016-03-01

    Considering the evident relationship between periodontitis and cardiovascular diseases in humans, we aimed to study the in vitro vascular reactivity of aorta rings prepared from rats with ligature-induced periodontitis. Seven days after the induction of unilateral periodontitis, the animals were euthanised; rings were prepared from the descending abdominal aortas and mounted in tissue baths for the in vitro measurement of the isometric force responses to norepinephrine (NE) and acetylcholine (ACh), as well as in the presence of inhibitors of nitric oxide synthase (NOS) and cycloxygenase (COX) isoenzymes. Aortic COX and NOS gene expressions were analysed by RT-PCR, as well as protein COX-2 expression by Western blot. Periodontitis resulted in significant alveolar bone loss and did not affect arterial pressure. However, both NE-induced contraction and ACh-induced relaxation were significantly decreased and related to the presence of endothelium. Diminished eNOS and augmented COX-2 and iNOS expressions were found in the aortas from rats with periodontitis, and the pharmacological inhibition of COX-2 or iNOS improved the observed vasomotor deficiencies. We can thus conclude that periodontitis induces significant endothelial dysfunction in rat aorta which is characterized by decreased eNOS expression and mediated by upregulated iNOS and COX-2 products. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Efficacy of functional foods mixture in improving hypercholesterolemia, inflammatory and endothelial dysfunction biomarkers-induced by high cholesterol diet.

    Science.gov (United States)

    Al-Muzafar, Hessah Mohammed; Amin, Kamal Adel

    2017-10-06

    Hypercholesterolemia associated with cardiovascular diseases is a global health issue that could be alleviated by functional foods. This study aimed to explore the effects of a high-cholesterol diet on lipid profile, cardiac, inflammatory, and endothelial dysfunction biomarkers, and the possible improvement by functional foods mixture. Male albino rats weighing 100-150 g were randomly divided into four equal groups: 1st control, giving a normal diet; the 2nd received high-cholesterol diet for 8 weeks, the 3rd received the high-cholesterol diet + functional foods mixture, and the 4th administered high-cholesterol diet +atorvastatin (20 mg) orally. The results showed a significant increase in lipid profile and cardiac biomarkers levels (lactate dehydrogenase, creatine kinase and homocystein), also inflammatory markers, as, tumor necrotic factor alpha and chronic reactive proteins were elevated, moreover, vascular adhesion molecule-1 and nitric oxide synthase were disturbed in high-cholesterol diet compared with normal group. While administration of atorvastatin and functional foods mixture ameliorated these alterations. Administration of functional foods mixture and atorvastatin were effective in treating hypercholesterolemia, reduce the risk of inflammation and cardiovascular biomarkers with a high safety margin. These efficiencies may be due to its active ingredient that improve the imbalance in the measured biomarkers.

  18. ROLE OF CENTRAL HEMODYNAMIC PARAMETERS, INTIMAL MEDIAL THICKNESS AND ENDOTHELIAL DYSFUNCTION IN CHILDREN WITH RENAL ARTERIAL HYPERTENSION

    Directory of Open Access Journals (Sweden)

    I. S. Kostyushina

    2013-01-01

    Full Text Available The increase in arterial hypertension is one of the most sensitive markers of the renal affection grade, including patients without chronic renal diseases; its rate is in inverse proportion to renal functions. Left ventricular hypertrophy development at chronic renal disease results from the development of increased left ventricular afterload and end diastolic pressure influence; it is a compensatory mechanism, which is closely interconnected with mortality from cardiovascular diseases. Echocardiography is the most widely used method of evaluating the condition of central hemodynamics both in adults and children with arterial hypertension. However, echocardiography does not give the researcher any complete presentation of the cardiovascular system’s affection and the consequences of it in the setting of a progressing arterial hypertension. Detection of changes in the arterial wall (intimal medial thickness and endothelial dysfunction is used to estimate the risk of developing such complications. Ultrasonic diagnostics allow to assess the wall’s structure, vascular lumen and determining the intimal medial thickness. Data from a range of foreign and domestic studies allows to suggest that the level of endothelin-1 in the blood serum and its excretion with urine may reflect the renovascular damage severity. The article presents a literary review on the given issue.

  19. Association of Type D personality with increased vulnerability to depression: Is there a role for inflammation or endothelial dysfunction? - The Maastricht Study.

    Science.gov (United States)

    van Dooren, Fleur E P; Verhey, Frans R J; Pouwer, Frans; Schalkwijk, Casper G; Sep, Simone J S; Stehouwer, Coen D A; Henry, Ronald M A; Dagnelie, Pieter C; Schaper, Nicolaas C; van der Kallen, Carla J H; Koster, Annemarie; Schram, Miranda T; Denollet, Johan

    2016-01-01

    Type D personality - the combination of negative affectivity (NA) and social inhibition (SI) - has been associated with depression but little is known about underlying mechanisms. We examined whether (1) Type D is a vulnerability factor for depression in general, (2) Type D is associated with inflammation or endothelial dysfunction, and (3) these biomarkers alter the possible association between Type D and depression. In the Maastricht Study, 712 subjects underwent assessment of NA, SI and Type D personality (DS14), depressive disorder (Mini-International Neuropsychiatric Interview) and depressive symptoms (Patient Health Questionnaire-9). Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) and endothelial dysfunction (sVCAM-1, sICAM-1, E-selectin, vWF) were measured with sandwich immunoassays or ELISA and combined into standardized sumscores. Regarding personality, 49% of the study population was low in NA and SI, 22% had SI only, 12% NA only and 17% had Type D. Depressive disorder and depressive symptoms were significantly more prevalent in Type D versus the other three personality subgroups. Multivariable regression analyses showed that Type D was associated with inflammation (β=0.228, p=0.014) and endothelial dysfunction (β=0.216, p=0.022). After adjustment for these biomarkers, Type D remained independently associated with increased vulnerability to depressive disorder (OR=13.20, ppersonality may be a vulnerability factor for depression, irrespective of levels of inflammation or endothelial dysfunction. Future research should examine possible underlying mechanisms. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Relationship of endothelial dysfunction with degree of renal function damage and lipidemic profile in patients with type 2 diabetes mellitus and hypertension

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    Pertseva N.O.

    2014-09-01

    Full Text Available In the article defining relationship between endothelial dysfunction, the degree of renal and lipidemic profile damage in 234 patients with type 2 diabetes mellitus with hypertension was carried depending on the quality of glycemic control. It is shown that the deepening of endothelial dysfunction in patients with insufficient and poor compensation tightly correlates with the degree of renal and lipidemic disorders. In these patients there was a significant increase in the level of albuminuria, reduction in glomerular filtration rate, increase of concentrations of urea and creatinine. Against the background of poor hyperglycemia, compensation total cholesterol, low density lipoprotein content increases by 73,3% (p<0.05, hype¬rtriglyceridemia twice exceeds the control values. In patients with type 2 diabetes mellitus with poor compensation the most significant correlation links were observed between the concentration of endothelin-1 and the level of microalbuminuria (r=+0,79, as well as the content of low density lipoprotein cholesterol (r=+0.81. Thrombomodulin concentration is in direct correlation with microalbuminuria (r=+0.76, hypercholesterolemia (r=+0.80 and hypertriglyceridemia (r=+0.83, indicating to increasing interaction between the pathogenetic mechanisms which cause depression of endothelial dysfunction, renal and dyslipidemic disorders with increasing hyperglycemia.

  1. LR-90 prevents methylglyoxal-induced oxidative stress and apoptosis in human endothelial cells

    Science.gov (United States)

    Figarola, James L.; Singhal, Jyotsana; Rahbar, Samuel; Awasthi, Sanjay

    2014-01-01

    Methylglyoxal (MGO) is a highly reactive dicarbonyl compound known to induce cellular injury and cytoxicity, including apoptosis in vascular cells. Vascular endothelial cell apoptosis has been implicated in the pathophysiology and progression of atherosclerosis. We investigated whether the advanced glycation end-product inhibitor LR-90 could prevent MGO-induced apoptosis in human umbilical vascular endothelial cells (HUVECs). HUVECs were pre-treated with LR-90 and then stimulated with MGO. Cell morphology, cytotoxicity and apoptosis were evaluated by light microscopy, MTT assay, and Annexin V-FITC and propidium iodide double staining, respectively. Levels of Bax, Bcl-2, cytochrome c, mitogen-activated protein kinases (MAPKs) and caspase activities were assessed by Western blotting. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. LR-90 dose-dependently prevented MGO-associated HUVEC cytotoxicity and apoptotic biochemical changes such as loss of MMP, increased Bax/Bcl-2 protein ratio, mitochondrial cytochrome c release and activation of caspase-3 and 9. Additionally, LR-90 blocked intracellular ROS formation and MAPK (p44/p42, p38, JNK) activation, though the latter seem to be not directly involved in MGO-induced HUVEC apoptosis. LR-90 prevents MGO-induced HUVEC apoptosis by inhibiting ROS and associated mitochondrial-dependent apoptotic signaling cascades, suggesting that LR-90 possess cytoprotective ability which could be beneficial in prevention of diabetic related-atherosclerosis. PMID:24615331

  2. C1q/TNF-Related Protein-9 Ameliorates Ox-LDL-Induced Endothelial Dysfunction via PGC-1α/AMPK-Mediated Antioxidant Enzyme Induction

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    Haijian Sun

    2017-05-01

    Full Text Available Oxidized low-density lipoprotein (ox-LDL accumulation is one of the critical determinants in endothelial dysfunction in many cardiovascular diseases such as atherosclerosis. C1q/TNF-related protein 9 (CTRP9 is identified to be an adipocytokine with cardioprotective properties. However, the potential roles of CTRP9 in endothelial function remain largely elusive. In the present study, the effects of CTRP9 on the proliferation, apoptosis, migration, angiogenesis, nitric oxide (NO production and oxidative stress in human umbilical vein endothelial cells (HUVECs exposed to ox-LDL were investigated. We observed that treatment with ox-LDL inhibited the proliferation, migration, angiogenesis and the generation of NO, while stimulated the apoptosis and reactive oxygen species (ROS production in HUVECs. Incubation of HUVECs with CTRP9 rescued ox-LDL-induced endothelial injury. CTRP9 treatment reversed ox-LDL-evoked decreases in antioxidant enzymes including heme oxygenase-1 (HO-1, nicotinamide adenine dinucleotide phosphate (NAD(PH dehydrogenase quinone 1, and glutamate-cysteine ligase (GCL, as well as endothelial nitric oxide synthase (eNOS. Furthermore, CTRP9 induced activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC1-α and phosphorylation of adenosine monophosphate-activated protein kinase (AMPK. Of interest, AMPK inhibition or PGC1-α silencing abolished CTRP9-mediated antioxidant enzymes levels, eNOS expressions, and endothelial protective effects. Collectively, we provided the first evidence that CTRP9 attenuated ox-LDL-induced endothelial injury by antioxidant enzyme inductions dependent on PGC-1α/AMPK activation.

  3. Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM{sub 10})

    Energy Technology Data Exchange (ETDEWEB)

    Miyata, Ryohei; Hiraiwa, Kunihiko; Cheng, Jui Chih [UBC James Hogg Research Centre, St. Paul' s Hospital, University of British Columbia, Vancouver (Canada); Bai, Ni [UBC James Hogg Research Centre, St. Paul' s Hospital, University of British Columbia, Vancouver (Canada); Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver (Canada); Vincent, Renaud [Environmental Health Sciences and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa (Canada); Francis, Gordon A.; Sin, Don D. [UBC James Hogg Research Centre, St. Paul' s Hospital, University of British Columbia, Vancouver (Canada); Van Eeden, Stephan F., E-mail: Stephan.vanEeden@hli.ubc.ca [UBC James Hogg Research Centre, St. Paul' s Hospital, University of British Columbia, Vancouver (Canada)

    2013-10-01

    Exposure to ambient air particulate matter (particles less than 10 μm or PM{sub 10}) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM{sub 10}. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM{sub 10}/saline exposure for 4 weeks ± lovastatin (5 mg/kg/day) treatment. PM{sub 10} exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM{sub 10} impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM{sub 10} increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM{sub 10}. Taken together, statins protect against PM{sub 10}-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties. - Highlights: • Coarse particulate matter (PM{sub 10}) accelerated balloon injury-induced plaque formation. • Lovastatin decreased intimal

  4. Correlation of Homocysteine with Cerebral Hemodynamic Abnormality, Endothelial Dysfunction Markers, and Cognition Impairment in Patients with Traumatic Brain Injury.

    Science.gov (United States)

    Hatefi, Masoud; Behzadi, Someyeh; Dastjerdi, Masoud Moghadas; Ghahnavieh, Alireza Abootalebi; Rahmani, Asghar; Mahdizadeh, Fatemeh; Hafezi Ahmadi, Mohammad Reza; Asadollahi, Khairollah

    2017-01-01

    This study aimed to assess any correlation between serum levels of homocysteine (Hcy) and markers of cerebral hemodynamics, endothelial dysfunction, and cognition impairment in patients with traumatic brain injury (TBI). By a cross-sectional study, all clinical data and serum levels of homocysteine of 85 TBI patients were collected. The pulsatility indices (PIs) of the middle cerebral artery were recorded by transcranial color-coded Doppler ultrasonography and cerebrovascular reactivity was measured by the increase in middle cerebral artery flow velocity in response to 5% inhaled CO 2 . Serum levels of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), cognition status by Montreal Cognitive Assessment, and Mini-Mental State Examination were measured in all participants. Totally, 85 patients including 51.76% male and the mean age of 54.48 years were studied. The level of Hcy in patients who died in the hospital or during 6 months after TBI was significantly higher than in survivors (P = 0.045, P = 0.020, respectively). Also, the levels of ICAM-1, VCAM-1, and PI in deceased patients were higher than their figures in survivors in both hospital and 6-month follow-ups (P = 0.450, P = 0.000; P = 0.072, P = 0.000, P = 0.090, and P = 0.000, respectively). Cerebrovascular reactivity in deceased patients was significantly lower than that in alive individuals (P = 0.008 and P = 0.000, respectively). A significant correlation was found between Hcy with cognition impairment according to Montreal Cognitive Assessment, Mini-Mental State Examination, and cerebral hemodynamic status according to PI (P = 0.000 for all). Also, this correlation was shown between Hcy with ICAM-1 and VCAM-1 in hospital and 6-month follow-ups (P = 0.000 for both). Hcy has a significant correlation with markers of cerebrovascular, endothelial, and cognition abnormality in TBI patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Blockade of Vascular Endothelial Growth Factor Receptor 1 Prevents Inflammation and Vascular Leakage in Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Jianbo He

    2015-01-01

    Full Text Available Diabetic retinopathy (DR is a leading cause of blindness in working age adults. The objective of this study is to investigate the effects of vascular endothelial growth factor receptor 1 (VEGFR1 blockade on the complications of DR. Experimental models of diabetes were induced with streptozotocin (STZ treatment or Insulin2 gene mutation (Akita in mice. Protein expression and localization were examined by western blots (WB and immunofluorescence (IF. mRNA expression was quantified by PCR array and real-time PCR. The activity of VEGFR1 signaling was blocked by a neutralizing antibody called MF1. Vascular leakage was evaluated by measuring the leakage of [3H]-mannitol tracer into the retina and the IF staining of albumin. VEGFR1 blockade significantly inhibited diabetes-related vascular leakage, leukocytes-endothelial cell (EC adhesion (or retinal leukostasis, expression of intercellular adhesion molecule- (ICAM- 1 protein, abnormal localization and degeneration of the tight junction protein zonula occludens- (ZO- 1, and the cell adhesion protein vascular endothelial (VE cadherin. In addition, VEGFR1 blockade interfered with the gene expression of 10 new cytokines and chemokines: cxcl10, il10, ccl8, il1f6, cxcl15, ccl4, il13, ccl6, casp1, and ccr5. These results suggest that VEGFR1 mediates complications of DR and targeting this signaling pathway represents a potential therapeutic strategy for the prevention and treatment of DR.

  6. A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling.

    Science.gov (United States)

    Mahmoud, Ayman M; Wilkinson, Fiona L; Jones, Alan M; Wilkinson, James A; Romero, Miguel; Duarte, Juan; Alexander, M Yvonne

    2017-01-01

    Glycomimetics are a diverse array of saccharide-inspired compounds, designed to mimic the bioactive functions of glycosaminoglycans. Therefore, glycomimetics represent a unique source of novel therapies to target aberrant signaling and protein interactions in a wide range of diseases. We investigated the protective effects of four newly synthesized small molecule glycomimetics against lipid-induced endothelial dysfunction, with an emphasis on nitric oxide (NO) and oxidative stress. Four aromatic sugar mimetics were synthesized by the stepwise transformation of 2,5-dihydroxybenzoic acid to derivatives (C1-C4) incorporating sulfate groups to mimic the structure of heparan sulfate. Glycomimetic-treated human umbilical vein endothelial cells (HUVECs) were exposed to palmitic acid to model lipid-induced oxidative stress. Palmitate-induced impairment of NO production was restored by the glycomimetics, through activation of Akt/eNOS signaling. Furthermore, C1-C4 significantly inhibited palmitate-induced reactive oxygen species (ROS) production, lipid peroxidation, and activity and expression of NADPH oxidase. These effects were attributed to activation of the Nrf2/ARE pathway and downstream activation of cellular antioxidant and cytoprotective proteins. In ex vivo vascular reactivity studies, the glycomimetics (C1-C4) also demonstrated a significant improvement in endothelium-dependent relaxation and decreased ROS production and NADPH oxidase activity in isolated mouse thoracic aortic rings exposed to palmitate. The small molecule glycomimetics, C1-C4, protect against lipid-induced endothelial dysfunction through up-regulation of Akt/eNOS and Nrf2/ARE signaling pathways. Thus, carbohydrate-derived therapeutics are a new class of glycomimetic drugs targeting endothelial dysfunction, regarded as the first line of defense against vascular complications in cardiovascular disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Effect of mesenchymal precursor cells on the systemic inflammatory response and endothelial dysfunction in an ovine model of collagen-induced arthritis.

    Directory of Open Access Journals (Sweden)

    Laura M Dooley

    Full Text Available Mesenchymal precursor cells (MPC are reported to possess immunomodulatory properties that may prove beneficial in autoimmune and other inflammatory conditions. However, their mechanism of action is poorly understood. A collagen-induced arthritis model has been previously developed which demonstrates local joint inflammation and systemic inflammatory changes. These include not only increased levels of inflammatory markers, but also vascular endothelial cell dysfunction, characterised by reduced endothelium-dependent vasodilation. This study aimed to characterise the changes in systemic inflammatory markers and endothelial function following the intravenous administration of MPC, in the ovine model.Arthritis was induced in sixteen adult sheep by administration of bovine type II collagen into the hock joint following initial sensitisation. After 24h, sheep were administered either 150 million allogeneic ovine MPCs intravenously, or saline only. Fibrinogen and serum amyloid-A were measured in plasma to assess systemic inflammation, along with pro-inflammatory and anti-inflammatory cytokines. Animals were necropsied two weeks following arthritis induction. Coronary and digital arterial segments were mounted in a Mulvaney-Halpern wire myograph. The relaxant response to endothelium-dependent and endothelium-independent vasodilators was used to assess endothelial dysfunction.Arthritic sheep treated with MPC demonstrated a marked spike in plasma IL-10, 24h following MPC administration. They also showed significantly reduced plasma levels of the inflammatory markers, fibrinogen and serum amyloid A, and increased HDL. Coronary arteries from RA sheep treated with MPCs demonstrated a significantly greater maximal relaxation to bradykinin when compared to untreated RA sheep (253.6 ± 17.1% of pre-contracted tone vs. 182.3 ± 27.3% in controls, and digital arteries also demonstrated greater endothelium-dependent vasodilation. This study demonstrated that MPCs

  8. Grape-derived polyphenols improve aging-related endothelial dysfunction in rat mesenteric artery: role of oxidative stress and the angiotensin system.

    Directory of Open Access Journals (Sweden)

    Noureddine Idris Khodja

    Full Text Available Aging is characterized by the development of an endothelial dysfunction, which affects both the nitric oxide (NO- and the endothelium-derived hyperpolarizing factor (EDHF-mediated relaxations, associated with vascular oxidative stress and the activation of the angiotensin system. This study investigated whether red wine polyphenols (RWPs, antioxidants and potent stimulators of NO- and EDHF-mediated relaxations improve aging-related endothelial dysfunction, and, if so, examined the underlying mechanism. Mesenteric artery reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine and MitoSOX staining, and expression of target proteins by immunohistochemical staining. Control young rats (16 weeks received solvent (ethanol, 3% v/v, and middle-aged rats (46 weeks either solvent or RWPs (100 mg/kg/day in the drinking water. The acetylcholine-induced endothelium-dependent NO component was slightly reduced whereas the EDHF component was markedly blunted in rings of middle-aged rats compared to young rats. The endothelial dysfunction was associated with oxidative stress, an upregulation of angiotensin II and AT1 receptors and a down-regulation of SK(Ca, IK(Ca, and angiotensin converting enzyme. Intake of RWPs for either one or two weeks improved the NO and the EDHF components of the relaxation, and normalized oxidative stress, the expression of SK(Ca, IK(Ca and the components of the angiotensin system. The protective effect of the 2-week RWPs treatment persisted for one and two weeks following stopping intake of RWPs. Thus, intake of RWPs caused a persistent improvement of the endothelial function, particularly the EDHF component, in middle-aged rats and this effect seems to involve the normalization of the expression of SK(Ca, IK(Ca and the angiotensin system.

  9. Tetrahydroxystilbene Glucoside Protects Against Oxidized LDL-Induced Endothelial Dysfunction via Regulating Vimentin Cytoskeleton and its Colocalization with ICAM-1 and VCAM-1

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    Wenjuan Yao

    2014-10-01

    Full Text Available Background: Endothelial cell dysfunction triggered by oxidized low-density lipoprotein (oxLDL is the main event occurring during the development of atherosclerosis. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG, an active component of the rhizome extract from Polygonum multiflorum, exhibits significant anti-atherosclerotic activity. However, the protective effects of TSG against oxLDL-induced endothelial dysfunction have not been clarified. We investigated the cytoprotective effects of TSG in human umbilical vein endothelial cells (HUVECs and explored underlying mechanisms. Methods and Results: TSG pretreatment markedly attenuated oxLDL-mediated loss of cell viability, release of lactate dehydrogenase (LDH, cell apoptosis, and monocyte adhesion. OxLDL increased vimentin mRNA and protein levels, vimentin cleavage, caspase-3 activation, adhesion molecules levels and their colocalization with vimentin in HUVECs. These alterations were attenuated by pretreatment with TSG. Meanwhile, TSG inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by oxLDL. Using shRNA, oxLDL-induced cell apoptosis and monocyte adhesion were significantly inhibited by vimentin suppression in HUVECs. Conclusions: These results suggest that TSG protects HUVECs against oxLDL-induced endothelial dysfunction through inhibiting vimentin expression and cleavage, and the expression of adhesion molecules and their colocalization with vimentin. The interruption of TGFβ/Smad pathway and caspase-3 activation appears to be responsible for the downregulation of TSG on vimentin expression and fragmentation, respectively.

  10. Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis

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    Constanza Ballesteros-Martinez

    2017-10-01

    Full Text Available Anaphylaxis, the most serious and life-threatening allergic reaction, produces the release of inflammatory mediators by mast cells and basophils. Regulator of calcineurin 1 (Rcan1 is a negative regulator of mast-cell degranulation. The action of mediators leads to vasodilation and an increase in vascular permeability, causing great loss of intravascular volume in a short time. Nevertheless, the molecular basis remains unexplored on the vascular level. We investigated Rcan1 expression induced by histamine, platelet-activating factor (PAF, and epinephrine in primary human vein (HV-/artery (HA-derived endothelial cells (ECs and human dermal microvascular ECs (HMVEC-D. Vascular permeability was analyzed in vitro in human ECs with forced Rcan1 expression using Transwell migration assays and in vivo using Rcan1 knockout mice. Histamine, but neither PAF nor epinephrine, induced Rcan1-4 mRNA and protein expression in primary HV-ECs, HA-ECs, and HMVEC-D through histamine receptor 1 (H1R. These effects were prevented by pharmacological inhibition of calcineurin with cyclosporine A. Moreover, intravenous histamine administration increased Rcan1 expression in lung tissues of mice undergoing experimental anaphylaxis. Functional in vitro assays showed that overexpression of Rcan1 promotes barrier integrity, suggesting a role played by this molecule in vascular permeability. Consistent with these findings, in vivo models of subcutaneous and intravenous histamine-mediated fluid extravasation showed increased response in skin, aorta, and lungs of Rcan1-deficient mice compared with wild-type animals. These findings reveal that endothelial Rcan1 is synthesized in response to histamine through a calcineurin-sensitive pathway and may reduce barrier breakdown, thus contributing to the strengthening of the endothelium and resistance to anaphylaxis. These new insights underscore its potential role as a regulator of sensitivity to anaphylaxis in humans.

  11. Association between glycemic control and morning blood surge with vascular endothelial dysfunction in type 2 diabetes mellitus patients

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    Rama Kumari Nuthalapati

    2016-01-01

    poor glycemic control and IR have predictive value for the occurrence of MBPS in T2DM patients, which might be significantly associated with endothelial dysfunction.

  12. Vasopressin-related copeptin is a novel predictor of early endothelial dysfunction in patients with adult polycystic kidney disease.

    Science.gov (United States)

    Kocyigit, Ismail; Yilmaz, Mahmut Ilker; Gungor, Ozkan; Eroglu, Eray; Unal, Aydin; Orscelik, Ozcan; Tokgoz, Bulent; Sipahioglu, Murat; Sen, Ahmet; Carrero, Juan Jesús; Oymak, Oktay; Axelsson, Jonas

    2016-11-30

    In this study, we examined the relative usefulness of serum copeptin levels as a surrogate marker of vasopressin (AVP) in adult polycystic kidney disease (ADPKD) by correlating it with baseline and longitudinal changes in markers of both renal function and common CVD manifestations (hypertensive vascular disease, atherosclerosis and endothelial dysfunction) that accompany the progression of this disease. We studied a cohort of young and otherwise healthy ADPKD patients (n = 235) and measured cardiovascular function using flow-mediation dilatation (FMD), carotid intima media thickness (cIMT) and pulse wave velocity (PWV), as well as serum copeptin (commercial ELISA, a stable marker of AVP activity). The same analyses were carried out at baseline and after 3 years of follow-up. At baseline, median eGFR was 69 mL/min./1.73 m 2 , mean FMD 6.9 ± 0.9%, cIMT 0.7 ± 0.1 mm, and PWV 8.1 ± 1.2 m/s. At follow-up, equivalent values were 65 (44-75) mL/min./1.73 m 2 , 5.8 ± 0.9%, 0.8 ± 0.1 mm. and 8.2 ± 1.3 m/s. with all changes statistically significant. Plasma copeptin also rose from 0.62 ± 0.12 to 0.94 ± 0.19 ng/mL and this change correlated with ΔeGFR (-0.33, p 0.76], and ΔPWV [cut-off:≤7.80]. Vascular dysfunction as reflected by FMD and cIMT, but not PWV or an altered cardiac geometry, precede most other signs of disease in ADPKD but is predicted by elevated levels of the circulating AVP-marker copeptin.

  13. Aortic stenting in the growing sheep causes aortic endothelial dysfunction but not hypertension: Clinical implications for coarctation repair.

    Science.gov (United States)

    Maschietto, Nicola; Semplicini, Luca; Ceolotto, Giulio; Cattelan, Arianna; Poser Dvm, Helen; Iacopetti, Ilaria; Gerardi, Gabriele; De Benedictis, Giulia Maria; Pilla, Tommaso; Bernardini, Daniele; Aresu, Luca; Rizzo, Stefania; Basso, Cristina; Semplicini, Andrea; Milanesi, Ornella

    2017-01-01

    Stent implantation is the treatment of choice for adolescents and adults with aortic coarctation (CoAo). Despite excellent short-term results, 20%-40% of the patients develop arterial hypertension later in life, which was attributed to inappropriate response of the aortic baroreceptors to increased stiffness of the ascending aorta (ASAO), either congenital or induced by CoAo repair. In particular, it has been hypothesized that stent itself may cause or sustain hypertension. Therefore, we aimed to study the hemodynamic and structural impact following stent implantation in the normal aorta of a growing animal. Eight female sheep completed the study and a stent was implanted in four. Every 3 mo we measured blood pressure of the anterior and posterior limbs and left ventricular function by echocardiography. Twelve months later invasive pressure was measured under baseline and simulated stress conditions. Expression of genes indicating oxidative stress (OS), endothelial dysfunction (ED) and stiffness, as well as pathological examination were performed in ascending (ASAO) and descending aorta (DSAO). SOD1 and MMP9 gene expression were higher in ASAO of the stented animals, compared to DSAO and controls, while NOS3 was decreased. No differences were found in blood pressure and echocardiographic parameters. No histological differences were found in the aorta of the two groups of animals. Stent does not affect central and peripheral hemodynamics, cardiac structure and function even in the long term. However, the finding of markers of OS and increased stiffness of ASAO, proximal to the stent, points to molecular mechanisms for increased cardiovascular risk of patients with stented CoAo. © 2016 The Authors Congenital Heart Disease published by Wiley Periodicals, Inc.

  14. Is Long Term Duration of Diabetes is a Factor to Cause Endothelial Dysfunction in Patients with Type 2 Diabetes Mellitus?

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    Siva Prasad Palem

    2017-12-01

    Full Text Available Introduction: Endothelial Dysfunction (ED is an earliest pathological process of atherosclerosis. Endothelium regulates vascular tone, platelet activity, leukocyte adhesion and thrombosis. Impaired function of endothelium initiates the development of atherosclerosis. Nitric oxide is one of the most effective endogenous vasodilator and also a marker for ED. Aim: To assess whether long term duration of diabetes is a factor to cause ED and its complications in patients with Type 2 diabetes mellitus. Hence, the study has been designed to assess the ED in patients with long term duration of Type 2 diabetes for early prediction of vascular complications. Materials and Methods: The study was conducted on 47 Type 2 diabetic subjects. Among these 27 subjects with 5 years duration of diabetes (Group-II. Glucose, HbA1c, BMI and lipid profile were estimated by well established methods in auto-analyzer, MDA by Thiobarbituric Acid Reactive Substances (TBARS, total antioxidant capacity as Ferric Reducing Ability of Plasma (FRAP and NO was estimated by kinetic cadmium reduction method using spectrophotometer. Statistical analysis was performed by “Kruskal-Wallis” test. Result: Significantly low level of NO was identified in Type 2 diabetic patients with >5 years duration of disease compared to 5 years duration of diabetes and no significant difference in the level of FRAP among the study groups. It has also shown significantly high level of age in >5 years duration of Type 2 diabetes than <5 years. But, no significant differences in the levels of HbA1c, lipid profile were identified between two study groups. Conclusion: Age and oxidative stress (lipid peroxidation has been recognized as risk factors for ED and future complications in patients with more than 5 years duration of Type 2 diabetes.

  15. Nailfold capillaroscopy assessment of microcirculation abnormalities and endothelial dysfunction in children with primary or secondary Raynaud syndrome.

    Science.gov (United States)

    Latuskiewicz-Potemska, Joanna; Chmura-Skirlinska, Antonina; Gurbiel, Ryszard J; Smolewska, Elzbieta

    2016-08-01

    Raynaud syndrome (RS) manifests as episodes of transient spasms of peripheral blood vessels, most often in response to cold. The reason of that symptom (primary RS (pRS)) usually cannot be found but may be accompanied by some autoimmune diseases (secondary RS (sRS)). In this study, we assessed microcapillary status and serum concentrations of chosen cytokines, adhesive molecules, and nitric oxide (NO) in patients with pRS and sRS in comparison with healthy children. Eighty-six patients with RS were enrolled into the study, including 52 with pRS and 34 with sRS. The control group consisted of 29 healthy children. A decrease in myorelaxative and anticoagulant abilities was observed, with simultaneous prevalence of vasopressor substances and procoagulative activity. Therefore, several important factors such as endothelin-1 (ET-1), E-selectin (E-sel), interleukin-18 (IL-18), and nitrogen oxide (NO) were also analyzed. Two types of capillaroscopy status were determined: normal and microangiopathic. There was a significant relationship between presence of microangiopathy and higher serum ET-1 (p = 0.018) and E-sel (p = 0.021) levels. Similarly, we have found a correlation between presence of ANA and higher ET-1 (p = 0.005), but not E-sel (p = 0.241). In patients with pRS, we found significant relationship between ANA and higher ET-1 (p = 0.008). No such relations were observed in sRS patients. Our data indicates that external factor-induced vasoconstrictive effects dominated in pRS, whereas in sRS in the course of connective tissue diseases, it was accompanied by coexistent vasodilation due to endothelial dysfunction. The latter phenomenon is at least partially dependent on insufficient NO release.

  16. Elevated CETP activity during acute phase of myocardial infarction is independently associated with endothelial dysfunction and adverse clinical outcome.

    Science.gov (United States)

    Carvalho, Luiz Sergio F; Virginio, Vitor W M; Panzoldo, Natalia B; Figueiredo, Valeria N; Santos, Simone N; Modolo, Rodrigo G P; Andrade, Joalbo M; Quinaglia E Silva, Jose C; Nadruz-Junior, Wilson; de Faria, Eliana C; Sposito, Andrei C

    2014-12-01

    Recent data suggests that cholesteryl ester transfer protein (CETP) activity may interact with acute stress conditions via inflammatory-oxidative response and thrombogenesis. We investigated this assumption in patients with ST-elevation myocardial infarction (STEMI). Consecutive patients with STEMI (n = 116) were enrolled <24-h of symptoms onset and were followed for 180 days. Plasma levels of C-reactive protein (CRP), interleukin-2 (IL-2), tumor necrosis factor (TNFα), 8-isoprostane, nitric oxide (NOx) and CETP activity were measured at enrollment (D1) and at fifth day (D5). Flow-mediated dilation (FMD) was assessed by ultrasound and coronary thrombus burden (CTB) was evaluated by angiography. Neither baseline nor the change of CETP activity from D1 to D5 was associated with CRP, IL-2, TNFα, 8-isoprostane levels or CTB. The rise in NOx from D1 to D5 was inferior [3.5(-1; 10) vs. 5.5(-1; 12); p < 0.001] and FMD was lower [5.9(5.5) vs. 9.6(6.6); p = 0.047] in patients with baseline CETP activity above the median value than in their counterparts. Oxidized HDL was measured by thiobarbituric acid reactive substances (TBARS) in isolated HDL particles and increased from D1 to D5, and remaining elevated at D30. The change in TBARS content in HDL was associated with CETP activity (r = 0.72; p = 0.014) and FMD (r = -0.61; p = 0.046). High CETP activity at admission was associated with the incidence of sudden death and recurrent MI at 30 days (OR 12.8; 95% CI 1.25-132; p = 0.032) and 180 days (OR 3.3; 95% CI 1.03-10.7; p = 0.044). An enhanced CETP activity during acute phase of STEMI is independently associated with endothelial dysfunction and adverse clinical outcome. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Endothelial nitric oxide synthase gene polymorphisms and risk of erectile dysfunction: An updated meta-analysis of genetic association studies.

    Science.gov (United States)

    Yao, Han-Xin; Ma, Fu-Zhe; Tan, Yu-Ying; Liu, Ling-Yun

    2018-04-11

    Endothelial nitric oxide synthase (eNOS) polymorphisms have been implicated as risk factors for erectile dysfunction (ED), but the results of genetic association studies are inconclusive. We performed a meta-analysis of published studies investigating the association between ED and three eNOS polymorphisms, intron 4 VNTR, G894T and T786C in humans. The PubMed, Web of Science, CNKI and Google Scholar databases were searched for relevant studies published up to November 2017. Association studies with case-control design were included. For each study with genotype information we calculated odds ratios (OR) and 95% confidence intervals (CI). The search identified 13 eligible studies. The G894T and T786C polymorphisms showed a significant association with ED risk in Caucasians (GT + TT versus GG for G894T: OR = 2.13, 95% CI = 1.08-4.19; CC versus CT + TT for T786C: OR = 3.29, 95% CI = 2.30-4.72) and Asians (GT + TT versus GG for G894T: OR = 2.08, 95% CI = 1.53-2.84; CC + CT versus TT for T786C: OR = 3.13, 95% CI = 1.35-7.25). In addition, the intron 4 VNTR polymorphism was associated with ED risk only among Caucasian subjects (aa versus bb + ab: OR = 2.38, 95% CI = 1.15-4.93). We found no evidence of publication bias. The robustness of overall analyses was ensured in sensitivity analyses excluding studies deviating from Hardy-Weinberg equilibrium. Our findings suggest that common genetic polymorphisms in the eNOS gene contribute to risk of ED, presumably by effects on eNOS activity and NO availability. Copyright © 2018. Published by Elsevier Ltd.

  18. Isoproterenol induces vascular oxidative stress and endothelial dysfunction via a Giα-coupled β2-adrenoceptor signaling pathway.

    Directory of Open Access Journals (Sweden)

    Ana P Davel

    Full Text Available OBJECTIVE: Sustained β-adrenergic stimulation is a hallmark of sympathetic hyperactivity in cardiovascular diseases. It is associated with oxidative stress and altered vasoconstrictor tone. This study investigated the β-adrenoceptor subtype and the signaling pathways implicated in the vascular effects of β-adrenoceptor overactivation. METHODS AND RESULTS: Mice lacking the β1- or β2-adrenoceptor subtype (β1KO, β2KO and wild-type (WT were treated with isoproterenol (ISO, 15 μg.g(-1 x day(-1, 7 days. ISO significantly enhanced the maximal vasoconstrictor response (Emax of the aorta to phenylephrine in WT (+34% and β1KO mice (+35% but not in β2KO mice. The nitric oxide synthase (NOS inhibitor L-NAME abolished the differences in phenylephrine response between the groups, suggesting that ISO impaired basal NO availability in the aorta of WT and β1KO mice. Superoxide dismutase (SOD, pertussis toxin (PTx or PD 98,059 (p-ERK 1/2 inhibitor incubation reversed the hypercontractility of aortic rings from ISO-treated WT mice; aortic contraction of ISO-treated β2KO mice was not altered. Immunoblotting revealed increased aortic expression of Giα-3 protein (+50% and phosphorylated ERK1/2 (+90% and decreased eNOS dimer/monomer ratio in ISO-treated WT mice. ISO enhanced the fluorescence response to dihydroethidium (+100% in aortas from WT mice, indicating oxidative stress that was normalized by SOD, PTx and L-NAME. The ISO effects were abolished in β2KO mice. CONCLUSIONS: The β2-adrenoceptor/Giα signaling pathway is implicated in the enhanced vasoconstrictor response and eNOS uncoupling-mediated oxidative stress due to ISO treatment. Thus, long-term β2-AR activation might results in endothelial dysfunction.

  19. l-Arginine Supplementation Alleviates Postprandial Endothelial Dysfunction When Baseline Fasting Plasma Arginine Concentration Is Low: A Randomized Controlled Trial in Healthy Overweight Adults with Cardiometabolic Risk Factors.

    Science.gov (United States)

    Deveaux, Ambre; Pham, Isabelle; West, Sheila G; André, Etienne; Lantoine-Adam, Frédérique; Bunouf, Pierre; Sadi, Samira; Hermier, Dominique; Mathé, Véronique; Fouillet, Hélène; Huneau, Jean-François; Benamouzig, Robert; Mariotti, François

    2016-07-01

    Vascular endothelial dysfunction, the hallmark of early atherosclerosis, is induced transiently by a high-fat meal. High doses of free l-arginine supplements reduce fasting endothelial dysfunction. We sought to determine the effects of a low dose of a sustained-release (SR) l-arginine supplement on postprandial endothelial function in healthy overweight adults with cardiometabolic risk factors and to investigate whether this effect may vary by baseline arginine status. In a randomized, double-blind, 2-period crossover, placebo-controlled trial (4-wk treatment, 4-wk washout), we compared the effects of 1.5 g SR-l-arginine 3 times/d (4.5 g/d) with placebo in 33 healthy overweight adults [body mass index (BMI, in kg/m(2)): 25 to >30] with the hypertriglyceridemic waist (HTW) phenotype [plasma triglycerides > 150 mg/dL; waist circumference > 94 cm (men) or > 80 cm (women)]. The main outcome variable tested was postprandial endothelial function after a high-fat meal (900 kcal), as evaluated by use of flow-mediated dilation (FMD) and Framingham reactive hyperemia index (fRHI), after each treatment. By use of subgroup analysis, we determined whether the effect was related to the baseline plasma arginine concentration. In the total population, the effects of SR-arginine supplementation on postprandial endothelial function were mixed and largely varied with baseline fasting arginine concentration (P-interaction supplementation attenuated the postprandial decrease in both FMD (29% decrease with SR-arginine compared with 50% decrease with placebo) and fRHI (5% increase with SR-arginine compared with 49% decrease with placebo), resulting in significantly higher mean ± SEM values with SR-arginine (FMD: 4.0% ± 0.40%; fRHI: 0.41 ± 0.069) than placebo (FMD: 2.9% ± 0.31%; fRHI: 0.21 ± 0.060) at the end of the postprandial period (P Supplementation with low-dose SR-arginine alleviates postprandial endothelial dysfunction in healthy HTW adults when the baseline plasma arginine

  20. Determination of the Diagnostic Values of Asymmetric Dimethylarginine as an Indicator for Evaluation of the Endothelial Dysfunction in Patients with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Dejan Spasovski

    2013-01-01

    Full Text Available Introduction. To compare the diagnostic values of laboratory variables, to present evaluations of the diagnostic test for asymmetric dimethyl arginine (ADMA, rheumatoid factor (RF, C-reactive protein (CRP, and DAS28 index, and to define the effect of untreated rheumatoid arthritis on endothelial function. In order to determine whether ADMA changes depending on the disease evolution, ADMA was used as an indicator for endothelial dysfunction. Methods. Using an ELISA technology of DLD-Diagnostika-GMBH for the detection of ADMA, the samples of serum and urine have been examined in 70 participants (35 RA who were not treated, 35 healthy controls. RF was defined with the test for agglutination (Latex RF test in the same participants. Results. Out of 35 examined patients with RA, RF appeared in 17 patients (sensitivity of the test, 51.42%. In 20 of the 35 examined patients with RA, we found the presence of ADMA (sensitivity of the test, 57.14%. Anti-CCP antibody was present in 24 examined patients with RA (sensitivity of the test, 68.57%. Conclusion. ADMA has equal or very similar sensitivity and specificity to RF in untreated RA (sensitivity of 57.14% versus 48.57%, specificity of 88.57% versus 91.42% in the detection of asymptomatic endothelial dysfunction in untreated RA.

  1. Anthocyanin prevents CD40-activated proinflammatory signaling in endothelial cells by regulating cholesterol distribution.

    Science.gov (United States)

    Xia, Min; Ling, Wenhua; Zhu, Huilian; Wang, Qing; Ma, Jing; Hou, Mengjun; Tang, Zhihong; Li, Lan; Ye, Qinyuan

    2007-03-01

    Intracellular tumor necrosis factor receptor-associated factors (TRAFs) translocation to lipid rafts is a key element in CD40-induced signaling. The purpose of this study was to investigate the influence of anthocyanin on CD40-mediated proinflammatory events in human endothelial cells and the underlying possible molecular mechanism. Treatment of endothelial cells with anthocyanin prevented from CD40-induced proinflammatory status, measured by production of IL-6, IL-8, and monocyte chemoattractant protein-1 through inhibiting CD40-induced nuclear factor-kappaB (NF-kappaB) activation. TRAF-2 played pivotal role in CD40-NF-kappaB pathway as TRAF-2 small interference RNA (siRNA) diminished CD40-induced NF-kappaB activation and inflammation. TRAF-2 overexpression increased CD40-mediated NF-kappaB activation. Moreover, TRAF-2 almost totally recruited to lipid rafts after stimulation by CD40 ligand and depletion of cholesterol diminished CD40-mediated NF-kappaB activation. Exposure to anthocyanin not only interrupted TRAF-2 recruitment to lipid rafts but also decreased cholesterol content in Triton X-100 insoluble lipid rafts. However, anthocyanin did not influence the interaction between CD40 ligand and CD40 receptor. Our findings suggest that anthocyanin protects from CD40-induced proinflammatory signaling by preventing TRAF-2 translocation to lipid rafts through regulation of cholesterol distribution, which thereby may represent a mechanism that would explain the anti-inflammatory response of anthocyanin.

  2. A method for preventive intervention regarding temporomandibular pain and dysfunction.

    Science.gov (United States)

    Ellie, Saghafi; Christina, Mejersjö

    2018-02-15

    Adolescent girls frequently suffer from temporomandibular disorder (TMD) symptoms and associated headache. A program aimed at informing about risk behavior for TMD symptoms, how to influence harmful habits and about general relaxation was tested. Eighty girls at two high schools, 16 years of age, with or without symptoms, were invited to the health information on two occasions and 60 girls participated. Firstly, a questionnaire regarding symptoms and oral parafunctional habits was administrated. Structured information was given about the normal anatomy and function of muscles and joints, about the occlusion, oral habits and symptoms of orofacial pain/dysfunction and headache. General relaxation was instructed and trained. At a three-month follow-up, the same questionnaire regarding symptoms as at baseline was completed. The information provided was perceived as useful and instructive. At the follow-up, 77% reported that they used what they had learned. Headache once a week or more decreased from 49% at baseline to 35% and headache 'never/rarely' changed from 11% to 25% (p = .002). Reported joint sounds had decreased by the follow-up (p = .053), as had the use of chewing gum (p = .002). A majority of the girls suggested that the information should be scheduled during school hours. Health information about the jaw system can influence risk factors for TMD symptoms and the frequency of symptoms among adolescent girls.

  3. Weight loss is associated with improved endothelial dysfunction via NOX2-generated oxidative stress down-regulation in patients with the metabolic syndrome.

    Science.gov (United States)

    Angelico, Francesco; Loffredo, Lorenzo; Pignatelli, Pasquale; Augelletti, Teresa; Carnevale, Roberto; Pacella, Antonio; Albanese, Fabiana; Mancini, Ilaria; Di Santo, Serena; Del Ben, Maria; Violi, Francesco

    2012-06-01

    The aim of this study was to assess whether adherence to a restricted-calorie, Mediterranean-type diet improves endothelial dysfunction and markers of oxidative stress in patients with metabolic syndrome. A moderately low-calorie (600 calories/day negative energy balance), low-fat, high-carbohydrate diet (fat, fat and 55% from carbohydrate) was prescribed to 53 outpatients with the metabolic syndrome. Participants were divided into two groups according to body weight loss > or weight (-6.8%), body-mass-index (-4.6%), waist circumference (-4.8%), HOMA-IR (-27.2%), plasma glucose, glycosylated haemoglobin, total and LDL-cholesterol, blood pressure, serum NOX2 (the catalytic core of NADPH oxidase) (-22.2%) and urinary8-isoprostanes (-39.0%) and an increase of serum NOx (Nitrite/Nitrate) (+116.8%) and adiponectine (+125.5%) as compared with those in group B (n = 30). A statistically significant increase in brachial artery flow-mediated dilatation was observed in group A (+24.7%; p weight loss is able to improve endothelial dysfunction in patients with the metabolic syndrome. The coexistent decrease of NOX2 activation suggests a role for oxidative stress in eliciting artery dysfunction.

  4. Influence of eNOS gene 4a/bVNTR polymorphism on development of endothelial dysfunction and respiratory system disorders in children - residents of radioactively contaminated areas

    International Nuclear Information System (INIS)

    Stepanova, Je.Yi.; Kolpakov, Yi.Je.; Zigalo, V.M.; And Others

    2015-01-01

    Total of 184 children were examined to determine the possible associative links between eNOS gene intron 4m polymorphism and indices characterizing the functional state of the endothelium and the bronchopulmonary system. Of them the main group of children consisted of 135 childrenresidents of radioactively contaminated areas, the control group - of 49 healthy children who lived in ''clean'' regions by the radioactive con tamination and were not belonging to victims of the Chernobyl accident contingents. The molecular genetic study determining the eNOS gene intron 4 polymorphism was performed. Children of the main group did not differ from that of control and literature data by the frequency of geno types 4a/b and eNOS gene allele polymorphism. An increase in the duration of circulation restoration up to the ini tial level after occlusion test was noted in children of the main group with genotype 4a/4b comparing to children with genotype 4b/4b ; a decrease in the nitrite content was observed in blood serum. The integral indices of elastic ity and tensility of the lung tissue, respiratory permeability were decreased; the signs of bronchospasm were record ed 1.5 times more often. These adverse effects were associated with the presence of genotype allele 4a , the signs of endothelial dysfunction and the level of the incorporated 137 Cs. More pronounced changes in vascular endothelial reaction to occlusion and the significant decrease of serum nitrite level in allele 4a carriers, especially in children who live in adverse ecological conditions, give the right to include them into the risk group for the development of endothelial dysfunction, and to conside pulmonary dysfunction as one of its manifestations

  5. Does tadalafil prevent erectile dysfunction in patients undergoing radiation therapy for prostate cancer?

    NARCIS (Netherlands)

    L. Incrocci (Luca)

    2014-01-01

    textabstractA recently published paper addressed the interesting topic of prevention of erectile dysfunction (ED) with tadalafil, a phosphodiesterase-type 5 inhibitor (PDE5i) in patients undergoing radiation therapy for localized prostate cancer. [1]Tadalafil 5 mg or placebo was

  6. Pre-weaning growth hormone treatment reverses hypertension and endothelial dysfunction in adult male offspring of mothers undernourished during pregnancy.

    Directory of Open Access Journals (Sweden)

    Clint Gray

    Full Text Available Maternal undernutrition results in elevated blood pressure (BP and endothelial dysfunction in adult offspring. However, few studies have investigated interventions during early life to ameliorate the programming of hypertension and vascular disorders. We have utilised a model of maternal undernutrition to examine the effects of pre-weaning growth hormone (GH treatment on BP and vascular function in adulthood. Female Sprague-Dawley rats were fed either a standard control diet (CON or 50% of CON intake throughout pregnancy (UN. From neonatal day 3 until weaning (day 21, CON and UN pups received either saline (CON-S, UN-S or GH (2.5 ug/g/day(CON-GH, UN-GH. All dams were fed ad libitum throughout lactation. Male offspring were fed a standard diet until the end of the study. Systolic blood pressure (SBP was measured at day 150 by tail cuff plethysmography. At day 160, intact mesenteric vessels mounted on a pressure myograph. Responses to pressure, agonist-induced constriction and endothelium-dependent vasodilators were investigated to determine vascular function. SBP was increased in UN-S groups and normalised in UN-GH groups (CON-S 121±2 mmHg, CON-GH 115±3, UN-S 146±3, UN-GH 127±2. Pressure mediated dilation was reduced in UN-S offspring and normalised in UN-GH groups. Vessels from UN-S offspring demonstrated a reduced constrictor response to phenylephrine and reduced vasodilator response to acetylcholine (ACh. Furthermore, UN-S offspring vessels displayed a reduced vasodilator response in the presence of L-NG-Nitroarginine Methyl Ester (L-NAME, carbenoxolone (CBX, L-NAME and CBX, Tram-34 and Apamin. UN-GH vessels showed little difference in responses when compared to CON and significantly increased vasodilator responses when compared to UN-S offspring. Pre-weaning GH treatment reverses the negative effects of maternal UN on SBP and vasomotor function in adult offspring. These data suggest that developmental cardiovascular programming is

  7. Menopause, estrogens, and endothelial dysfunction: current concepts Menopausa, estrogênios e disfunção endotelial: aspectos atuais

    Directory of Open Access Journals (Sweden)

    Maria Augusta Maturana

    2007-02-01

    Full Text Available Menopause is defined as the permanent cessation of menses. Cardiovascular disease is the leading cause of death among postmenopausal women in developed countries. The disparity between the incidence of cardiovascular disease among women in pre- and postmenopause has been ascribed to the actions of endogenous estrogen on the cardiovascular system and, particularly, on the vascular endothelium. The endothelium plays an important role in cardiovascular homeostasis, either through the vascular tonus and its regulation, or through coagulation and the inflammatory response. Endothelial dysfunction is implicated in the genesis of atherosclerosis and other chronic disorders, such as diabetes mellitus and hypertension. The pharmacological use of estrogen exerts influence on the circulating levels of markers of vascular tonus, and inflammation, as well as prothrombotic, and fibrinolytic markers, but the impact of these changes on the atherosclerotic disease is still uncertain.A menopausa é definida como a cessação permanente das menstruações. A doença cardiovascular é a principal causa de mortalidade em mulheres na pós- menopausa, em países desenvolvidos. A disparidade entre a incidência de doença cardiovascular entre mulheres na pré e pós menopausa tem sido atribuída a ações do estrogênio endógeno sobre o sistema cardiovascular e, em especial, sobre a função do endotélio vascular. O endotélio tem importante papel na homestase cardiovascular, seja no controle do tônus e permeabilidade vascular, ou da coagulação e resposta inflamatória. A disfunção endotelial está implicada na gênese da aterosclerose e de outras doenças crônicas, como diabete melito e hipertensão arterial. O uso farmacológico de estrogênio exerce influência sobre concentrações circulantes de marcadores do tônus vascular, inflamatórios, pró-trombóticos e fibrinolíticos, porém o impacto destas alterações sobre a doença aterosclerótica ainda n

  8. Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Lund, Søren S; Tarnow, Lise; Stehouwer, Coen D A

    2008-01-01

    OBJECTIVE: In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti......-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1...

  9. Markers of inflammation and endothelial dysfunction are associated with incident cardiovascular disease, all-cause mortality, and progression of coronary calcification in type 2 diabetic patients with microalbuminuria.

    Science.gov (United States)

    von Scholten, Bernt Johan; Reinhard, Henrik; Hansen, Tine Willum; Schalkwijk, Casper G; Stehouwer, Coen; Parving, Hans-Henrik; Jacobsen, Peter Karl; Rossing, Peter

    2016-03-01

    We evaluated markers of inflammation and endothelial dysfunction and their associations with incident cardiovascular disease (CVD), all-cause mortality and progression of coronary artery calcium (CAC) in patients with type 2 diabetes (T2D) and microalbuminuria but without known coronary artery disease (CAD). Prospective study including 200 patients receiving multifactorial treatment. Markers of inflammation (TNF-ɑ, sICAM-1, sICAM-3, hsCRP, SAA, IL-1β, IL-6, IL-8) and endothelial dysfunction (thrombomodulin, sVCAM-1, sICAM-1, sICAM-3, sE-selectin, sP-selectin) were measured at baseline. Adjustment included traditional CVD risk factors, and full adjustment additionally NT-proBNP and CAC. The "SQRT method" assessed CAC progression after 5.8years, and cut-point was an annualised difference >2.5. Occurrence of CVD (n=40) and all-cause mortality (n=26) was traced after 6.1years. In adjusted and fully adjusted Cox models, TNF-ɑ was a determinant of CVD and all-cause mortality (p≤0.007). Further, in adjusted and fully adjusted logistic regression, TNF-ɑ was related to CAC progression (p≤0.042). Of the other biomarkers, sICAM-3 and thrombomodulin were also associated with both endpoints (p≤0.046), IL-1β with CVD endpoints (p=0.021), and sVCAM-1 and sICAM-1 with all-cause mortality (p≤0.005). Higher composite z-scores including all markers of inflammation and endothelial dysfunction were associated with CVD and all-cause mortality (p≤0.008). In patients with T2D and microalbuminuria without known CAD and receiving multifactorial treatment, biomarkers of inflammation and endothelial dysfunction were independently associated with CVD, all-cause mortality and CAC progression. Especially TNF-ɑ was a robust determinant, even after adjusting for NT-proBNP and CAC. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Bee products prevent VEGF-induced angiogenesis in human umbilical vein endothelial cells

    Directory of Open Access Journals (Sweden)

    Mishima Satoshi

    2009-11-01

    Full Text Available Abstract Background Vascular endothelial growth factor (VEGF is a key regulator of pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. Bee products [royal jelly (RJ, bee pollen, and Chinese red propolis] from the honeybee, Apis mellifera, have been used as traditional health foods for centuries. The aim of this study was to investigate the anti-angiogenic effects of bee products using human umbilical vein endothelial cells (HUVECs. Methods In an in vitro tube formation assay, HUVECs and fibroblast cells were incubated for 14 days with VEGF and various concentrations of bee products [RJ, ethanol extract of bee pollen, ethanol extract of Chinese red propolis and its constituent, caffeic acid phenethyl ester (CAPE]. To clarify the mechanism of in vitro angiogenesis, HUVEC proliferation and migration were induced by VEGF with or without various concentrations of RJ, bee pollen, Chinese red propolis, and CAPE. Results RJ, bee pollen, Chinese red propolis, and CAPE significantly suppressed VEGF-induced in vitro tube formation in the descending order: CAPE > Chinese red propolis >> bee pollen > RJ. RJ and Chinese red propolis suppressed both VEGF-induced HUVEC proliferation and migration. In contrast, bee pollen and CAPE suppressed only the proliferation. Conclusion Among the bee products, Chinese red propolis and CAPE in particular showed strong suppressive effects against VEGF-induced angiogenesis. These findings indicate that Chinese red propolis and CAPE may have potential as preventive and therapeutic agents against angiogenesis-related human diseases.

  11. High-polyphenol chocolate reduces endothelial dysfunction and oxidative stress during acute transient hyperglycaemia in Type 2 diabetes: a pilot randomized controlled trial.

    Science.gov (United States)

    Mellor, D D; Madden, L A; Smith, K A; Kilpatrick, E S; Atkin, S L

    2013-04-01

    To investigate the effects of high-polyphenol chocolate upon endothelial function and oxidative stress in Type 2 diabetes mellitus during acute transient hyperglycaemia induced following a 75-g oral glucose challenge. Ten subjects with Type 2 diabetes underwent a double-blinded randomized controlled crossover study. A 75-g oral glucose load was used to induce hyperglycaemia, which was administered to participants 60 min after they had ingested either low (control) or high-polyphenol chocolate. Participants undertook testing at weekly intervals, following an initial cocoa-free period. Endothelial function was assessed by both functional [reactive hyperaemia peripheral artery tonometry (EndoPAT-2000) and serum markers (including intercellular adhesion molecule 1, P-selectin and P-selectin glycoprotein ligand 1]. Urinary 15-F2t-isoprostane adjusted for creatinine was used as an oxidative stress marker. Measurements were made at baseline and 2 h post-ingestion of the glucose load. Prior consumption of high-polyphenol chocolate before a glucose load improved endothelial function (1.7 ± 0.1 vs. 2.3 ± 0.1%, P = 0.01), whereas prior consumption of control chocolate resulted in a significant increase in intercellular adhesion molecule 1 (321.1 ± 7.6 vs. 373.6 ± 10.5 ng/ml, P = 0.04) and 15-F2t-isoprostane (116.8 ± 5.7 vs. 207.1 ± 5.7 mg/mol, P = 0.02). Analysis of percentage changes from baseline comparing control and high-polyphenol chocolate showed a significant improvement for high-polyphenol chocolate in both measures of endothelial function (P chocolate protected against acute hyperglycaemia-induced endothelial dysfunction and oxidative stress in individuals with Type 2 diabetes mellitus. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  12. The hypoglycemic effects of guava leaf (Psidium guajava L.) extract are associated with improving endothelial dysfunction in mice with diet-induced obesity.

    Science.gov (United States)

    Díaz-de-Cerio, Elixabet; Rodríguez-Nogales, Alba; Algieri, Francesca; Romero, Miguel; Verardo, Vito; Segura-Carretero, Antonio; Duarte, Juan; Galvez, Julio

    2017-06-01

    Obesity is associated with a low-grade inflammatory status that affects vascular function. Previous studies have reported the beneficial effects of Psidium guajava L. (guava) on diabetes. Here we evaluate the how guava leaf extract at the dose of 5 mg/kg, affects vascular dysfunction in obese mice fed a high-fat diet for 7 weeks. Extract intake did not alter weight over time, although it reduced glycemia and insulin resistance, improving the serum lipid profile in obese mice. Additionally, guava leaf extract reversed the endothelial dysfunction found in obese mice in terms of endothelium- and NO (nitric oxide)-dependent vasodilatation induced by acetylcholine in aortic rings. In conclusion, the beneficial effects of guava leaf extract in obese mice were associated with improved vascular functions altered by obesity, probably due to its phenolic content. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Algunas consideraciones de la disfunción endotelial en pacientes con hiperprolactinemia Some considerations of endothelial dysfunction in patients presenting with hyperprolactinemia

    Directory of Open Access Journals (Sweden)

    Maité Cabrera Gámez

    2012-04-01

    Full Text Available Se realizó una revisión de las publicaciones a nuestro alcance de la actualidad sobre el tema disfunción endotelial en pacientes con hiperprolactinemia: existencia, mecanismos de producción y consecuencias. Teniendo en cuenta que la hiperprolactinemia tiene hoy un nuevo enfoque relacionado con la disfunción endotelial, nos propusimos realizar la revisión siguiente. La disfunción endotelial es una alteración en la relajación vascular inducida por la reducción de los factores de relajación derivados del endotelio, principalmente el óxido nítrico, que causa un aumento del estímulo vasoconstrictor con tendencia protrombótica de la vasculatura. La resistencia a la insulina actúa como principal factor de disfunción endotelial asociado o no con la diabetes mellitus. Hasta el presente, el estado hiperprolactinémico se asocia con trastornos de la tolerancia a la glucosa (tolerancia a la glucosa disminuida con hiperinsulinemia. Existe disfunción endotelial en mujeres hiperprolactinémicas y puede deberse a su relación con resistencia a la insulina, a la disminución de los estrógenos y a la propia hiperprolactinemia. También se han encontrado marcadores de inflamación (como la proteína C reactiva elevada en pacientes con esta enfermedad. La hiperprolactinemia se asocia con resistencia a la insulina, disfunción endotelial y bajo grado de inflamación, parámetros que son determinantes en el proceso de aterosclerosis, por lo que esta enfermedad puede ser un factor predisponente de aterosclerosis, y por tanto, un riesgo de morbilidad y mortalidad cardiovasculares.A review of the publications available of current situation on the subject related to endothelial dysfunction in patients with hyperprolactinemia: existence, production mechanisms and consequences. Taking into account that the hyperprolactinemia has a new approach related to endothelial dysfunction authors made present review. Above mentioned dysfunction is a alteration in

  14. Protein kinase C-α signals P115RhoGEF phosphorylation and RhoA activation in TNF-α-induced mouse brain microvascular endothelial cell barrier dysfunction

    Directory of Open Access Journals (Sweden)

    Deng Xiaolu

    2011-04-01

    Full Text Available Abstract Background Tumor necrosis factor-α (TNF-α, a proinflammatory cytokine, is capable of activating the small GTPase RhoA, which in turn contributes to endothelial barrier dysfunction. However, the underlying signaling mechanisms remained undefined. Therefore, we aimed to determine the role of protein kinase C (PKC isozymes in the mechanism of RhoA activation and in signaling TNF-α-induced mouse brain microvascular endothelial cell (BMEC barrier dysfunction. Methods Bend.3 cells, an immortalized mouse brain endothelial cell line, were exposed to TNF-α (10 ng/mL. RhoA activity was assessed by pull down assay. PKC-α activity was measured using enzyme assasy. BMEC barrier function was measured by transendothelial electrical resistance (TER. p115RhoGEF phosphorylation was detected by autoradiography followed by western blotting. F-actin organization was observed by rhodamine-phalloidin staining. Both pharmacological inhibitors and knockdown approaches were employed to investigate the role of PKC and p115RhoGEF in TNF-α-induced RhoA activation and BMEC permeability. Results We observed that TNF-α induces a rapid phosphorylation of p115RhoGEF, activation of PKC and RhoA in BMECs. Inhibition of conventional PKC by Gö6976 mitigated the TNF-α-induced p115RhoGEF phosphorylation and RhoA activation. Subsequently, we found that these events are regulated by PKC-α rather than PKC-β by using shRNA. In addition, P115-shRNA and n19RhoA (dominant negative mutant of RhoA transfections had no effect on mediating TNF-α-induced PKC-α activation. These data suggest that PKC-α but not PKC-β acts as an upstream regulator of p115RhoGEF phosphorylation and RhoA activation in response to TNF-α. Moreover, depletion of PKC-α, of p115RhoGEF, and inhibition of RhoA activation also prevented TNF-α-induced stress fiber formation and a decrease in TER. Conclusions Taken together, our results show that PKC-α phosphorylation of p115RhoGEF mediates TNF

  15. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration.

    Science.gov (United States)

    Detaille, D; Vial, G; Borel, A-L; Cottet-Rouselle, C; Hallakou-Bozec, S; Bolze, S; Fouqueray, P; Fontaine, E

    2016-01-01

    Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy.

  16. Maternal melatonin administration mitigates coronary stiffness and endothelial dysfunction, and improves heart resilience to insult in growth restricted lambs.

    Science.gov (United States)

    Tare, Marianne; Parkington, Helena C; Wallace, Euan M; Sutherland, Amy E; Lim, Rebecca; Yawno, Tamara; Coleman, Harold A; Jenkin, Graham; Miller, Suzanne L

    2014-06-15

    Intrauterine growth restriction (IUGR) is associated with impaired cardiac function in childhood and is linked to short- and long-term morbidities. Placental dysfunction underlies most IUGR, and causes fetal oxidative stress which may impact on cardiac development. Accordingly, we investigated whether antenatal melatonin treatment, which possesses antioxidant properties, may afford cardiovascular protection in these vulnerable fetuses. IUGR was induced in sheep fetuses using single umbilical artery ligation on day 105-110 of pregnancy (term 147). Study 1: melatonin (2 mg h(-1)) was administered i.v. to ewes on days 5 and 6 after surgery. On day 7 fetal heart function was assessed using a Langendorff apparatus. Study 2: a lower dose of melatonin (0.25 mg h(-1)) was administered continuously following IUGR induction and the ewes gave birth normally at term. Lambs were killed when 24 h old and coronary vessels studied. Melatonin significantly improved fetal oxygenation in vivo. Contractile function in the right ventricle and coronary flow were enhanced by melatonin. Ischaemia-reperfusion-induced infarct area was 3-fold greater in IUGR hearts than in controls and this increase was prevented by melatonin. In isolated neonatal coronary arteries, endothelium-dependent nitric oxide (NO) bioavailability was reduced in IUGR, and was rescued by modest melatonin treatment. Melatonin exposure also induced the emergence of an indomethacin-sensitive vasodilation. IUGR caused marked stiffening of the coronary artery and this was prevented by melatonin. Maternal melatonin treatment reduces fetal hypoxaemia, improves heart function and coronary blood flow and rescues cardio-coronary deficit induced by IUGR. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  17. Effects of helium on inflammatory and oxidative stress-induced endothelial cell damage

    NARCIS (Netherlands)

    Smit, Kirsten F.; Kerindongo, Raphaela P.; Böing, Anita; Nieuwland, Rienk; Hollmann, Markus W.; Preckel, Benedikt; Weber, Nina C.

    2015-01-01

    Helium induces preconditioning in human endothelium protecting against postischemic endothelial dysfunction. Circulating endothelial microparticles are markers of endothelial dysfunction derived in response to injury. Another noble gas, xenon, protected human umbilical vein endothelial cells (HUVEC)

  18. Rhynchophylline Ameliorates Endothelial Dysfunction via Src-PI3K/Akt-eNOS Cascade in the Cultured Intrarenal Arteries of Spontaneous Hypertensive Rats.

    Science.gov (United States)

    Hao, Hui-Feng; Liu, Li-Mei; Pan, Chun-Shui; Wang, Chuan-She; Gao, Yuan-Sheng; Fan, Jing-Yu; Han, Jing-Yan

    2017-01-01

    Objectives: To examine the protective effect of Rhynchophylline (Rhy) on vascular endothelial function in spontaneous hypertensive rats (SHRs) and the underlying mechanism. Methods: Intrarenal arteries of SHRs and Wistar rats were suspended in myograph for force measurement. Expression and phosphorylation of endothelial nitric oxide (NO) synthase (eNOS), Akt, and Src kinase (Src) were examined by Western blotting. NO production was assayed by ELISA. Results: Rhy time- and concentration-dependently improved endothelium-dependent relaxation in the renal arteries from SHRs, but had no effect on endothelium-independent relaxation in SHR renal arteries. Wortmannin (an inhibitor of phosphatidylinositol 3-kinase) or PP2 (an inhibitor of Src) inhibited the improvement of relaxation in response to acetylcholine by 12 h-incubation with 300 μM Rhy. Western blot analysis revealed that Rhy elevated phosphorylations of eNOS, Akt, and Src in SHR renal arteries. Moreover, wortmannin reversed the increased phosphorylations of Akt and eNOS induced by Rhy, but did not affect the phosphorylation of Src. Furthermore, the enhanced phosphorylations of eNOS, Akt, and Src were blunted by PP2. Importantly, Rhy increased NO production and this effect was blocked by inhibition of Src or PI3K/Akt. Conclusion: The present study provides evidences for the first time that Rhy ameliorates endothelial dysfunction in SHRs through the activation of Src-PI3K/Akt-eNOS signaling pathway.

  19. Endothelial dysfunction and brachial intima-media thickness: long term cardiovascular risk with claudication related to peripheral arterial disease: a prospective analysis.

    Science.gov (United States)

    Hafner, Franz; Kieninger, Andrea; Meinitzer, Andreas; Gary, Thomas; Froehlich, Harald; Haas, Elke; Hackl, Gerald; Eller, Philipp; Brodmann, Marianne; Seinost, Gerald

    2014-01-01

    Endothelial dysfunction plays a key role in the development, progression, and clinical manifestation of atherosclerosis, and in symptomatic peripheral arterial disease, endothelial dysfunction and enlarged intima-media thickness might be associated with increased cardiovascular risk. Flow-mediated dilatation and serologic parameters are used to evaluate individual endothelial function. Brachial intima-media thickness, a less recognized parameter of cardiovascular risk, is independently associated with coronary artery disease. The aim of this study was to evaluate the prognostic value of ultrasound and serologic parameters of endothelial function in relation to cardiovascular mortality in peripheral arterial disease. monocentric, prospective cohort study. Flow mediated dilatation and brachial intima-media thickness were assessed in 184 (124 male) patients with peripheral arterial disease (Rutherford stages 2-3). Serologic parameters of endothelial function included asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-homoarginine. Cardiovascular events were recorded during a follow-up of 99.1±11.1 months. Subjects who died of noncardiovascular causes were excluded from further analysis. Eighty-two patients (44.6%) died during follow-up after a mean duration of 49.7±28.3 months. There were 49 cardiovascular deaths (59.8%) and 33 other deaths (40.2%). Flow mediated dilatation was associated with cardiovascular death [1.17% (0.0, 4.3) vs. 4.1% (1.2, 6.4), p<0.001]. Intima-media thickness was greater in patients who succumbed to cardiovascular disease [0.37 mm (0.30, 0.41)] than in survivors [0.21 mm (0.15, 0.38), p<0.001]. Brachial intima-media thickness above 0.345 mm was most predictive of cardiovascular death, with sensitivity and specificity values of 0.714 and 0.657, respectively (p<0.001). Furthermore, ADMA levels above 0.745 µmol/l and SDMA levels above 0.825 µmol/l were significantly associated with cardiovascular death (p<0.001 and

  20. Endothelial dysfunction and brachial intima-media thickness: long term cardiovascular risk with claudication related to peripheral arterial disease: a prospective analysis.

    Directory of Open Access Journals (Sweden)

    Franz Hafner

    Full Text Available OBJECTIVE: Endothelial dysfunction plays a key role in the development, progression, and clinical manifestation of atherosclerosis, and in symptomatic peripheral arterial disease, endothelial dysfunction and enlarged intima-media thickness might be associated with increased cardiovascular risk. Flow-mediated dilatation and serologic parameters are used to evaluate individual endothelial function. Brachial intima-media thickness, a less recognized parameter of cardiovascular risk, is independently associated with coronary artery disease. The aim of this study was to evaluate the prognostic value of ultrasound and serologic parameters of endothelial function in relation to cardiovascular mortality in peripheral arterial disease. DESIGN: monocentric, prospective cohort study. METHODS: Flow mediated dilatation and brachial intima-media thickness were assessed in 184 (124 male patients with peripheral arterial disease (Rutherford stages 2-3. Serologic parameters of endothelial function included asymmetric dimethylarginine (ADMA, symmetric dimethylarginine (SDMA, and L-homoarginine. Cardiovascular events were recorded during a follow-up of 99.1±11.1 months. Subjects who died of noncardiovascular causes were excluded from further analysis. RESULTS: Eighty-two patients (44.6% died during follow-up after a mean duration of 49.7±28.3 months. There were 49 cardiovascular deaths (59.8% and 33 other deaths (40.2%. Flow mediated dilatation was associated with cardiovascular death [1.17% (0.0, 4.3 vs. 4.1% (1.2, 6.4, p<0.001]. Intima-media thickness was greater in patients who succumbed to cardiovascular disease [0.37 mm (0.30, 0.41] than in survivors [0.21 mm (0.15, 0.38, p<0.001]. Brachial intima-media thickness above 0.345 mm was most predictive of cardiovascular death, with sensitivity and specificity values of 0.714 and 0.657, respectively (p<0.001. Furthermore, ADMA levels above 0.745 µmol/l and SDMA levels above 0.825 µmol/l were significantly

  1. Association of Vitamin B12 Deficiency with Homozygosity of the TT MTHFR C677T Genotype, Hyperhomocysteinemia, and Endothelial Cell Dysfunction.

    Science.gov (United States)

    Shiran, Avinoam; Remer, Eric; Asmer, Ihab; Karkabi, Basheer; Zittan, Eran; Cassel, Aliza; Barak, Mira; Rozenberg, Orit; Karkabi, Khaled; Flugelman, Moshe Y

    2015-05-01

    Hyperhomocysteinemia is associated with increased cardiovascular risk, but treatment with folic acid has no effect on outcome in unselected patient populations. To confirm previous observations on the association of homozygosity for the TT MTHFR genotype with B12 deficiency and endothelial dysfunction, and to investigate whether patients with B12 deficiency should be tested for 677MTHFR genotype. We enrolled 100 individuals with B12 deficiency, tested them for the MTHFR C677T polymorphism and measured their homocysteine levels. Forearm endothelial function was checked in 23 B12-deficient individuals (13 with TT MTHFR genotype and 10 with CT or CC genotypes). Flow-mediated dilatation (FMD) was tested after short-term treatment with B12 and folic acid in 12 TT MTHFR homozygotes. Frequency of the TT MTHFR genotype was 28/100 (28%), compared with 47/313 (15%) in a previously published cohort of individuals with normal B12 levels (P = 0.005). Mean homocysteine level was 21.2 ± 16 μM among TT homozygotes as compared to 12.3 ± 5.6 μM in individuals with the CC or CT genotype (P = 0.008). FMD was abnormal ( 6%) in 9/13 TT individuals with B12 deficiency (69%), and was still abnormal in 7/12 of those tested 6 weeks after B12 and folic treatment (58%). Among individuals with B12 deficiency, the frequency of the TT MTHFR genotype was particularly high. The TT polymorphism was associated with endothelial dysfunction even after 6 weeks of treatment with B12 and folic acid. Based on our findings we suggest that B12 deficiency be tested for MTHFR polymorphism in order to identify potential vascular abnormalities and increased cardiovascular risk.

  2. Coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone improves postprandial endothelial dysfunction in patients with borderline and stage 1 hypertension.

    Science.gov (United States)

    Kajikawa, Masato; Maruhashi, Tatsuya; Hidaka, Takayuki; Nakano, Yukiko; Kurisu, Satoshi; Matsumoto, Takeshi; Iwamoto, Yumiko; Kishimoto, Shinji; Matsui, Shogo; Aibara, Yoshiki; Yusoff, Farina Mohamad; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Noma, Kensuke; Nakashima, Ayumu; Watanabe, Takuya; Tone, Hiroshi; Hibi, Masanobu; Osaki, Noriko; Katsuragi, Yoshihisa; Higashi, Yukihito

    2018-01-12

    The purpose of this study was to evaluate acute effects of coffee with a high content of chlorogenic acids and different hydroxyhydroquinone contents on postprandial endothelial dysfunction. This was a single-blind, randomized, placebo-controlled, crossover-within-subject clinical trial. A total of 37 patients with borderline or stage 1 hypertension were randomized to two study groups. The participants consumed a test meal with a single intake of the test coffee. Subjects in the Study 1 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or coffee with a high content of chlorogenic acids and a high content of hydroxyhydroquinone with crossover. Subjects in the Study 2 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or placebo coffee with crossover. Endothelial function assessed by flow-mediated vasodilation and plasma concentration of 8-isoprostanes were measured at baseline and at 1 and 2 h after coffee intake. Compared with baseline values, single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee, significantly improved postprandial flow-mediated vasodilation and decreased circulating 8-isoprostane levels. These findings suggest that a single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone is effective for improving postprandial endothelial dysfunction. URL for Clinical Trial: https://upload.umin.ac.jp ; Registration Number for Clinical Trial: UMIN000013283.

  3. Stretching Exercises Improve Vascular Endothelial Dysfunction Through Attenuation of Oxidative Stress in Chronic Heart Failure Patients With an Implantable Cardioverter Defibrillator.

    Science.gov (United States)

    Kato, Michitaka; Masuda, Takashi; Ogano, Michio; Hotta, Kazuki; Takagi, Hisato; Tanaka, Shinya; Kamada, Yumi; Akiyama, Ayako; Kamekawa, Daisuke; Shimizu, Ryosuke; Tabata, Minoru; Tanabe, Jun; Umemoto, Takuya

    2017-03-01

    Endurance training improves oxidative stress and vascular endothelial dysfunction in patients with chronic heart failure (CHF). However, patients with CHF and an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) often avoid endurance training for fear of ICD shock. Recent studies have reported that stretching exercises enhance antioxidant activity and improve vascular responses. Therefore, we aimed to assess the effects of 4 weeks of stretching exercises on oxidative stress and vascular endothelial function in patients with CHF with an ICD or CRT-D. Fifty sedentary patients with CHF (78% males; mean age = 70 ± 9 years; left ventricular ejection fraction = 26% ± 8%) with an ICD or CRT-D were randomly divided into a group that performed 4 weeks of stretching exercises (stretching group) and a group that continued a sedentary lifestyle (control group). We compared the reactive hyperemia peripheral arterial tonometry (RH-PAT) index and blood parameters, such as von Willebrand factor (vWF), malondialdehyde-modified low-density lipoprotein cholesterol (MDA-LDL), reactive oxygen species (ROS), high-sensitivity C-reactive protein, pentraxin 3, and fibrinogen between the 2 groups before and after the 4-week study period. In the stretching group, a significant increase in the RH-PAT index and significant decreases in vWF, MDA-LDL, ROS, and fibrinogen concentrations were observed after the study compared with before (all P stretching exercises improved vascular endothelial dysfunction through attenuation of oxidative stress in sedentary patients with CHF with an ICD or CRT-D.

  4. Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

    Directory of Open Access Journals (Sweden)

    Quan He

    2014-01-01

    Full Text Available Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress.

  5. Endothelial dysfunction in obstructive sleep apnea measured by peripheral arterial tone response in the finger to reactive hyperemia.

    Science.gov (United States)

    Itzhaki, Sarah; Lavie, Lena; Pillar, Giora; Tal, Galit; Lavie, Peretz

    2005-05-01

    The aim of this study was to investigate endothelial functioning in sleep apnea patients using a novel plethysmographic device that monitors peripheral arterial tone response in the finger to reactive hyperemia induced by forearm ischemia. Forty-six sleep apnea patients, 74.0% men, mean age 46.8 +/- 9.3 years, and 17 control subjects without sleep apnea, 64.7% men, mean age 47.1 +/- 6.7 years. Eight-bed Technion Sleep Medicine Center in Haifa, Israel. Endothelial functioning assessed by the reactive hyperemia peripheral arterial tone index was measured twice, before sleep and after waking from sleep monitored by polysomnography in the laboratory. The reactive hyperemia peripheral arterial tone index was calculated as the average amplitude of the peripheral arterial tone signal after the cuff deflation divided by the average amplitude before the cuff inflation. Morning index of endothelial functioning was significantly lower in patients with moderate to severe sleep apnea (apnea-hypopnea index > or = 30) than in patients with mild sleep apnea (30 disease had significantly lower morning and evening indexes of endothelial functioning than patients without such a history. Multivariate analysis revealed that apnea-hypopnea index and sleep efficiency were significant predictors of the morning index. Measurements of the response of the peripheral arterial tone in the finger to reactive hyperemia can be used as a substitute for the brachial artery ultrasound technique to measure endothelial functioning in patients with sleep apnea.

  6. Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction

    Czech Academy of Sciences Publication Activity Database

    Koudelka, Adolf; Ambrožová, Gabriela; Klinke, A.; Fidlerová, Táňa; Martíšková, Hana; Kuchta, R.; Rudolph, T.K.; Kadlec, J.; Kuchtová, Z.; Woodcock, S.R.; Freeman, B.A.; Kubala, Lukáš; Pekarová, Michaela

    2016-01-01

    Roč. 30, č. 6 (2016), s. 579-586 ISSN 0920-3206 R&D Projects: GA ČR GP13-40824P; GA MŠk(CZ) LD15069 Institutional support: RVO:68081707 Keywords : fatty acids * arterial-hypertension * oxide synthase * murine model Subject RIV: BO - Biophysics Impact factor: 2.820, year: 2016

  7. Lithium prevents early cytosolic calcium increase and secondary injurious calcium overload in glycolytically inhibited endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Bosche, Bert, E-mail: bert.bosche@uk-essen.de [Department of Neurology, University of Duisburg-Essen (Germany); Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne (Germany); Schäfer, Matthias, E-mail: matthias.schaefer@sanofi.com [Institute of Physiology, Justus-Liebig-University Giessen (Germany); Graf, Rudolf, E-mail: rudolf.graf@nf.mpg.de [Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne (Germany); Härtel, Frauke V., E-mail: frauke.haertel@tu-dresden.de [Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden (Germany); Schäfer, Ute, E-mail: ute.schaefer@medunigraz.at [Research Unit for Experimental Neurotraumatology, Medical University of Graz (Austria); Noll, Thomas, E-mail: thomas.noll@tu-dresden.de [Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden (Germany)

    2013-05-03

    Highlights: •We investigate free calcium as a central signalling element in endothelial cells. •Inhibition of glycolysis with 2-deoxy-D-glucose reduces cellular ATP. •This manoeuvre leads to a biphasic increase and overload of free calcium. •Pre-treatment with lithium for 24 h abolishes both phases of the calcium increase. •This provides a new strategy to protect endothelial calcium homeostasis and barrier function. -- Abstract: Cytosolic free calcium concentration ([Ca{sup 2+}]{sub i}) is a central signalling element for the maintenance of endothelial barrier function. Under physiological conditions, it is controlled within narrow limits. Metabolic inhibition during ischemia/reperfusion, however, induces [Ca{sup 2+}]{sub i} overload, which results in barrier failure. In a model of cultured porcine aortic endothelial monolayers (EC), we addressed the question of whether [Ca{sup 2+}]{sub i} overload can be prevented by lithium treatment. [Ca{sup 2+}]{sub i} and ATP were analysed using Fura-2 and HPLC, respectively. The combined inhibition of glycolytic and mitochondrial ATP synthesis by 2-desoxy-D-glucose (5 mM; 2-DG) plus sodium cyanide (5 mM; NaCN) caused a significant decrease in cellular ATP content (14 ± 1 nmol/mg protein vs. 18 ± 1 nmol/mg protein in the control, n = 6 culture dishes, P < 0.05), an increase in [Ca{sup 2+}]{sub i} (278 ± 24 nM vs. 71 ± 2 nM in the control, n = 60 cells, P < 0.05), and the formation of gaps between adjacent EC. These observations indicate that there is impaired barrier function at an early state of metabolic inhibition. Glycolytic inhibition alone by 10 mM 2-DG led to a similar decrease in ATP content (14 ± 2 nmol/mg vs. 18 ± 1 nmol/mg in the control, P < 0.05) with a delay of 5 min. The [Ca{sup 2+}]{sub i} response of EC was biphasic with a peak after 1 min (183 ± 6 nM vs. 71 ± 1 nM, n = 60 cells, P < 0.05) followed by a sustained increase in [Ca{sup 2+}]{sub i}. A 24-h pre-treatment with 10 mM of lithium

  8. Induced thyme product prevents VEGF-induced migration in human umbilical vein endothelial cells.

    Science.gov (United States)

    Krill, Diane; Madden, John; Huncik, Kevin; Moeller, Peter D

    2010-12-17

    Compounds with anti-angiogenic properties are useful in combating cancer by preventing new blood vessel formation to support the tumor. In this report we introduce a rapid method for screening potential anti-angiogenic compounds in a model system that stimulates the production of secondary defense chemicals in plants. This methodology identified an inducible vascular factor (IVF3), which was found to be inhibitory in all of the model systems tested. Thyme plants were exposed to highly vascular mint plants and the methanol extracts were analyzed by reverse phase HPLC. The thyme compounds induced by the invading mint tissue, and not present in the thyme plants grown alone, were tested in a vertical plate assay measuring root length as a quantitative assay for drug sensitivity. The HPLC-purified extract, referred to as IVF3, reduced the growth of root vascular tissue compared to the control and vehicle control, and 50% as well as known angiogenesis inhibitors, VEGF receptor tyrosine kinase inhibitor and amiloride hydrochloride. Extracted compounds that were effective inhibitors of plant roots were assayed in Madin Darby canine kidney epithelial cells (MDCK) for toxicity, and in human umbilical vein endothelial cells (HUVEC) for their effect on migration. IVF3 was effective at limiting HUVEC migration in VEGF-stimulated cultures. In vivo video capture of intersegmental vessel circulation between 48 and 72 h post fertilization in the developing vasculature of zebrafish embryos showed IVF3 also significantly reduced ISV functional circulation. This report demonstrates the anti-angiogenic effects of IVF3 extract in endothelial cells and in an intact vertebrate model for angiogenesis. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. Exercise Training Prevents Arterial Baroreflex Dysfunction in Rats Treated With Central Angiotensin II

    OpenAIRE

    Pan, Yan-Xia; Gao, Lie; Wang, Wei-Zhong; Zheng, Hong; Liu, Dongmei; Patel, Kaushik P.; Zucker, Irving H.; Wang, Wei

    2007-01-01

    Angiotensin II (Ang II)–induced arterial baroreflex dysfunction is associated with superoxide generation in the brain. Exercise training (EX) improves baroreflex function and decreases oxidative stress in cardiovascular diseases linked to elevated central Ang II. The aim of this study was to determine whether previous EX prevents baroreflex impairment caused by central administration of exogenous Ang II via an Ang II–superoxide mechanism. Four groups of rats were used: non-EX artificial cereb...

  10. Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

    Science.gov (United States)

    Rexhaj, Emrush; Pireva, Agim; Paoloni-Giacobino, Ariane; Allemann, Yves; Cerny, David; Dessen, Pierre; Sartori, Claudio; Scherrer, Urs; Rimoldi, Stefano F

    2015-10-01

    Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans. Copyright © 2015 the American Physiological Society.

  11. The Association between Left Verticle Diastolic Dysfunction and Endothelial Dysfunction and the Result of Stress Myocardial SPECT in Asymptomatic Patients with Type 2 Diabetes

    Czech Academy of Sciences Publication Activity Database

    Charvát, J.; Michalová, K.; Chlumský, J.; Valenta, Zdeněk; Kvapil, M.

    2005-01-01

    Roč. 33, - (2005), s. 473-482 ISSN 0300-0605 Institutional research plan: CEZ:AV0Z10300504 Keywords : coronary heart disease * type 2 diabetes mellitus * left ventricular diastolic dysfunction * left ventricular hyperthropy * stress myocardial SPECT Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 0.653, year: 2005

  12. Renal Dysfunction after Off-Pump Coronary Artery Bypass Surgery- Risk Factors and Preventive Strategies

    Directory of Open Access Journals (Sweden)

    Gaurab Maitra

    2009-01-01

    Full Text Available Postoperative renal dysfunction is a relatively common and one of the serious complications of cardiac surgery. Though off-pump coronary artery bypass surgery technique avoids cardiopulmonary bypass circuit induced adverse effects on renal function, multiple other factors cause postoperative renal dysfunction in these groups of patients. Acute kidney injury is generally defined as an abrupt and sustained decrease in kidney function. There is no consen-sus on the amount of dysfunction that defines acute kidney injury, with more than 30 definitions in use in the literature today. Although serum creatinine is widely used as a marker for changes in glomerular filtration rate, the criteria used to define renal dysfunction and acute renal failure is highly variable. The variety of definitions used in clinical studies may be partly responsible for the large variations in the reported incidence. Indeed, the lack of a uniform definition for acute kidney injury is believed to be a major impediment to research in the field. To establish a uniform definition for acute kidney injury, the Acute Dialysis Quality Initiative formulated the Risk, Injury, Failure, Loss, and End-stage Kidney (RIFLE classification. RIFLE , defines three grades of increasing severity of acute kidney injury -risk (class R, injury (class I and failure (class F - and two outcome classes (loss and end-stage kidney disease. Various perioperative risk factors for postoperative renal dysfunction and failure have been identified. Among the important preoperative factors are advanced age, reduced left ventricular function, emergency surgery, preoperative use of intraaortic balloon pump, elevated preoperative serum glucose and creatinine. Most important intraoperative risk factor is the intraoperative haemodynamic instability and all the causes of postoperative low output syndrome com-prise the postoperative risk factors. The most important preventive strategies are the identification of the

  13. Interval exercise, but not endurance exercise, prevents endothelial ischemia-reperfusion injury in healthy subjects.

    NARCIS (Netherlands)

    Seeger, J.P.; Lenting, C.J.; Schreuder, T.H.A.; Landman, T.R.; Cable, N.T.; Hopman, M.T.; Thijssen, D.H.J.

    2015-01-01

    Endothelial ischemia-reperfusion (I/R) injury importantly contributes to the poor prognosis during ischemic (myocardial) events. Preconditioning, i.e., repeated exposure to short periods of ischemia, effectively reduces endothelial I/R injury. In the present study, we examined the hypothesis that

  14. Prevention of paracentesis-induced circulatory dysfunction: midodrine vs albumin. A randomized pilot study.

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    Appenrodt, Beate; Wolf, Andrea; Grünhage, Frank; Trebicka, Jonel; Schepke, Michael; Rabe, Christian; Lammert, Frank; Sauerbruch, Tilman; Heller, J

    2008-08-01

    Large-volume paracentesis in patients with cirrhosis and ascites induces arterial vasodilatation and decreases effective arterial blood volume, termed paracentesis-induced circulatory dysfunction (PICD), which can be prevented by costly intravenous albumin. Vasoconstrictors, e.g. terlipressin, may also prevent PICD. The aim was to compare the less expensive vasoconstrictor midodrine, an alpha-adrenoceptor agonist, with albumin in preventing PICD. Twenty-four patients with cirrhosis and ascites were randomly assigned to be treated with either midodrine (n=11) (12.5 mg three times per day; over 2 days) or albumin (n=13) (8 g/L of removed ascites) after large-volume paracentesis. Effective arterial blood volume was assessed indirectly by measuring plasma renin and aldosterone concentration on days 0 and 6 after paracentesis; renal function and haemodynamic changes were also measured. PICD was defined as an increase in plasma renin concentration on day 6 by more than 50% of the baseline value. PICD developed in six patients of the midodrine group (60%) and in only four patients (31%) of the albumin group. Six days after paracentesis, the aldosterone concentration increased significantly in the midodrine group, but not in the albumin group. This pilot study suggests that midodrine is not as effective as albumin in preventing circulatory dysfunction after large-volume paracentesis in patients with cirrhosis and ascites.

  15. Correlation of microvascular abnormalities and endothelial dysfunction in Type-1 Diabetes Mellitus (T1DM): a real-time intravital microscopy study.

    Science.gov (United States)

    Cheung, Anthony T W; Tomic, M Meighan Smith; Chen, Peter C Y; Miguelino, Eric; Li, Chin-Shang; Devaraj, Sridevi

    2009-01-01

    We hypothesize that real-time in vivo microvascular abnormalities should correlate with biochemical markers of inflammation/endothelial dysfunction in T1DM. Real-time quantification of T1DM and healthy non-diabetic control microcirculation was conducted utilizing computer-assisted intravital microscopy. Selected biochemical markers (high sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecules (sVCAM), soluble intercellular adhesion molecules (sICAM), soluble E-selectin (sE-selectin), nitrotyrosine, superoxide anion (O2-), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha)) were used for correlation. The severity of microvascular abnormalities, as reflected by the arithmetic severity index (SI), was significantly increased in T1DM vs. controls (5.89 +/- 1.47 vs. 2.34 +/- 1.48; Pprogression and therapeutic efficacy studies.

  16. Physical exercise, fitness and dietary pattern and their relationship with circadian blood pressure pattern, augmentation index and endothelial dysfunction biological markers: EVIDENT study protocol

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    Nicolás Eguskiñe

    2010-05-01

    Full Text Available Abstract Background Healthy lifestyles may help to delay arterial aging. The purpose of this study is to analyze the relationship of physical activity and dietary pattern to the circadian pattern of blood pressure, central and peripheral blood pressure, pulse wave velocity, carotid intima-media thickness and biological markers of endothelial dysfunction in active and sedentary individuals without arteriosclerotic disease. Methods/Design Design: A cross-sectional multicenter study with six research groups. Subjects: From subjects of the PEPAF project cohort, in which 1,163 who were sedentary became active, 1,942 were sedentary and 2,346 were active. By stratified random sampling, 1,500 subjects will be included, 250 in each group. Primary measurements: We will evaluate height, weight, abdominal circumference, clinical and ambulatory blood pressure with the Radial Pulse Wave Acquisition Device (BPro, central blood pressure and augmentation index with Pulse Wave Application Software (A-Pulse and SphymgoCor System Px (Pulse Wave Analysis, pulse wave velocity (PWV with SphymgoCor System Px (Pulse Wave Velocity, nutritional pattern with a food intake frequency questionnaire, physical activity with the 7-day PAR questionnaire and accelerometer (Actigraph GT3X, physical fitness with the cycle ergometer (PWC-170, carotid intima-media thickness by ultrasound (Micromax, and endothelial dysfunction biological markers (endoglin and osteoprotegerin. Discussion Determining that sustained physical activity and the change from sedentary to active as well as a healthy diet improve circadian pattern, arterial elasticity and carotid intima-media thickness may help to propose lifestyle intervention programs. These interventions could improve the cardiovascular risk profile in some parameters not routinely assessed with traditional risk scales. From the results of this study, interventional approaches could be obtained to delay vascular aging that combine physical

  17. New insights into the non-hemostatic role of von Willebrand factor in endothelial protection.

    Science.gov (United States)

    Agostini, Silvia; Lionetti, Vincenzo

    2017-10-01

    During exposure to ischemia-reperfusion (I/R) insult, angiotensin II (AngII)-induced endothelin-1 (ET-1) upregulation in endothelial cells progressively impairs nitric oxide (NO) bioavailability while increasing levels of superoxide anion (O 2 - ) and leading to the onset of endothelial dysfunction. Moreover, the overexpression of ET-1 increases the endothelial and circulating levels of von Willebrand factor (vWF), a glycoprotein with a crucial role in arterial thrombus formation. Nowadays, the non-hemostatic role of endothelial vWF is emerging, although we do not yet know whether its increased expression is cause or consequence of endothelial dysfunction. Notably, the vWF blockade or depletion leads to endothelial protection in cultured cells, animal models of vascular injury, and patients as well. Despite the recent efforts to develop an effective pharmacological strategy, the onset of endothelial dysfunction is still difficult to prevent and remains closely related to adverse clinical outcome. Unraveling the non-hemostatic role of endothelial vWF in the onset of endothelial dysfunction could provide new avenues for protection against vascular injury mediated by AngII.

  18. Sofalcone upregulates the nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 pathway, reduces soluble fms-like tyrosine kinase-1, and quenches endothelial dysfunction: potential therapeutic for preeclampsia.

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    Onda, Kenji; Tong, Stephen; Nakahara, Anzu; Kondo, Mei; Monchusho, Hideaki; Hirano, Toshihiko; Kaitu'u-Lino, Tu'uhevaha; Beard, Sally; Binder, Natalie; Tuohey, Laura; Brownfoot, Fiona; Hannan, Natalie J

    2015-04-01

    Preeclampsia is a severe complication of pregnancy, characterized by hypertension, oxidative stress, and severe endothelial dysfunction. Antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin, play key pathophysiological roles in preeclampsia. Heme oxygenase-1 (HO-1) is a cytoprotective, antioxidant enzyme reported to be downregulated in preeclampsia. Studies propose that inducing HO-1 may also decrease sFlt-1 production. Sofalcone, a gastric antiulcer agent in clinical use, is known to induce HO-1 in gastric epithelium. We aimed to investigate whether sofalcone induces HO-1 and reduces sFlt-1 release from primary human placental and endothelial cells and blocks endothelial dysfunction in vitro. We isolated human trophoblasts and endothelial cells (human umbilical vein endothelial cells) and also used uterine microvascular cells. We investigated the effects of sofalcone on (1) HO-1 production, (2) activation of the nuclear factor (erythroid-derived 2)-like 2 pathway, (3) sFlt-1 and soluble endoglin release, (4) tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule upregulation, and (5) endothelial tubule formation. Sofalcone potently increased HO-1 mRNA and protein in both primary trophoblasts and human umbilical vein endothelial cells. Furthermore, sofalcone treatment caused nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and transactivation of other nuclear factor (erythroid-derived 2)-like 2 responsive genes (NQO1, TXN, and GCLC). Importantly, sofalcone significantly decreased the secretion of sFlt-1 from primary human trophoblasts. Sofalcone potently suppressed endothelial dysfunction in 2 in vitro models, blocking tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule 1 expression in human umbilical vein endothelial cells. These results indicate that in primary human tissues, sofalcone can potently activate antioxidant nuclear factor

  19. IMPACT OF ANTICOAGULANT THERAPY ON THE INDICATORS OF ARTERIAL STIFFNESS AND ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH ATRIAL FIBRILLATION AFTER CARDIOEMBOLIC STROKE

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    I. A. Zolotovskaya

    2016-01-01

    Full Text Available Objective: to investigate the impact of anticoagulant therapy on the indicators of arterial stiffness and endothelial dysfunction (ED in patients with atrial fibrillation (AF after cardioembolic stroke (CES.Patients and methods. The investigation enrolled 93 patients with AF after CES. The patients were divided into two groups: a study group in which all patients (n=48 received anticoagulants and a comparison group (n=45 in which the patients did not take anticoagulants, although the latter had been prescribed. The follow-up duration was 180.5±5.5 days. During this time the patients visited their doctors twice: the first visit was at baseline, the second one was after 24 weeks.All the patients underwent three-dimensional sphygmography. The levels of glucose, creatinine, total cholesterol, high-density lipoproteins, and triglycerides were determined. The markers of endothelial function, such as von Willebrand factor, plasminogen, antithrombin III,  and tissue plasminogen activator inhibitor-1, were estimated.Results. All the patients in the study and comparison groups had a higher comorbidity index of obvious somatic pathology. The patients from both groups showed changes in all cardiac morphometric and functional parameters. It was noted that after 6 months of a follow-up, there was a statistically significant positive trend in the indicators of arterial stiffness in the patients taking anticoagulants. The study group showed a significant correlation of blood pressure with the argumentation index. The 6-month follow-up revealed a strong correlation between the cardioankle vascular index and all the indicators of ED in the study group. After 24 weeks, in both groups there were 12 (12.9% deaths: 3 (6.25% and 8 (17.8% in the study and comparison groups, respectively.Conclusion. The findings suggest that in patients with AF after CES, the indicators of arterial stiffness and endothelial function tend to improve during anticoagulant therapy.

  20. Serum oxidative stress-induced repression of Nrf2 and GSH depletion: a mechanism potentially involved in endothelial dysfunction of young smokers.

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    Anna Fratta Pasini

    Full Text Available Although oxidative stress plays a major role in endothelial dysfunction (ED, the role of glutathione (GSH, of nuclear erythroid-related factor 2 (Nrf2 and of related antioxidant genes (ARE are yet unknown. In this study we combined an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD, GSH concentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs.52 healthy subjects (26 non-smokers and 26 heavy smokers were enrolled in this study. In smokers we demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC in serum and in peripheral blood mononuclear cells (PBMC, used as in vivo surrogates of endothelial cells. Moreover we showed impairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECs exposed to smokers' serum but not to non-smokers' serum we found that oxidative stress increased, whereas nitric oxide and GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1 and of glutamate-cysteine ligase catalytic (GCLC subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesis that the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposed HUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found in smokers' serum the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significant reduction of HO-1 and GCLC expression induced by oxPAPC in ECs.In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/ARE pathway leading to GSH depletion.

  1. Buyang Huanwu Decoction attenuates H2O2-induced apoptosis by inhibiting reactive oxygen species-mediated mitochondrial dysfunction pathway in human umbilical vein endothelial cells.

    Science.gov (United States)

    Shen, Jian; Zhu, Yu; Huang, Kaiyuan; Jiang, Hao; Shi, Chengzhang; Xiong, Xiaoxing; Zhan, Renya; Pan, Jianwei

    2016-05-31

    Apoptosis of endothelial cells caused by reactive oxygen species plays an important role in ischemia/reperfusion injury after cerebral infarction. Buyang Huanwu Decoction (BYHWD) has been used to treat stroke and stroke-induced disability, however, the mechanism for this treatment remains unknown. In this study, we investigated whether BYHWD can protect human umbilical vein endothelial cells (HUVECs) from H2O2-induced apoptosis and explored the underlying mechanisms. To investigate the effect of BYHWD on the apoptosis of HUVECs, we established a H2O2-induced oxidative stress model and detected apoptosis by Hoechst 33342 and propidium iodide staining. JC-1 and DCFH-DA assays,western blotting and electron microscopy were used to examine the mechanism of BYHWD on apoptosis. Pretreatment with BYHWD significantly inhibited H2O2-induced apoptosis and protein caspase-3 expression in a concentration-dependent manner. In addition, BYHWD reduced reactive oxygen species production and promoted endogenous antioxidant defenses. Furthermore, loss of mitochondrial membrane potential and structural disruption of mitochondria were both rescued by BYHWD. BYHWD protects HUVECs from H2O2-induced apoptosis by inhibiting oxidative stress damage and mitochondrial dysfunction. These findings indicate that BYHWD is a promising treatment for cerebral ischemia diseases.

  2. The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease