endothelin-1 and Dyslipidemias

Hyperlipidemia and oxidative stress are indispensable features of chronic kidney disease (CKD) that favor the development of atherogenic plaques and cardiovascular disease (CVD). A number of vasoactive mediators including proprotein convertase subtilisin-kexin type 9 (PCSK9), endothelin-1, nitric oxide, and angiotensin II have fundamental roles in the pathophysiology of atherosclerotic events; moreover, their levels are affected by dyslipidemia and oxidative stress due to renal dysfunction. Therefore, therapeutic measures aimed at correcting dyslipidemia and alleviating oxidative stress could potentially protect against CVD in CKD patients. In this review, we discuss the relation between dyslipidemia, oxidative stress, and vasoactive mediators as well as the available treatment options against these disturbances in CKD patients.

Topics: Angiotensin II; Dyslipidemias; Endothelin-1; Humans; Nitric Oxide; Oxidative Stress; Proprotein Convertase 9; Renal Insufficiency, Chronic

Retinal vein occlusion (RVO) is a common vascular disease of retina; however, the pathomechanism leading to RVO is not yet clear. In general, increasing age, hypertension, arteriosclerosis, diabetes mellitus, dyslipidemia, cardiovascular disorder, and cerebral stroke are systemic risk factors of RVO. However, RVO often occur in the unilateral eye and sometimes develop in young subjects who have no arteriosclerosis. In addition, RVO show different variations on the degrees of severity; some RVO are resolved without any treatment and others develop vision-threatening complications such as macular edema, combined retinal artery occlusion, vitreous hemorrhage, and glaucoma. Clinical conditions leading to RVO are still open to question. In this review, we discuss how to treat RVO in practice by presenting some RVO cases. We also deliver possible pathomechanisms of RVO through our clinical experience and animal experiments.

Topics: Animals; Arteriosclerosis; Diabetes Complications; Dyslipidemias; Endothelin-1; Humans; Hypertension; Retina; Retinal Vein Occlusion; Risk Factors; Stroke; Veins

Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations.. The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD: -0.30 pg/mL, 95%CI: -0.47, -0.13; p < 0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD: -0.51 pg/mL, 95%CI: -0.89, -0.14, p < 0.01; >12 week -WMD: -0.19 pg/mL, 95%CI: -0.36, -0.02; p < 0.05) or by dose of statins (<40 mg/day - WMD: -0.27 pg/mL, 95%CI: -0.49, -0.05; p = 0.01; >40 mg/day - WMD: -0.38 pg/mL, 95%CI: -0.68, -0.08; p = 0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD: -0.34 pg/mL, 95%CI: -0.55, -0.13; p < 0.01), but not a hydrophilic statin (pravastatin - WMD: -0.18 pg/mL, 95%CI: -0.44 -0.08; p > 0.05) had a significant effect in promoting ET-1 reduction.. Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events.

Topics: Adult; Aged; Biomarkers; Chi-Square Distribution; Dyslipidemias; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Middle Aged; Odds Ratio; Randomized Controlled Trials as Topic; Treatment Outcome

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances and therefore plays a fundamental role in the basal and dynamic regulation of the circulation. Nitric oxide (NO)-originally described as endothelium-derived relaxing factor-is released from endothelial cells in response to shear stress produced by blood flow, and in response to activation of a variety of receptors. After diffusion from endothelial to vascular smooth muscle cells, NO increases intracellular cyclic guanosine-monophosphate concentrations by activation of the enzyme guanylate cyclase leading to relaxation of the smooth muscle cells. NO has also antithrombogenic, antiproliferative, leukocyte-adhesion inhibiting effects, and influences myocardial contractility. Endothelium-derived NO-mediated vascular relaxation is impaired in spontaneously hypertensive animals. NO decomposition by free oxygen radicals is a major mechanism of impaired NO bioavailability. The resulting imbalance of endothelium-derived relaxing and contracting substances disturbs the normal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. Besides its arterial blood pressure rising effect in humans, endothelin-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering low-density lipoprotein cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms play an important role in vascular disease and inflammatory plasma markers correlate with prognosis. The production of reactive oxygen species under pathological conditions may represent an important inflammatory trigger. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease. In this context, the vascular actions of flavanol-rich cocoa, particularly with regard to enhanced NO synthesis and endothelial function observed in humans following consumption, warrants further attention. This review discusses pharmacological and dietary intervention.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Arginine; Atherosclerosis; Biopterins; Cacao; Calcium Channel Blockers; Cyclooxygenase Inhibitors; Dyslipidemias; Endothelin-1; Endothelins; Endothelium, Vascular; Flavonoids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipoproteins, HDL; Nitric Oxide; Oxidative Stress; Reactive Oxygen Species

Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients.. FF impaired the capacity of transforming growth factor-β to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1.. FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity.

Topics: Apoptosis Regulatory Proteins; Binding Sites; Brachial Artery; Cell Cycle Proteins; Cell Line; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Down-Regulation; Dyslipidemias; Endothelial Cells; Endothelin-1; Fenofibrate; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Hypolipidemic Agents; Phosphorylation; PPAR alpha; Promoter Regions, Genetic; Repressor Proteins; Signal Transduction; Time Factors; Transcription, Genetic; Transfection; Transforming Growth Factor beta; Vasodilation

We investigated the effects of three different daily doses (10 mg, 20 mg, and 40 mg) of atorvastatin, a relatively new and potent statin, on plasma endothelin (ET)-1 and highly sensitive C-reactive protein (CRP) levels in type 2 diabetic subjects. Twenty-nine type 2 diabetic patients with dyslipidemia were enrolled and randomly assigned to receive atorvastatin orally at 10 mg (A10; n = 10), 20 mg (A20; n = 10), or 40 mg (A40; n = 9) daily for 12 weeks. Levels of plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol (C) in all three studied groups were significantly decreased after treatment with atorvastatin for 12 weeks (all groups, P < 0.001). However, the greatest LDL-C lowering effect and the highest percentage of subjects achieving the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) LDL-C goal were observed in the A20 group. All diabetic subjects had a higher plasma ET-1 concentration (A10, 1.02 +/- 0.37 pg/ml, mean +/- SD; A20, 1.17 +/- 0.55 pg/ml; and A40, 0.87 +/- 0.45 pg/ml) than that of age- and sex-matched normal control subjects (0.64 +/- 0.15 pg/ml; all groups, P < 0.001). Plasma ET-1 levels showed a borderline significant decrease at the end of study, by 22% in diabetic subjects treated with 10 mg atorvastatin (P = 0.05 compared with baseline), and by 30% in subjects treated with 20 mg atorvastatin (P = 0.06, compared with baseline). Paradoxically, the 40-mg dose of atorvastatin provided an increase of 2% in plasma ET-1 levels at the end of study, which is significantly different (P < 0.05) and marginally significant (P = 0.057) from the levels of the 10- and 20-mg doses, respectively. Similarly, although insignificantly, plasma concentrations of CRP also tended to decrease by 12% and 48%, and paradoxically increased by 18% in diabetic patients treated with 10 mg, 20 mg, and 40 mg atorvastatin, respectively. The clinical significance of these biphasic lipid-independent statin effects is unknown and the present study suggests that 20 mg atorvastatin may have the best benefits in treating diabetic patients with dyslipidemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atorvastatin; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyslipidemias; Endothelin-1; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, LDL; Male; Middle Aged; Pyrroles

High salt intake (HS) is associated with obesity and insulin resistance. ET-1, a peptide released in response to HS, inhibits the actions of insulin on cultured adipocytes through ET-1 type B (ETB) receptors; however, the in vivo implications of ETB receptor activation on lipid metabolism and insulin resistance is unknown. We hypothesized that activation of ETB receptors in response to HS intake promotes dyslipidemia and insulin resistance. In normal salt (NS) fed rats, no significant difference in body mass or epididymal fat mass was observed between control and ETB deficient rats. After 2 weeks of HS, ETB-deficient rats had significantly lower body mass and epididymal fat mass compared to controls. Nonfasting plasma glucose was not different between genotypes; however, plasma insulin concentration was significantly lower in ETB-deficient rats compared to controls, suggesting improved insulin sensitivity. In addition, ETB-deficient rats had higher circulating free fatty acids in both NS and HS groups, with no difference in plasma triglycerides between genotypes. In a separate experiment, ETB-deficient rats had significantly lower fasting blood glucose and improved glucose and insulin tolerance compared to controls. These data suggest that ET-1 promotes adipose deposition and insulin resistance via the ETB receptor.

Topics: Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Dyslipidemias; Endothelin-1; Fatty Acids, Nonesterified; Humans; Insulin; Insulin Resistance; Male; Mutation; Rats; Rats, Transgenic; Receptor, Endothelin B; Sodium Chloride, Dietary

The effect of sulfated polysaccharide from brown alga Fucus evanescens (fucoidan) administered via different routes (peroral and parenteral) on the dynamic of some lipid metabolism parameters and markers of systemic inflammation in mice with experimental dyslipidemia induced by prolonged administration of poloxamer P-407. It was found that fucoidan corrected the main parameters of lipid metabolism, reduced the level of endothelial dysfunction marker endothelin-1 and proinflammatory cytokines TNFα, IFNγ in blood serum in animals with experimental dyslipidemia. These findings open prospects for using fucoidan in the complex treatment of metabolic disorders and atherosclerotic inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Dyslipidemias; Endothelin-1; Fucus; Gene Expression Regulation; Inflammation; Interferon-gamma; Lipid Metabolism; Male; Mice; Mice, Inbred BALB C; Poloxamer; Polysaccharides; Triglycerides; Tumor Necrosis Factor-alpha

Micro and macrovascular complications occurring during hyperlipidemia are mostly attributed to haemostatic impairment and vascular endothelial dysfunction. Cholesteryl ester transfer protein (CETP) inhibitors have been emerged recently as promising hypocholesterolemic agents to confer protection against lipid-mediated atherosclerosis. Therefore, 10-dehydrogingerdione (DHGD), a novel CETP inhibitor isolated from ginger rhizomes, was selected as a natural product in the present study to illustrate its effect on haemostatic impairment associated with hyperlipidemia as compared to a currently used hypocholesterolemic agent, atorvastatin (ATOR). Rabbits were fed a high cholesterol diet (HCD) and divided into three groups. One group served as control group while the other groups received DHGD or ATOR. Dyslipidemic rabbits showed a significant increase in serum endothelin-1, ischemia modified albumin, plasminogen activator inhibitor-1, prothrombin fragments (1+2) and plasma fibrinogen along with a decrease of nitric oxide level in serum. Daily administration of ATOR or DHGD significantly decreased the aforementioned coagulation and ischemia biomarkers and increased serum nitric oxide. DHGD (natural) results seem to be more remarkable as compared to ATOR (synthetic).

Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Atorvastatin; Blood Coagulation; Cholesterol Ester Transfer Proteins; Disease Models, Animal; Dyslipidemias; Endothelin-1; Endothelium, Vascular; Guaiacol; Nitric Oxide; Plasminogen Activator Inhibitor 1; Rabbits; Treatment Outcome

Endothelial dysfunction plays an essential role in the development and progression of atherosclerotic lesions. Endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) are considered important molecules in the endothelial dysfunction process. The aim of the present study was to evaluate the role of eNOS and ET-1 (EDN1) gene polymorphisms as susceptibility markers for acute coronary syndrome (ACS). Six polymorphisms (rs1799983, rs2070744, rs1800783, rs3087459, rs1800541, and rs5369) of eNOS and EDN1 genes were analyzed by 5' exonuclease TaqMan genotyping assays in a group of 452 patients with ACS and 283 healthy controls. The results showed increased frequencies of the A allele of the END1-914 C>A (rs3087459) polymorphism in ACS patients when compared to controls (OR=1.56, Pc=0.01). Under an additive model, the "AA" genotype was associated with an increased risk of developing ACS, adjusted for gender, hypertension, dyslipidemia, alcohol consumption, smoking, and diabetes (OR=1.56, p=0.045). Linkage disequilibrium analysis showed one EDN1 haplotype (AT) with increased frequency in ACS patients when compared to healthy controls (OR=1.65, Pc=0.0015). The "AT" haplotype was associated with the risk of developing ACS after adjusting for cardiovascular risk factors using multiple logistic analysis. In this case, the adjusted OR was 1.73 for the AT haplotype (Pc=0.0018). In summary, resulting data suggest that the END1-914 C>A gene polymorphism could be involved in the risk of developing ACS in Mexican individuals.

Topics: Acute Coronary Syndrome; Aged; Case-Control Studies; Dyslipidemias; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Linkage Disequilibrium; Male; Mexico; Middle Aged; Nitric Oxide Synthase Type III; Polymorphism, Single Nucleotide

In the article the concentration of endothelin-1 in patients with different variants of APS was analyzed and its relationship with disease course, dyslipidemia, levels of antiphospholipid antibodies and ath rosclerotic vascular lesions was assessed. It was established that high levels of endothelin-1 is a circulating marker of early atherosclerosis, since !it was closely associated'with subclinical manifestations of atherosclerotic vascular lesions, lipid profile. The concentration of endothelin-1 significantly increased with active inflammation and with high levels of antiphospholipid antibodies and does not depend on age, sex, smoking, obesity and physical inactivity.

Topics: Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Atherosclerosis; Biomarkers; Case-Control Studies; Disease Progression; Dyslipidemias; Early Diagnosis; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Motor Activity; Obesity; Smoking

The aim of this study was to assess relationship of insulin resistance, oxidant-antioxidant status, endothelial dysfunction, lipid metabolism, and their contribution to the risks of cardiovascular disease in women with polycystic ovary syndrome (PCOS). Forty-five women with PCOS and 17 healthy women were included in this study. Nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA), Apo A1, Apo B, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride, small, dense LDL cholesterol (sdLDL-C), large buoyant LDL cholesterol (LbLDL-C) levels, and paraoxonase 1 (PON1) activity were measured in serum/plasma obtained from study groups. Insulin resistance [homeostasis model assessment (HOMA) index] and serum sex hormone binding globulin (SHBG), total testosterone (tT), free testosterone (fT), androstenedione, and dehydroepiandrosteronsulfate (DHEAS) levels were also evaluated. Significantly decreased SHBG, NO, HDL-C levels, and PON1 activities, but increased tT, fT, androstenedione, DHEAS, HOMA index, MDA, ET-1, LDL-C, sdLDL-C, and LbLDL-C values were found in PCOS patients compared with those of controls. There was a positive correlation between MDA and fT levels; and a negative correlation between PON1 activity and fT. Our data show that insulin resistance, dyslipidemia, endothelial dysfunction, and oxidative stress might contribute to the excess risk of cardiovascular disease reported in PCOS patients.

Topics: Adolescent; Apolipoprotein A-I; Apolipoproteins B; Aryldialkylphosphatase; Cardiovascular Diseases; Dyslipidemias; Endothelin-1; Endothelium, Vascular; Female; Humans; Insulin Resistance; Lipoproteins, LDL; Malondialdehyde; Nitric Oxide; Oxidative Stress; Polycystic Ovary Syndrome; Risk Factors; Testosterone; Turkey; Young Adult