endothelin-1 and Hyperhomocysteinemia

Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. HHcy induces phenotypic switching of VSMCs, but the mechanism is unclear. Endothelin-1 (ET-1) promotes proliferation and migration of VSMCs by inducing phenotypic switching during atherosclerosis. This review examined recent findings on the relationship between HHcy or the ET-1 system (including ET-1 and its receptors) and phenotypic switching of VSMCs as well as the molecular mechanism of HHcy-regulated ET-1 signaling. In particular, we focused on the potential mechanisms and pharmacological targets of phenotypic switching of VSMCs regulated by HHcy through ET-1 signaling.

Topics: Animals; Atherosclerosis; Cell Proliferation; Endothelin-1; Humans; Hyperhomocysteinemia; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Phosphorylation; Signal Transduction

: After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.

Topics: Angiogenesis Inhibitors; Animals; Consensus; Diabetic Nephropathies; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Humans; Hyperhomocysteinemia; Hypertension; Kidney; Kidney Transplantation; Pre-Eclampsia; Pregnancy; Renal Insufficiency, Chronic; Vitamin D

Endothelin-1 (ET-1) is a key regulator of arterial blood pressure in humans, and homocysteinemia is associated with increased oxidative stress. It is still unclear whether homocysteine-induced oxidative stress is implicated in the regulation of ET-1 expression. We examined the impact of acute homocysteinemia on endothelial function in hypertensive patients and healthy individuals, and the potential role of ET-1.. In this double-blind, placebo-controlled study, 39 hypertensive and 49 healthy individuals were randomized to receive high-dose vitamins (2 g vitamin C and 800IU vitamin E) or placebo followed by methionine loading 100 mg/kg body weight. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) of the brachial artery were evaluated by plethysmography, at baseline and 4 h postloading (4 h PML). ET-1 was measured by ELISA, whereas total lipid hydroperoxides (per-ox) levels were measured by a commercially available photometric technique.. Acute, methionine-induced homocysteinemia decreased EDD in all study groups (P < 0.001 for all), whereas vitamins pretreatment failed to prevent this effect, despite the vitamins-induced reduction of peroxidation in the hypertensives group (P < 0.05). On the contrary, methionine loading significantly increased plasma ET-1 levels only in hypertensives (P < 0.05), an effect which was not prevented by antioxidant vitamins (P < 0.05). EID remained unchanged after methionine loading, in all study groups (P = NS for all groups).. Experimental homocysteinemia rapidly blunts endothelial function in both hypertensive individuals and healthy individuals. The rapid elevation of ET-1 levels observed only in hypertensives, suggests that ET-1 may be the key mediator of homocysteine-induced endothelial dysfunction, independently of oxidative stress.

Topics: Adult; Ascorbic Acid; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Female; Homocysteine; Humans; Hyperhomocysteinemia; Hypertension; Male; Methionine; Oxidative Stress; Signal Transduction; Vasodilation; Vitamin E

Homocysteinemia is associated with elevated oxidative stress and impaired endothelial function. In the present study we examined the impact of oxidative stress in the development of endothelial dysfunction in both chronic and acute (methionine-induced) homocysteinemia in humans. We also examined the role of endothelin-1 (ET-1) in the development of endothelial dysfunction in these two conditions.. In this double-blind placebo controlled study, 28 subjects of both genders (14 with homocysteinemia and 14 healthy controls) underwent methionine-loading (100mg/Kg body weight) in a standard juice, containing vitamins C (2g) plus E (800IU) (n = 14) or no vitamins (placebo group, n = 14). Forearm vasodilatory response to reactive hyperemia, plasma total homocysteine (tHcy), oxidized LDL (ox-LDL), ET-1 and soluble vascular cell adhesion molecule (sVCAM-1), were evaluated at baseline and 4 hours post methionine loading (4hPML).. Chronic homocysteinemia was associated with increased oxLDL (p < 0.01), higher ET-1 (p < 0.05) and impaired endothelial function (p < 0.01). However, oxLDL (but not ET-1) was increased 4hPML in the placebo group, an effect prevented by antioxidant vitamins. The development of severe endothelial dysfunction 4hPML was not however prevented by antioxidants. In linear regression analysis, fasting tHcy was an independent predictor of baseline oxLDL (p = 0.0001), but not of ET-1 levels. On the contrary, oxLDL was the main predictor of ET-1 (p = 0.008), suggesting that tHcy may increase ET-1 by enhancing the production of oxLDL.. Both chronic and acute methionine-induced homocysteinemia are associated with elevated oxidative stress status. Although ET-1 is increased in chronic homocysteinemia, it does not participate in the rapid development of endothelial dysfunction after methionine loading. These findings suggest that despite its potential role in chronic homocysteinemia, ET-1 has a limited contribution to the development of endothelial dysfunction in acute, methionine-induced homocysteinemia in humans.

Topics: Analysis of Variance; Antioxidants; Ascorbic Acid; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Fasting; Female; Forearm; Homocysteine; Humans; Hyperhomocysteinemia; Lipoproteins, LDL; Male; Methionine; Oxidative Stress; Regional Blood Flow; Vitamin E

Hyperhomocysteinemia is a risk factor for atherosclerosis and venous thrombosis, probably exerting its effects through endothelial function. Homocysteine levels are lowered by folate supplementation, and such treatment improves endothelial function. However, whether folate supplementation decreases vascular risk and improves survival is unknown. The aim of this study was to evaluate endothelial function and mononuclear leukocyte inflammatory activity during homocysteine lowering in patients with hyperhomocysteinemia and vascular disease.. Endothelial function assessed as plasma (p-)endothelin(ET)-1 and intraplatelet cGMP and cAMP, and mononuclear leukocyte inflammatory activity, assessed as p-neopterin were studied during homocysteine lowering in 50 patients with hyperhomocysteinemia and vascular disease, randomized to folate supplementation or no treatment for 3 months.. P-homocysteine decreased during the 3 months not only in patients on folate supplementation (from 27 [21-52] to 14 [8-41] micromol/l; p<0.001), but also in the untreated group (from 23 [20-35] to 19 [4-31] micromol/l; p<0.001). P-ET-1 decreased during folate supplementation (from 5.7 [2.7-11.6] to 4.1 [1.8-9.0] pg/ml; p<0.01), but was unchanged in the untreated group 4.1 [2.0-9.5] pg/ml and 4.5 [2.7-7.1] pg/ml). P-neopterin was unchanged in patients on folate supplementation (9.7 [5.1-54.4] and 7.6 [5.7-73.0] nmol/l), but increased in the untreated group (from 8.2 [4.7-19.5] to 8.6 [4.6-24.6] nmol/l; p<0.05). Intraplatelet cGMP decreased in patients on folate supplementation (from 0.86 [0.21-2.00] platelets to 0.56 [0.17-1.42] pmol/10(9) platelets; p<0.05), but was unchanged in the untreated group. No significant differences concerning intraplatelet cAMP occurred in either group.. Folate supplementation in hyperhomocysteinemia is associated with decreasing levels of both ET-1 and intraplatelet cGMP, and the absence of an increase in the levels of the inflammatory mediator neopterin.

Topics: Aged; Blood Platelets; Cyclic AMP; Cyclic GMP; Endothelin-1; Female; Folic Acid; Humans; Hyperhomocysteinemia; Male; Neopterin; Vascular Diseases

Acute coronary syndromes (ACS) are complex and polygenic diseases which are a real problem of public health. These syndromes require multidisciplinary studies to understand the pathogenesis mechanisms and metabolic interactions between different risk factors.This study aimed to explore the variation of two coronary risk parameters not mentioned by Framingham cohorts, hyperhomocysteinemia and endothelin-1 (ET-1) in Tunisian coronary and the study of the variation of these parameters based on various cardiac risk factors and metabolic relationship between them.To 157 coronary and 142 healthy subjects, the concentration of homocysteine was quantified by fluorescence polarization immunoassay; the concentration of ET-1 was measured by an analytical technique, the High Performance Liquid Chromatography (HPLC) coupled with mass spectrometry.. Our study showed that homocysteine and ET-1 were significantly higher in patients compared to healthy subjects (24.40 ± 12.5 μmol/L vs 7.44 ± 2.5 μmol/L p <0.00001) for homocysteine and (15.2 ± 5.3 nmol/L vs 7.1 ± 2.7 nmol/L, p <0.00001) for ET-1. On the other hand, homocysteine varies according to tobacco and diabetes while ET-1 depends on the sex, hypertension, smoking, obesity and dyslipidemia and a statistically negative correlation was shown between homocysteine and ET-1 in coronary patients (r = -0.66 p <0.00001).. The study of the variation of these two parameters in coronary patients and metabolic exploration of the relationship between homocysteine and ET-1 according to various risk factors and the interactions between themselves facilitates the decision of therapeutic treatment.

Topics: Acute Coronary Syndrome; Aged; Case-Control Studies; Chromatography, High Pressure Liquid; Endothelin-1; Female; Fluorescence Polarization Immunoassay; Homocysteine; Humans; Hyperhomocysteinemia; Male; Mass Spectrometry; Middle Aged; Prospective Studies; Risk Factors; Sex Factors; Statistics as Topic; Tunisia

Hyperhomocysteinemia (HHcy) is a well-known independent risk factor for vascular diseases in the general population. This study was to explore the effect of genistein (GST), a natural bioactive compound derived from legumes, on HHcy-induced vascular endothelial impairment in ovariectomized rats in vivo. Thirty-two adult female Wistar rats were assigned randomly into four groups (n = 8): (a) Con: control; (b) Met: 2.5% methionine diet; (c) OVX + Met: ovariectomy + 2.5% methionine diet; (d) OVX + Met + GST: ovariectomy + 2.5% methionine diet + supplementation with genistein. After 12 wk of different treatment, the rats' blood, toracic aortas and liver samples were collected for analysis. Results showed that high-methionine diet induced both elevation of plasma Hcy and endothelial dysfunction, and ovariectomy deteriorated these injuries. Significant improvement of both functional and morphological changes of vascular endothelium was observed in OVX + Met + GST group; meanwhile the plasma Hcy levels decreased remarkably. There were significant elevations of plasma ET-1 and liver MDA levels in ovariectomized HHcy rats, and supplementation with genistein could attenuate these changes. These results implied that genistein could lower the elevated Hcy levels, and prevent the development of endothelial impairment in ovariectomized HHcy rats. This finding may shed a novel light on the anti-atherogenic activities of genistein in HHcy patients.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Endothelin-1; Endothelium, Vascular; Estradiol; Female; Genistein; Homocysteine; Hyperhomocysteinemia; Immunohistochemistry; In Vitro Techniques; Liver; Malondialdehyde; Muscle Contraction; Nitroprusside; Ovariectomy; Phenylephrine; Rats; Rats, Wistar

Previous studies have showed that phytoestrogen α-zearalanol (α-ZAL) could antagonize homocysteine (Hcy) induced endothelin-1 (ET-1) expression, oxidative stress and apoptosis in human umbilical vein endothelial cells in vitro, however, its effect on vascular function in vivo remains to be determined. This study was designed to investigate the effects of α-ZAL on vascular function in ovariectomized (OVX) hyperhomocysteinemia (HHcy) rats and explore the mechanisms involved primarily. HHcy rat model was induced by diets containing 2.5% methionine (Met) for 12 weeks. Forty adult female Wistar rats were assigned randomly into five groups: (1) Con; (2) Met; (3) OVX+Met; (4) OVX+Met+α-ZAL; (5) OVX+Met+17β-E(2) (17β-estradiol). Blood was collected to analyze plasma estradiol, Hcy and ET-1. Thoracic aortas were isolated to detect its response to phenylephrine (PE) and acetylcholine (ACh) or sodium nitroprusside (SNP). Aortas eNOS expression was determined by Western blot. Thoracic aortas histological characterization was analyzed by optical microscope and scanning electron microscope (SEM). Rat plasma Hcy was significantly elevated after fed with 2.5% methionine diets, and ovariectomy aggravated this elevation. Phytoestrogen α-ZAL or 17β-E(2) could attenuate this elevation. Plasma ET-1 levels increased significantly in ovariectomized HHcy rats, and supplement with α-ZAL or 17β-E(2) could reverse these changes. In rats of OVX+Met group, PE elicited significantly greater contraction in a dose-dependent manner in endothelium-intact thoracic aortas rings; ACh elicited significantly less percentage relaxation. These effects were significantly attenuated by supplement with α-ZAL or 17β-E(2). There was no significant difference between groups in relaxation induced by SNP whether endothelium intact or not. Thoracic aortas morphology study also showed severe endothelium injury in ovariectomized HHcy rats, both α-ZAL and 17β-E(2) could attenuate this change. Aortas eNOS expression was decreased in ovariectomized HHcy rats, and supplement with α-ZAL or 17β-E(2) could reverse these changes. These findings demonstrated that α-ZAL could effectively alleviate the impairment of endothelial cells and improve vascular function in ovariectomized HHcy rats by decreasing plasma Hcy and antagonizing decreasing of aortas eNOS expression. This protective effect is somewhat similar with 17β-E(2).

Topics: Acetylcholine; Animals; Aorta, Thoracic; Endothelin-1; Estradiol; Female; Homocysteine; Hyperhomocysteinemia; Methionine; Nitric Oxide Synthase Type III; Nitroprusside; Ovariectomy; Phenylephrine; Phytoestrogens; Rats; Rats, Wistar; Zeranol

We investigated the possible protective effect of poly (ADP-ribose) polymerase (PARP) inhibition in preventing endothelial dysfunction induced by hyperhomocysteinemia (Hhcy).. Sprague-Dawley rats were divided into Hhcy group, Hhcy + 3-aminobenzamide(3-AB) group, control group and control + 3-AB group. A high-methionine diet was given to induce hyperhomocysteinemia. In Hhcy + 3-AB and control + 3-AB groups, rats were injected intraperitoneally with 3-AB (inhibitor of PARP). After 45 days, ultrastructural changes of aortas were observed by transmission electron microscope. Vascular reactivity of thoracic aortic rings was measured in organ chambers. PARP activity was detected. The levels of plasma total homocysteine, nitrite/nitrate, endothelin (ET)-1 and malondialdehyde were assayed.. Rats in Hhcy group developed severe hyperhomocysteinemia and significant loss of endothelial function as measured by both vascular rings and levels of nitrite/nitrate and ET-1. Malondialdehyde levels increased significantly in Hhcy rats compared with control rats. 3-AB improved Ach-induced, NO-mediated vascular relaxation and stabilized the level of nitrite/nitrate and ET-1. Obvious improvement of ultrastructure can be observed in Hhcy + 3-AB group.. These results suggest that pharmacological inhibition of PARP prevents the development of endothelial dysfunction in rats with hyperhomocysteinemia which may represent a novel approach to improve vascular dysfunction associated with hyperhomocysteinemia.

Topics: Animals; Aorta, Thoracic; Benzamides; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Hyperhomocysteinemia; Male; Malondialdehyde; Microscopy, Electron, Transmission; Nitric Oxide; Oxidative Stress; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley

There are interactions between endothelin-1 (ET-1) and endothelial vascular injury in hyperhomocysteinemia (HHcy), but the underlying mechanisms are poorly understood. Here we evaluated the effects of HHcy on the endothelin system in rat carotid arteries.. Vascular reactivity to ET-1 and ET(A) and ET(B) receptor antagonists was assessed in rings of carotid arteries from normal rats and those with HHcy. ET(A) and ET(B) receptor expression was assessed by mRNA (RT-PCR), immunohistochemistry and binding of [(125)I]-ET-1.. HHcy enhanced ET-1-induced contractions of carotid rings with intact endothelium. Selective antagonism of ET(A) or ET(B) receptors produced concentration-dependent rightward displacements of ET-1 concentration response curves. Antagonism of ET(A) but not of ET(B) receptors abolished enhancement in HHcy tissues. ET(A) and ET(B) receptor gene expressions were not up-regulated. ET(A) receptor expression in the arterial media was higher in HHcy arteries. Contractions to big ET-1 served as indicators of endothelin-converting enzyme activity, which was decreased by HHcy, without reduction of ET-1 levels. ET-1-induced Rho-kinase activity, calcium release and influx were increased by HHcy. Pre-treatment with indomethacin reversed enhanced responses to ET-1 in HHcy tissues, which were reduced also by a thromboxane A(2) receptor antagonist. Induced relaxation was reduced by BQ788, absent in endothelium-denuded arteries and was decreased in HHcy due to reduced bioavailability of NO.. Increased ET(A) receptor density plays a fundamental role in endothelial injury induced by HHcy. ET-1 activation of ET(A) receptors in HHcy changed the balance between endothelium-derived relaxing and contracting factors, favouring enhanced contractility.

Topics: Animals; Aspartic Acid Endopeptidases; Calcium; Carotid Arteries; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Hyperhomocysteinemia; In Vitro Techniques; Male; Metalloendopeptidases; Nitrogen Oxides; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction; Vasodilation

The aim of this study was to investigate the effect of lycopene on the vascular endothelial function and the expression of inflammatory agents in hyperhomocysteinemic rats. Fifty male Sprague-Dawley rats weighed 145- 155g were on a commercial rat chow diet for seven days, and then were randomized into five groups: normal control group (NC) fed with AOAC diet and four hyperhomocysteinemic groups fed with AOAC diet plus 3% L-methionine. Four hyperhomocysteinemic groups were daily supplemented with 0 (HC), 10 mg/kg (HL1), 15 mg/kg (HL2), 20 mg/kg (HL3) lycopene dissolved in corn oil respectively by intragastric administration for 12 weeks. At the end of experiment, their blood and abdominal aortas were collected after etherization. Serum levels of Hcy were determined by HPLC, nitric oxide (NO) and nitric oxide synthase (NOS) by chromatometry, endothelin- 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) by ELISA. Hematoxylin and eosin staining and oil red staining were used to analyze abdominal aortas histologically. Moderate hyperhomocysteinemia was induced in hyperhomocysteinemic groups. Serum level of NO was lower and ET-1 was higher in HC rats than in NC, NL2 and NL3 rats (p<0.01). There was no difference of serum NOS activity among five groups. There were some foam cells and depositions of lipochondria in aortic tunica intima in HC and HL1 rats, which were not found in HL2 and HL3 rats. Serum levels of VCAM-1, MCP-1, IL-8 were higher in HC rats than in NC, NL1, NL2 and NL3 rats (p<0.01). The present study indicated that lycopene exerts an antiatherogenic effect by inhibiting the expression of inflammatory agents in hyperhomocysteninemic rats.

Topics: Animals; Antioxidants; Aorta, Abdominal; Carotenoids; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Hyperhomocysteinemia; Inflammation; Lycopene; Male; Methionine; Nitric Oxide; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Vascular Cell Adhesion Molecule-1

The aim of this study was to evaluate traditional risk factors for coronary artery disease (CAD), homocysteine, anti-oxidized low-density lipoprotein (anti-oxLDL), anti-lipoprotein lipase (anti-LPL) and endothelin-1 (ET-1) in patients with primary anti-phospholipid syndrome (APS), furthermore verify possible association among these variables and arterial thrombosis. Thirty-eight women with primary APS and 30 age-and-sex-matched controls were evaluated. Patients presented higher-LDL and triglycerides levels and lower-HDL levels than controls. Anti-LPL antibodies were not detected in both groups. The mean number of risk factors was higher in patients than in controls (P = 0.030). Anti-oxLDL antibodies, homocysteine and ET-1 mean levels were similar between groups, but abnormal homocysteine levels were found only among primary APS patients (P = 0.031). Hypertension and the presence of at least one risk factor for CAD were more prevalent in patients with arterial involvement than those without. Homocysteine levels and mean number of risk factors for CAD were significantly higher in patients with arterial thrombosis than controls. In a multivariate analysis hypertension was the only independently associated with arterial thrombosis (OR 14.8, 95% CI = 2.1-100.0, P = 0.006). This study showed that in primary APS patients other risk factors besides anti-phospholipid antibodies contribute for the occurrence of arterial events and the most important factor was hypertension.

Topics: Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoantibodies; Case-Control Studies; Coronary Artery Disease; Endothelin-1; Female; Homocysteine; Humans; Hyperhomocysteinemia; Hypertension; Lipoprotein Lipase; Lipoproteins, LDL; Middle Aged; Risk Factors; Thrombosis

Behçet's disease (BD) is a systemic inflammatory vasculitis of young adults with unknown aetiology, characterised by endothelial dysfunction and occlusion in both deep venous and retinal circulation. Ocular involvement occurs in 70% of cases and is characterised by periphlebitis, periarteritis, vascular occlusion, and thrombosis leading to blindness despite vigorous treatment. Endothelin-1 (ET-1) is a vasoconstricting peptide while nitric oxide (NO) is a relaxing molecule and both are released by endothelium for blood flow regulation. Homocysteinaemia is a newly defined term connected to the increased risk of atherothrombotic and atherosclerotic systemic and retinal vascular occlusive diseases, and its role in the course of BD has not been previously described. The authors aimed to detect serum total homocysteine (tHcy), ET-1, and NO in BD and to assess if tHcy, ET-1, and NO are associated with ocular BD or disease activity.. 43 consecutive patients with ocular (n = 27) or non-ocular (n = 16) BD (36.95 (SD 9.80) years, 22 male, 21 female) satisfying international criteria, and 25 age and sex matched healthy control subjects (37.88 (8.73) years, 13 male, 12 female) without a history of systemic or retinal venous thrombosis were included in this study. Patients were examined by two ophthalmologists with an interest in BD. Serum tHcy, ET-1, and NO concentrations were measured in both groups. Hyperhomocysteinaemia was defined as a tHcy level above the 95th percentile in the control group. Patients were divided into active and inactive period by acute phase reactants including alpha(1) antitrypsin, alpha(2) macroglobulin, erythrocyte sedimentation rate, and neutrophil count.. The overall mean serum tHcy, ET-1, and NO levels were significantly higher in patients with BD than in control subjects (tHcy = 15.83 (4.44) v 7.96 (2.66) ng/ml, p <0.001; ET-1 = 17.47 (4.33) v 5.74 (2.34) micromol/ml, p <0.001; NO = 37.60 (10.31) v 27.08 (7.76) micromol/l, p <0.001). Serum tHcy, ET-1, and NO levels were significantly higher in active patients than in inactive patients and control subjects. In addition, among patients with ocular BD, the mean tHcy levels were significantly increased and correlated with ET-1 and NO levels when compared with non-ocular disease and control subjects. All acute phase reactant levels were significantly higher in active period than in inactive stage and controls.. Elevated tHcy may be responsible for the endothelial damage in BD and may be an additional risk factor for the development of retinal vascular occlusive disease, contributing to the poor visual outcome in these patients. Assessment of tHcy may be important in the investigation and management of patients with BD, especially with ocular disease.

Topics: Acute-Phase Proteins; Adolescent; Adult; Behcet Syndrome; Biomarkers; Blood Sedimentation; Endothelin-1; Female; Homocysteine; Humans; Hyperhomocysteinemia; Leukocyte Count; Male; Middle Aged; Neutrophils; Nitric Oxide; Retinal Diseases

The endothelium can greatly influence vascular tone and structure. The main endothelium-derived factor is nitric oxide (NO), which is not only a potent vasodilator but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro- and microcirculation and in renal circulation. The mechanism responsible for endothelial alteration in essential hypertensive patients appears to be the activation of an alternative pathway involving cyclooxygenase, which reduces NO availability through production of oxidative stress. In the presence of impaired NO availability a hyperpolarizing factor seems to act as a compensatory pathway to sustain endothelium-dependent relaxation. This compensatory pathway can be further depressed by the simultaneous presence of essential hypertension and hyperhomocysteinaemia, another cardiovascular risk factor causing endothelial dysfunction. Finally, reduced NO availability can increase the biological activity of endothelin-1 because, while in healthy conditions the vasoconstrictor effect of endothelin-1 is partially blunted by endothelial ETB-receptor mediated NO production, in essential hypertensive patients this protective mechanism is lacking on account of impaired NO availability. This alteration in the NO pathway could be the main mechanism through which a dysfunctional endothelium could be a promoter of atherosclerosis and thrombosis and therefore lead to cardiovascular events in essential hypertensive patients.

Topics: Biological Factors; Endothelin-1; Endothelium, Vascular; Humans; Hyperhomocysteinemia; Hypertension; Muscle, Smooth, Vascular; Nitric Oxide; Oxidative Stress; Prostaglandin-Endoperoxide Synthases