endothelin-1 and Hyperlipidemias

Hypertension and hyperlipidemia, two powerful risk factors of cardiovascular disease (CVD), often coexist. Therefore, treatment should consider the beneficial properties of drugs used to treat either condition. Statins, the mainstay of lipid-lowering therapy, result in a significant clinical benefit both in primary and secondary CVD prevention. In addition to their hypolipidemic capacity, other properties may contribute to statin-induced benefits. Clinical and experimental evidence indicates that statins may modulate blood pressure (BP). The mechanisms by which statins reduce BP seem to be largely independent of their lipid effects. Although small, reductions in BP are possibly clinically relevant. Large landmark studies confirm that statins can reduce CVD risk in hypertensive patients. These findings suggest that statins could be prescribed as an adjunct in treating hypertension with dyslipidemia or even in patients with "normal" cholesterol levels. Whether the effect of statins on BP is accompanied by an additional decrease in clinical outcomes needs to be investigated in long-term, large-scale trials.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Endothelin-1; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypertension; Intracellular Signaling Peptides and Proteins; Nitric Oxide; Protein Serine-Threonine Kinases; Renin-Angiotensin System; rho-Associated Kinases

The aim of the present paper is to analyze recent literature concerning the incidence of cardiovascular complications in women suffering from polycystic ovary syndrome (PCOS). The study takes into consideration all the studies that have been published to date in the international literature in order to clarify whether or not PCOS is able to determine an early onset or whether it is responsible for a higher global incidence of cardiovascular complications in adult age. The main difficulty lies in the absence of prospective studies owing to the long period of time existing between the diagnosis of PCOS and cardiovascular disease which notoriously has a long latency period. Much attention has been paid in the literature, on the other hand, to the analysis of the incidence of cardiovascular risk factors in women suffering from PCOS. Although epidemiological studies have not evidenced an increased incidence of death from cardiovascular events in women suffering from PCOS, the above conclusions might well be invalidated by a patient selection bias, by obsolete diagnostic criteria or by medical or surgical therapies that could influence the outcome of the disease and which are not considered as a confusion factor. Undoubtedly, all the data available up to the present suggest that PCOS possesses the intrinsic conditions that lead to an increased incidence of factors predisposing to cardiovascular diseases. Future longitudinal studies of a prospective nature might be useful for understanding whether the higher incidence of predisposing factors might also lead to greater expectation of cardiovascular events or whether medical therapies or other factors (improvement in endocrine symptomatology with the menopause?) may prevent the increase in the expected incidence of these events.

Topics: Biomarkers; Blood Coagulation Disorders; Cardiovascular Diseases; Carotid Stenosis; Endothelin-1; Endothelium, Vascular; Female; Humans; Hyperlipidemias; Hypertension; Incidence; Menstrual Cycle; Myocardial Ischemia; Polycystic Ovary Syndrome; Risk Factors

Topics: Antioxidants; Apoptosis; Biological Availability; Blood Platelets; Cardiomegaly; Endothelial Growth Factors; Endothelin-1; Endothelium, Vascular; Fibrinolysis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Intercellular Signaling Peptides and Proteins; Leukocytes; Lipids; Lymphokines; Macrophage Activation; Models, Animal; Models, Biological; Muscle, Smooth, Vascular; Neovascularization, Pathologic; Nitric Oxide; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Two syndromes are called syndromes X: cardiac (effort anginal pain, positive exercise tolerance test and absence of angiographically documented critical stenosis in coronary arteries) and metabolic (according to WHO definition: impaired glucose tolerance and insulin resistance and > or = 2 risk factors from the following list: hypertension, dyslipidaemia, visceral obesity and microalbuminuria). Hyperinsulinaemia and endothelial dysfunction are present in both syndromes. The contribution of endothelial nitric oxide synthase gene mutations to the etiology of these syndromes is also studied. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of nitric oxide (NO), enhanced inactivation of NO after its release from endothelial cells or enhanced synthesis of vasoconstricting agents. It has been demonstrated that insulin exerts a direct hypertrophic effect on the vascular endothelium and the smooth muscle cells. The hemodynamic properties of insulin have also been discussed. Some findings suggest that in the skeletal muscle circulation, insulin stimulates both endothelin-1 (ET-1) and nitric oxide activity and an imbalance between the release of these two substances may be involved in the pathophysiology of endothelial dysfunction.

Topics: Albuminuria; Endothelin-1; Humans; Hyperinsulinism; Hyperlipidemias; Hypertension; Insulin; Metabolic Syndrome; Microvascular Angina; Mutation; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Obesity; Risk Factors

Coronary arteries are regulated by neuronal mechanisms, hormones and paracrine mediators. The importance of endothelium-dependent mechanisms has recently been recognized. The endothelium responds to mechanical and chemical signals from the blood by releasing mediators that modulate vascular tone and structure, platelet function, coagulation and monocyte adhesion. Important relaxing factors are nitric oxide, prostacyclin and a putative hyperpolarizing factor. Nitric oxide also inhibits smooth muscle proliferation and, together with prostacyclin, platelet function. Bradykinin-induced nitric oxide production is reduced by angiotensin-converting enzyme. Endothelin-1, thromboxane A2 and prostaglandin H2 are contracting factors. Thromboxane A2 and prostaglandin H2 activate platelets, while endothelin has no direct platelet effects, but causes smooth muscle proliferation. In hypercholestermia, endothelium-dependent relaxation is impaired and contraction as well as adhesion of monocytes and platelets enhanced. Pharmacological correction of hyperlipidemia by statins also improves or normalizes endothelial dysfunction in patients. Angiotensin-converting enzyme inhibitors have similar effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anticholesteremic Agents; Arginine; Arteriosclerosis; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Humans; Hyperlipidemias; Lipids; Lipoproteins, LDL; Lovastatin; Nitric Oxide; Swine

To observe the influence of moxibustion temperature on blood lipids, endothelin-1 (ET-1), nitric oxide (NO), and ET-1/NO in hyperlipidemia patients.. Forty-two primary hyperlipidemia patients were randomly divided into two groups of 21 and treated with moxibustion at different temperatures. Moxibustion was performed with the moxa roll 2.5-3.0 cm from the skin in the treatment group and 4 cm in the control group, 10 min per point, once every other day. Skin temperature was precisely measured with a thermometer during moxibustion. After a 12-week treatment, seven measurements of blood lipids, ET-1, and NO were recorded.. Total cholesterol and triglyceride, were lower in the treatment group than in the control group (P < 0.05). Serum ET-1 and ET-1/NO was obviously lowered in the treatment group (P < 0.001). Moxibustion regulated NO and ET-1/NO in the treatment group much better than in the control group.. Moxibustion can regulate blood lipids and clear blood vessels. Moxibustion at 45 degrees C has a better effect than moxibustion at 38 degrees C on regulating blood lipids and protecting vascular endothelial function, indicating that suitable temperature influences the curative effect of moxibustion.

Topics: Aged; Endothelin-1; Female; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Moxibustion; Nitric Oxide

Statins and fibrates have different effects on lipid abnormalities of familial combined hyperlipidemia (FCHL); thus, the selection of the first-line drug is troublesome. We evaluated to what extent monotherapy with a potent statin is more effective than fibrate in reaching the recommended lipid targets in FCHL. Fifty-six patients were randomized to receive optimal dosage of atorvastatin (n = 27) or 200 mg/d micronized fenofibrate (n = 29) for 24 weeks. To reach the optimal dosage, atorvastatin was up-titrated at each follow-up visit if low-density lipoprotein (LDL) cholesterol >130 mg/dL (>100 mg/dL in patients with coronary or cerebrovascular disease). The effects of fenofibrate and atorvastatin on lipoprotein fractions as well as on plasma levels of endothelin-1 (ET-1) and adrenomedullin (AM) were also evaluated. At end of trial, a greater proportion of patients on atorvastatin (average dosage, 20.8 mg/d) reached lipid targets in comparison with those on fenofibrate (64% vs 32.1%, P = .02). Atorvastatin was significantly more effective in reducing total cholesterol, LDL cholesterol, apolipoprotein B, and non-high-density lipoprotein (HDL) cholesterol. Conversely, triglycerides decreased and HDL increased more during fenofibrate. Nevertheless, atorvastatin produced a marked reduction in very low-density lipoprotein and very low-density lipoprotein remnants. Atorvastatin lowered all LDL subtypes, although fenofibrate appeared to be more effective on denser LDL. Compared with 43 normolipemic controls, FCHL patients presented increased baseline plasma levels of ET-1 (P = .007) but not of AM. Fenofibrate, but not atorvastatin, significantly lowered ET-1 levels by 16.7% (P < .05). Neither drug significantly affected plasma concentrations of AM. In summary, although fenofibrate showed superiority in raising HDL and reducing ET-1, atorvastatin was more effective in reaching lipid targets in FCHL so that it can be proposed as the first-line option in the management of this atherogenic hyperlipidemia.

Topics: Adult; Aged; Atorvastatin; Biomarkers; Endothelin-1; Endothelium, Vascular; Female; Fenofibrate; Heptanoic Acids; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Pyrroles

Type 2 diabetes and metabolic syndrome are major cardiovascular risk factors in postmenopausal women, but the role of vasoconstrictive endothelin-1 (ET-1) in these conditions is not known. We studied the levels of ET-1 and the effect of postmenopausal hormonal therapy on ET-1 levels in postmenopausal women.. We compared plasma levels of ET-1 in 22 postmenopausal type 2 diabetic women and 14 postmenopausal women with metabolic syndrome with plasma levels in 10 healthy postmenopausal control women. The basal values for ET-1 were measured for all groups. These women were then randomised to receive in a double-dummy, crossover trial: either oral continuous oestradiol (2.0 mg) + norethisterone acetate (1.0 mg) per day or continuous transdermal oestrogen-only (50 mg/day) for 3 months. Between the active therapy there were 3-month wash-out periods. ET-1-values were measured again at the end of each treatment period.. The type 2 diabetic women had significantly (p < 0.003) elevated ET-1 levels (4.8+/-1.0 pg/ml) whereas those with metabolic syndrome (4.4+/-1.7 pg/ml]) had non-significantly (NS) elevated ET-1 levels compared to controls (3.6+/-0.3 pg/ml). Both oral and transdermal hormone replacement therapy (HRT) failed to affect plasma ET-1 except in 14 hypertensive women from the diabetes and metabolic syndrome groups who were on angiotensin convertase enzyme (ACE) inhibitors. These women's ET-1 levels before oral HRT (4.6+/-1.1 pg/ml) fell to 4.1+/-0.9 pg/ml (p < 0.05).. Type 2 diabetes in postmenopausal women is associated with elevated ET-1 levels. Oestrogen replacement therapy does not affect the levels of ET-1 in postmenopausal women with type 2 diabetes or metabolic syndrome.

Topics: Administration, Cutaneous; Administration, Oral; Biomarkers; Body Constitution; Body Mass Index; Cholesterol, HDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Female; Humans; Hyperlipidemias; Hypertension; Middle Aged; Norethindrone; Norethindrone Acetate; Postmenopause; Reference Values; Syndrome; Triglycerides

Kidney disease is a universal public health problem, and epidemiological studies demonstrated that the incidences of chronic kidney disease are increasing day by day. However, the efficiency of currently available drugs on the progression of nephropathy is limited. Therefore, the current research was designed to evaluate the therapeutic efficacy of captopril and BQ123 against hyperlipidemia-induced nephropathy in rats.. The objective of this study was to examine the implication of Endothelin-1 in experimentally induced hyperlipidemic nephropathy in rats.. Animals were divided into various groups, and the administration of a high-fat diet for six weeks induced hyperlipidemia. After confirmation of hyperlipidemia, treatment was started for the next 14 days. At the end of the experimental period, the animals were sacrificed, and various biochemical parameters and histopathological studies were performed.. Treatment of both the agents in combination effectively decreased BUN levels, serum creatinine, serum nitrite, and proinflammatory markers and ameliorated the pathological injuries to kidneys.. Furthermore, both treatments also inhibited oxidative stress and restored the hyperlipidemia-induced reduction in the level of antioxidant enzymes.

Topics: Animals; Captopril; Endothelin-1; Hyperlipidemias; Kidney Diseases; Rats

To investigate the effect of heme oxygenase/carbon monoxide (HO-1/CO) system on lipid deposition at aortic intima and the mechanism involved in hyperlipidemic rabbits.. Totally 32 rabbits, were divided into four groups. One group as control. Three groups for the following treatments: 1.5% cholesterol ration (Ch group, n = 8); 1.5% cholesterol ration plus HO-1 inducer hemin (Hm group, n = 8); and instead of hemin, the HO-1 inhibitor, zinc protoporphyrin IX (Zn group, n = 8) was given by injection into the abdominal cavity. Experiments were lasted for 12 weeks. Rabbit aortas were then isolated as the samples for histopathologic and ultrastructural examination. The protein expressions of HO-1 and endothelin-1 (ET-1) were investigated by immunohistochemical staining and Western blot analysis.. Comparing with the Ch group, rabbits of the Hm group showed a remarkably less extent of lipid deposition at the aortic intima [(17.9 ± 3.0)% vs (54.0 ± 4.2)%], and rabbits of the Zn group had a marked extent of lesion development [(61.1 ± 3.5)%]. Lipid deposition, endothelial damage and neo-intimal formation were less severe in rabbits of the Hm group than those in the Zn or Ch group, respectively. Comparing with the control group, rabbits of the Ch group showed a significant decrease of aortic NO production and cNOS activity. However, there were an enhancement of CO production and HO-1 activity (P < 0.01). Compared with Ch group, rabbits of the Hm group showed a remarkable elevation of aortic HO activity and CO production, whereas rabbits of the Zn group showed a marked decrease of both parameters. Compared with the Ch group, rabbits of the Hm group demonstrated a marked reduction of aorta ET-1 expression, whereas Zn group had a significantly higher ET-1 expression.. Modulation of HO-1/CO system may improve vascular endothelial function and inhibit smooth muscle cell proliferation in hypercholesterolemic rabbits, likely through a compensatory mechanism and a reduction of ET-1 expression, eventually leading to an inhibition of atherosclerotic plaque development.

Topics: Animals; Aorta; Carbon Monoxide; Cholesterol; Endothelin-1; Enzyme Inhibitors; Heme Oxygenase-1; Hemin; Hyperlipidemias; Nitric Oxide; Nitric Oxide Synthase; Plaque, Atherosclerotic; Protoporphyrins; Rabbits; Tunica Intima

To systematically clarify the effects of apolipoprotein E (aopE) and low-density lipoprotein receptor (LDLR) gene mutant on hyperlipidemia, vascular inflammation impairment and pathogenesis of atherosclerosis (AS), total RNA was isolated from fresh aortas of young apoE/LDLR double knockout (apoE(-/-)/LDLR(-/-)) and wild type (WT) mice using TRIzol reagent. Then RNA was reversely transcribed to first-strand cDNA by reverse transcriptase for reverse transcription polymerase chain reaction (RT-PCR) and real-time RT-PCR. Primer pairs were designed using primer design software according to the gene sequences available in GenBank. β-actin was used as an internal control. Then RT-PCR assay was used to analyze the expression patterns of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB), granulocyte-macrophage colony-stimulating factor (GM-CSF), CD36, endothelin-1 (ET-1), toll-like receptor 2 (TLR2), monocyte chemoattractant protein-1 (MCP-1), vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and platelet-derived growth factor-α (PDGF-α). SYBR Green quantitative real-time RT-PCR was used to validate gene expressions identified by RT-PCR. Blood samples were taken from the retro-orbital venous plexus, and serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured by using biochemical techniques. Serum concentrations of circulating TNF-α, IL-1β and oxidized LDL (ox-LDL) were determined by ELISA. Frozen sections of aortic sinus were stained with Sudan IV to visualize intimal fatty lesions. The results showed that the relative expressions of IL-1β, GM-CSF, ET-1, TLR2, CD36, MCP-1, ICAM-1 and VCAM-1 in apoE(-/-)/LDLR(-/-) mice at the age of 1 month were higher than those in age-matched WT mice (P<0.05, P<0.01), respectively. The expressions of PDGF-α and TNF-α in apoE(-/-)/LDLR(-/-) mice at the age of 2 months were up-regulated compared to those in age-matched WT mice (P<0.05). All the expressions of target genes continued to be up-regulated (P<0.05, P<0.01) except that ET-1 expression at the age of 2 months, TLR2, VCAM-1 and ICAM-1 expressions at the age of 3 months were down-regulated to that in WT mice. NF-κB expression had no significant changes between two genotype mice at different ages. All the gene expressions kept unchanged in WT mice at different ages, except that IL-1b expressions were slightly up-regulated at the age

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; CD36 Antigens; Chemokine CCL2; Endothelin-1; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor; Hyperlipidemias; Intercellular Adhesion Molecule-1; Interleukin-1beta; Lipoproteins, LDL; Mice; Mice, Knockout; NF-kappa B; Platelet-Derived Growth Factor; Receptors, LDL; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Endothelin-1 (ET-1) signaling mechanisms have been implicated in the pathogenesis of excess coronary artery disease in diabetic dyslipidemia. We hypothesized that in diabetic dyslipidemia ET-1-induced coronary smooth muscle calcium (Ca2+m) and tyrosine phosphorylation would be increased, and the lipid lowering agent, atorvastatin, would inhibit these increases. Male Yucatan miniature swine groups were treated for 20 weeks: normal low-fat fed control, high-fat/cholesterol fed (hyperlipidemic), hyperlipidemic made diabetic with alloxan (diabetic dyslipidemic), and diabetic dyslipidemic treated with atorvastatin (atorvastatin-treated). Blood glucose values were 5-fold greater in diabetic dyslipidemic and atorvastatin-treated versus control and hyperlipidemic. Total and low-density lipoprotein (LDL) plasma cholesterol in hyperlipidemic, diabetic dyslipidemic, and atorvastatin-treated were approximately 5-fold greater than control. Intravascular ultrasound detectable coronary disease and hypertriglyceridemia were only observed in diabetic dyslipidemic and were abolished by atorvastatin. In freshly isolated cells, the Ca2+m response to ET-1 in diabetic dyslipidemic was greater than in control, hyperlipidemic, and atorvastatin-treated groups. Selective ET-1 receptor antagonists showed in the control group that the ETB subtype inhibits ETA regulation of Ca2+m. There was almost a complete switch of receptor subtype regulation of Ca2+m from largely ETA in control to an increased inhibitory interaction between ETA and ETB in hyperlipidemic and diabetic dyslipidemic groups, such that neither ETA nor ETB antagonist alone could block the ET-1-induced Ca2+m response. The inhibitory interaction was attenuated in the atorvastatin-treated group. In single cells, basal and ET-1-induced tyrosine phosphorylation in diabetic dyslipidemic were more than 3- and 6-fold greater, respectively, than in control, hyperlipidemic, and atorvastatin-treated. Attenuation by atorvastatin of coronary disease and ET-1-induced Ca2+m and tyrosine phosphorylation signaling with no change in cholesterol provides strong evidence for direct actions of atorvastatin and/or triglycerides on the vascular wall.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Calcium; Calcium Signaling; Coronary Artery Disease; Diabetes Complications; Diet; Disease Models, Animal; Endothelin-1; Endothelins; Heptanoic Acids; Hyperlipidemias; Male; Phosphorylation; Pyrroles; Receptor, Endothelin A; Receptors, Endothelin; Swine; Tyrosine

VasoCare therapy, which involves the administration of autologous blood following the ex vivo exposure to physico-chemical stressors, has been shown to modulate immune responses. Since immune mechanisms have been recognized to be pivotal in the pathogenesis of atherosclerosis, we hypothesized that VasoCare treatment would inhibit atherosclerosis in LDL-R (-/-) mice. Three groups of LDL-R (-/-) mice were studied: a control group that was fed normal chow (Group I) and no other treatment; a control group that received a high cholesterol (HC) diet for 8 weeks (group II) with sham saline injections; and a third group (III) that received HC diet for 8 weeks and VasoCare treatment initiated after four weeks of HC feeding. Atherosclerotic area (AA), relative to total aortic area (TA), was assessed after 8 weeks of HC feeding by oil red O staining, and cross sectional plaque area at the level of the aortic valve leaflets was determined by quantitative morphometry. HC mice exhibited substantial aortic lipid deposition which was profoundly reduced in the VasoCare treated animals (AA/TA ratios in group II: 0.32+/-0.15 vs. group III: 0.17+/-0.06; P<0.05). This was associated with a significant decrease in cross sectional area of plaque in the aortic sinuses. VasoCare therapy also reduced the xanthoma formation and limb swelling characteristic of this animal model. However, cholesterol levels, measured by an enzymatic assay, showed similar marked increases in total serum cholesterol (CHO) in the animals receiving HC diet alone and those receiving the HC diet and VasoCare treatment [group I: 5.4+/-0.8 mM, group II: 46.7+/-3.6 mM, and group III: 44.7+/-2.8 mM (P<0.01 vs. group I)]. We conclude that VasoCare treatment inhibits progression of atherosclerotic lesions in a murine model of human familial hypercholesterolemia by a mechanism independent of cholesterol lowering.

Topics: Actins; Animals; Antibody Specificity; Aortic Valve; Cholesterol, Dietary; Cholesterol, LDL; Coronary Artery Disease; Disease Models, Animal; Disease Progression; Endothelin-1; Hyperlipidemias; Immunohistochemistry; Immunotherapy; Lipid Metabolism; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Cardiovascular; Muscle, Smooth, Vascular; Pilot Projects; Receptors, LDL; T-Lymphocytes; Treatment Outcome; Xanthomatosis

To study the protective effect of Xinhe granule (XHG) on vascular endothelial damage in rats fed with high lipid diet.. Model of vascular endothelial damage was formed by feeding high lipid diet in rats. The model animal were divided into high dosage XHG group, low dosage XHG group, composite Salvia dripping pellet group and model control group, and a blank (normal) control group was also set up. The degree of endothelial damage and positive cell count of synthesizing and secreting endothelin (ET-1) and intercellular adhesion molecule-1 (ICAM-1) were determined by endothelial cell spreading technique and immunohistochemical technique quantitatively.. Comparison of the degree on vascular endothelial damage and endothelial secreting ICAM-1 and ET-1 showed model control group > composite Salvia dripping pellet group > low dosage XHG group > high dosage XHG group > blank control group. XHG did not show obvious lowering action on blood lipid.. XHG could inhibit the endothelial expressed ICAM-1 and ET-1 in hyperlipidemia rats, thus displaying the protective effect on vascular endothelium.

Topics: Animals; Cholesterol, Dietary; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Hyperlipidemias; Intercellular Adhesion Molecule-1; Male; Phytotherapy; Protective Agents; Random Allocation; Rats; Rats, Wistar

The development and progression of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits is associated with increases in inducible nitric oxide synthase (NOS2) and endothelin-1 (ET-1) immunoreactivity. In contrast, there is a reduction of immunoreactivity for neuronal NOS (NOS1) in aortic endothelial cells, but no change in endothelial NOS (NOS3) immunoreactivity. However, subendothelial macrophages and smooth muscle showed a different pattern of immunoreactivity of NADPH-diaphorase (NADPH-d), NOS2, ET-1, and NOS1. The lipid-rich macrophages in the intima were positively labeled for NADPH-d, NOS1, NOS2, NOS3, and ET-1. Smooth muscle cells in the subendothelium and the medial layers of the vascular wall were also positive for these markers. These results are consistent with the reduction of endothelium-dependent vasorelaxation that is known to occur during the development and progression of atherosclerosis in familial hypercholesterolemia. The data suggest a key role for vasoactive substances in the development of atherosclerosis.

Topics: Aging; Animals; Animals, Newborn; Aorta, Thoracic; Arteriosclerosis; Cytoplasm; Dihydrolipoamide Dehydrogenase; Endoplasmic Reticulum; Endothelin-1; Hyperlipidemias; Macrophages; Male; Microscopy, Immunoelectron; Mitochondria, Muscle; Muscle Development; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rabbits; Tunica Intima

The aim of this study was to investigate vascular endothelin-converting enzyme activity and the tissue level of endothelin-1 in the aorta related to atherosclerotic lesions in high cholesterol diet-fed rabbits. Rabbits were fed two atherogenic diets, 0.5% and 1.5% cholesterol, and a normal diet for 16 weeks. Vascular endothelin-converting enzyme activity in the aortic arch and thoracic aorta was significantly increased (2.0-4.4 times) by the atherogenic diet as compared with the normal diet group as well as the levels of lipids and lipid peroxide in plasma were significantly increased. Tissue endothelin-1 levels in both aortas were also elevated (2.3-6.8 times), corresponding well to the increased tissue enzyme activity. In contrast, plasma endothelin-1 levels increased only in the 1.5% cholesterol diet group (2.7 times). These results indicate that the endothelin-converting enzyme activity and the corresponding endothelin-1 level in the vascular walls increase in association with the development of atherosclerotic lesions.

Topics: Animals; Arteriosclerosis; Aspartic Acid Endopeptidases; Blood Vessels; Endothelin-1; Endothelin-Converting Enzymes; Hyperlipidemias; Isoenzymes; Lipid Peroxides; Lipids; Male; Metalloendopeptidases; Oxidative Stress; Rabbits

The damage of endothelial integrity is an important step in the atherogenic process. To evaluate the role of circulating endothelin-1 (ET-1) in Type 1 diabetes mellitus (T1DM), plasma ET-1 levels were evaluated in T1DM patients either with (n=9) or without hyperlipidaemia (n=11), or with (n=9) and without (n=11) late diabetic complications, in non-diabetic hyperlipidaemic patients (n=17) and in healthy volunteers. Groups were matched for age, sex and body mass index.. Serum total cholesterol and apolipoprotein B were significantly higher in the diabetic group (p<0.05). Plasma ET-1 level was similar in controls and in non-diabetic hyperlipidaemic subjects (5.77+/-1.74 ng/l vs 4.97+/-1.58 ng/l); however, diabetic hyperlipidaemic patients had a significantly higher plasma ET-1 concentration compared to control subjects (6.67+/-2.44 ng/l vs 4.97+/-1.58 ng/l, p<0.05). Diabetic patients with vascular complications had a significantly higher plasma ET-1 concentration than found in diabetic patients without complications (6.99+/-2.17 ng/l vs 4.74+/-1.27 ng/l, p<0.01) and in controls (6.99+/-2.17 ng/l vs 4.97+/ 1.58 ng/l, p<0.01). Patients with diabetic complications also had a significantly higher apolipoprotein B level compared to healthy controls (0.94+/-0.37 g/l vs 0.66+/-0.12 g/l, p<0.005).. The susceptibility of T1DM patients to the development of atherosclerosis might be attributed to the relationship between elevated lipid levels and ET-1.

Topics: Adolescent; Adult; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Triglycerides

Endothelial markers endothelin 1 (ET-1) and von Willebrand factor (vWF) were assessed in patients with type 2 diabetes and dyslipidemia and in patients with hypercholesterolemia.. In this case-control study, plasma ET-and vWF levels were measured by enzyme-linked immunosorbent assay in 35 normoalbuminuric type 2 diabetic patients with dyslipidemia (56+/-5 years), in 21 nondiabetic patients with hypercholesterolemia (52+/-7 years), and in 19 healthy control subjects (45+/-4 years). All of the individuals were normotensive and nonsmokers. Urinary albumin was measured by immunoturbidimetry.. ET-1 levels were higher (P<0.0001) in type 2 diabetic dyslipidemic patients (1.62+/-0.73 pg/ml) than in both nondiabetic hypercholesterolemic patients (0.91+/-0.73 pg/ml) and control subjects (0.69+/-0.25 pg/ml). vWF levels were significantly increased (P = 0.02) in type 2 diabetic (185.49+/-72.1%) and hypercholesterolemic (163.29+/-50.7%) patients compared with control subjects (129.70+/-35.2%). In the multiple linear regression analysis. ET-1 was significantly associated (adjusted r2 = 0.42) with serum triglyceride levels (P<0.001), age (P<0.01), insulin sensitivity index (P<0.02), and albuminuria levels (P<0.04). vWF levels were associated (adjusted r2 = 0.22) with albuminuria (P<0.001), fibrinogen levels (P<0.02), and BMI (P<0.03).. Compared with hypercholesterolemic patients, type 2 diabetic patients with dyslipidemia have increased levels of ET-1 and vWF which may indicate more pronounced endothelial injury. These findings appear to be related to components of the insulin resistance syndrome.

Topics: Albuminuria; Blood Pressure; Case-Control Studies; Diabetes Mellitus, Type 2; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Lipoproteins; Male; Middle Aged; Reference Values; Triglycerides; von Willebrand Factor

To observe the changes of some neuropeptides and the effect of Fusheng powder (FSP) on neuropeptides in rat's brains in a stable cerebral ischemia and reperfusion (I/L) model.. The models of rat's brain injured were established by repeated cerebral I/R in rats with hyperlipidemia. Radioimmunoassay (RIA) was performed to determine the level of neuropeptides.. After 1 day of I/R, compared with the control group, the contents of endothelin-1 (ET-1), calcitonin gene related peptide (CGRP) and neuropeptide Y (NPY) in the model animals were significantly increased by 24.3%, 33.7% and 51.86% respectively, while the level of somatostatin (SS) decreased by 37.86% (all P < 0.01). Meanwhile after FSP treatment, the contents of neuropeptides were alleviated respectively (P < 0.05, P < 0.01). Apart from the ET, the releases of CGRP, NPY and SS were all recovered in different degree after 7 days of I/R.. There were obvious imbalance of neuropeptides in rat's brains after cerebral I/R and the FSP might antagonize ischemic injury of brain through modulating neuropeptides, which may be one of the therapeutical mechanism in treating cerebral vascular diseases with FSP.

Topics: Animals; Brain; Brain Ischemia; Calcitonin Gene-Related Peptide; Drugs, Chinese Herbal; Endothelin-1; Hyperlipidemias; Male; Neuropeptide Y; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury

This study aimed to identify those factors in the non-pregnant state that distinguished women who developed pre-eclampsia from those who had normotensive pregnancies.. This was a retrospective analysis of anthropometry, blood pressure, biochemical and haematological variables in 62 women with pre-eclampsia and 84 normotensive pregnant women who took part in studies of the pathophysiology of pre-eclampsia. Pregnant volunteers were seen, after admission to hospital or in the outpatient clinic, and followed-up at 6 weeks and 6 months post-partum in the outpatient clinic or their home. Participants Proteinuric pre-eclampsia was defined as blood pressure > or = 140/90 mmHg with proteinuria of at least 300 mg/24 h after 20 weeks gestation, in women with no history of hypertension and whose blood pressure returned to normal levels by 6 months post-partum. Normotensive pregnancy was defined as blood pressure < 130/90 mmHg without proteinuria.. The primary outcome measures were blood pressure, body mass index (BMI), triglycerides, total cholesterol, low density lipoprotein (LDL) and high density lipoprotein cholesterol and markers of severity of pre-eclampsia.. Regardless of parity, women with pre-eclampsia had elevated BMI before, during and after pregnancy compared with women who had normotensive pregnancies. Triglycerides were significantly elevated in women who had pre-eclampsia both before and after delivery, while total and LDL cholesterol were elevated significantly at both visits after delivery. Systolic and diastolic blood pressure, which by definition were elevated antepartum in women with pre-eclampsia, remained higher at post-partum visits compared with women who had normotensive pregnancies. Women with pre-eclampsia reported a greatly increased frequency of both maternal hypertension and pre-eclampsia. Markers of severity of pre-eclampsia, which normalized by 6 months postpartum, included plasma creatinine, uric acid, albumin, endothelin 1 and urinary protein, 2,3, dinor-6-keto-PGF1alpha, blood platelet and neutrophil counts.. The relative elevation of blood pressure, BMI and lipids in the non-pregnant state are features of the metabolic syndrome and may be important sensitizing factors contributing to the pathogenesis of pre-eclampsia. A familial predisposition to pre-eclampsia may operate partly through these mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Body Mass Index; Causality; Creatinine; Endothelin-1; Female; Heart Rate; Humans; Hyperlipidemias; Hypertension; Lipids; Parity; Pre-Eclampsia; Pregnancy; Retrospective Studies; Serum Albumin; Uric Acid

Reactive oxygen species (ROS) play an important role in the damage of vascular endothelium during atherogenesis and impaired endothelium-dependent vasorelaxation. We have studied the effect of two ROS generators (H2O2 and menadione) and one of the most potent antioxidants (morin) on the double immunofluorescent staining of endothelial cells (EC) from both Watanabe Heritable Hyperlipidemic (WHHL) and New Zealand White (NZW) rabbits in primary cultures using antibodies against endothelin-1 (ET-1), endothelial (eNOS), and inducible nitric oxide synthase (iNOS). In aortic EC from normal rabbits, ROS decreased the immunoreactivity of eNOS and ET-1 and this effect was significantly reversed by morin. In atherosclerotic rabbits, ROS had the same effect on the immunoreactivity of eNOS and ET-1 but also induced the expression of iNOS immunoreactivity. In general, the cells from WHHL rabbits were less sensitive to the protective effects of morin and more sensitive to the effects of ROS. It thus appears that the protective effect of morin may be due to neutralization of ROS and may be considered for the treatment of early stages of atherosclerosis, before macroscopic lesions have occurred.

Topics: Animals; Antioxidants; Aorta; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Flavonoids; Hyperlipidemias; Immunohistochemistry; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rabbits; Reactive Oxygen Species; Vitamin K

We investigated whether endogenous pulmonary big endothelin has arrhythmogenic properties under normal conditions and in heritable hyperlipidemia.. Endothelin (ET), one of the most potent vasoconstrictors, is known to induce ventricular arrhythmias. It is unclear, however, whether its precursor, big endothelin, released from the lung, contributes to arrhythmogenesis.. In a lung-heart model in which a Langendorff heart is serially perfused with the effluent from the isolated lung of the same animal, we evaluated arrhythmias in control and in Watanabe heritable hyperlipidemic (WHHL) rabbits.. In both controls (n=12) and WHHL (n=8), serial perfusion evoked a decrease in coronary flow (controls, -11+/-3%; WHHL, -25+/-6%) and a fourfold increase of ventricular extrasystoles (VES) (controls, 40.7+/-8; WHHL, 40.2+/-5 VES/40 min, p < 0.05). However, WHHL developed more and longer nonsustained ventricular tachycardias (VT) compared with controls (incidence, 1.38+/-1.1 vs. 0.33+/-0.5 VT/40 min, p < 0.05; length, 14.36+/-3.1 vs. 7.25+/-1.5 beats/VT, p < 0.05). Arrhythmias were not ischemia-induced because corresponding mechanical flow reduction had no arrhythmogenic effect (n=6 in controls and WHHL). Although vasoconstriction disappeared entirely, arrhythmias were only partly suppressed by ET(A) antagonists (BQ-123, 2 micromol/liter; A-127722, 20 micromol/liter). The ET-converting enzyme inhibitor phosphoramidon (50 micromol/liter) completely suppressed arrhythmias and vasoconstriction. The ET(B) antagonists (IRL-1038, 4 micromol/liter; IRL-1025, 5 micromol/liter) had no effect (n=6).. Endogenous pulmonary big ET produces arrhythmogenic effects that are aggravated in heritable hyperlipidemia. These effects, requiring coronary conversion of big ET into ET, are partly ET(A)-mediated and ET(B)-independent.

Topics: Animals; Aspartic Acid Endopeptidases; Cardiac Complexes, Premature; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Glycopeptides; Hyperlipidemias; In Vitro Techniques; Male; Metalloendopeptidases; Myocardium; Perfusion; Protease Inhibitors; Protein Precursors; Rabbits; Tachycardia, Ventricular

Circulating endothelin-1 concentration was evaluated in 93 lean patients with essential hypertension, of whom 16 had impaired glucose tolerance and hyperlipidaemia, 25 had impaired glucose tolerance, 28 had hyperlipidaemia and 24 had no metabolic abnormalities; we also studied 22 control subjects. All groups were age- and sex-matched. Plasma endothelin-1 levels were higher (p < 0.05) in hypertensive patients with impaired glucose tolerance and hyperlipidaemia than in the remaining groups and were directly correlated with fasting insulin levels (r = 0.506, p = 0.045). Therefore, circulating endothelin-1 concentrations are elevated in hypertensive patients with a high-risk profile due to the presence of metabolic abnormalities, and might favour the development of vascular damage.

Topics: Cohort Studies; Endothelin-1; Fasting; Female; Glucose Intolerance; Humans; Hyperlipidemias; Hypertension; Insulin; Male; Metabolic Diseases; Middle Aged; Risk Factors