Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) has been implicated in atherosclerosis, hypertension, and restenosis, all of which involve abnormal vascular smooth muscle cell function and/or proliferation. We have previously established that human umbilical vein smooth-muscle cells (HUVSMCs) can secrete ET, (1) whereas A10 cells do not. Therefore, we investigated the effect of exogenously added ET-1 on receptor density (Bmax) of A10 cells. Compared to controls, A10s exposed to ET-1 for 48 h showed a significant decrease (79%) in receptor density, with no change in affinity. In contrast, incubation of A10s with the ETA-selective antagonist FR139317 (at a concentration blocking 99% of ET receptors) for 48 h caused a significant increase (245%) in Bmax and a significant decrease in affinity. These changes persisted after coincubation with both ET-1 and FR139317, indicating that the antagonist was able to block the effects of exogenous ET-1. In concordance, incubation of HUVSMCs with FR139317 for 24 h caused a significant increase in receptor density (> 1,000%), although there was no change in levels of immunoreactive (IR) ET or big ET-1. However, after a shorter incubation (1 h), there was no change in Bmax but IR ET was significantly elevated by 878%, whereas IR big ET-1 was depressed by 86% compared to controls. Incubation of HUVSMCs with FR139317 did not affect receptor affinity. Our observations suggest that whereas the application of exogenous ET to A10s causes downregulation of ET receptor expression, the ETA antagonist FR139317 causes upregulation of ET receptor expression in VSMCs regardless of their ability to secrete ET. In VSMCs capable of secreting ET, acute antagonism of the ETA receptor causes a significant increase in IR-ET and a decrease of IR-big ET-1 levels.
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PMID:Regulation of endothelin receptor expression in vascular smooth-muscle cells. 858 11

It has been suggested that the potent vasoconstrictor and proliferative agent endothelin (ET) may contribute to the development and effects of atherosclerosis. The aim of this study was to use autoradiography to examine the distribution of ET receptors in human coronary artery with a range of pre-atherosclerotic and atherosclerotic lesions. ET-1 receptors in epicardial coronary artery sections were visualized according to the binding of [125I]ET-1 (100 pM), the ETA-selective radioligand [125I]PD151242 (100 pM), and the ETB-selective [125I]BQ3020 (300 pM). Dense [125I]ET-1 binding was demonstrated in the smooth muscle of the media of all arteries studied and ETA receptors, defined by [125I]PD151242 binding, predominated. Intense [125I]BQ3020 binding to ETB receptors was apparent on perivascular structures, such as adventitial lymphatics. In contrast, ET receptors were absent in neointimal smooth muscle. In regions of recanalized organized thrombus, microautoradiography revealed ETA receptors on the smooth muscle of new vessels. Discrete clusters of ETB receptors were detected in sections through the atherosclerotic arterial wall. A similar pattern of staining for von Willebrand factor was seen in adjacent sections. This suggests that ETB receptors are present on endothelial cells of neovascularization, penetrating the diseased media.
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PMID:Distribution of endothelin receptors in atherosclerotic human coronary arteries. 858 38

Endothelin-1 (ET-1) enhances the biosynthesis of interleukin-6 (IL-6) in endothelial cells and bone marrow-derived stromal cells of the rat. This study investigates (i) whether ET-1 stimulates the formation of tumour necrosis factor alpha (TNF alpha) or interferon-gamma (IFN gamma) in cultured macrophages or in the anaesthetized rat. Incubation of J774.2 macrophages with ET-1 (0.001-1 microM) caused a concentration- and time-dependent increase in the concentration of TNF alpha, but not of IFN gamma, in the culture medium. The increase in TNF alpha caused by stimulation of J774.2 macrophages was abolished by pretreatment of cells with (i) the protein synthesis inhibitor cycloheximide, (ii) with the selective ETA-receptor antagonists BQ-123 or BQ-485 (but not the selective ETB-receptor antagonist BQ-788), (iii) the tyrosine kinase inhibitors genistein or tyrphostin AG126, or (iv) with the glucocorticoid, dexamethasone. The inhibition by dexamethasone of the formation of TNF alpha by cells activated with ET-1 is not due to the formation of lipocortin-1 (LC1), as it was not reduced by a monoclonal antibody against LC1. Systemic administration (i.v.) of ET-1 (1 nmol.kg-1) to anaesthetized rats caused a rapid and sustained (maximum: 45 min; return to baseline: within 180 min) rise in the plasma levels of TNF alpha. This is the first demonstration that ET-1 can release proinflammatory cytokines in vitro and in vivo. The generation of TNF alpha caused by ET-1 involves (in sequence) the (i) activation of ETA-receptors, (ii) activation of tyrosine kinase resulting in the phosphorylation of intracellular proteins, (iii) the activation of, hitherto, unknown transcription factors, finally resulting in (iv) transcription and translation of the TNF alpha gene. The generation of TNF alpha by cells activated with ET-1 points to a pro-inflammatory role of ET-1 in diseases associated with local (e.g. atherosclerosis, heart failure) or systemic inflammation (circulatory shock), which are associated with high ET-1 plasma levels.
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PMID:Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone. 944 16

The migration of coronary artery medial smooth-muscle cells (SMCs) is one of the key events in the process of intimal thickening in coronary atherosclerotic lesions. The objectives of the present study were to determine whether any of the three isoforms of endothelin (ET), ET-1, ET-2, and ET-3, or an intermediate form of ET, big ET-1, induces migration of human coronary artery SMCs, and to investigate the possible interaction of ET peptides and well-known migration-stimulatory factors, platelet-derived growth factor (PDGF)-BB and angiotensin II (Ang II), on SMC migration by the Boyden's chamber method. None of the ET peptides alone induced SMC migration between 10(-9) and 10(-7) mol/L. In contrast, ET-1 and ET-2 significantly induced SMC migration in the presence of low concentrations of PDGF-BB (0.5 ng/mL) or Ang II (10(-9) mol/L), although ET-3 was less active (ET-1 = ET-2 > ET-3). In contrast, big ET-1 was without significant activity on PDGF-BB-or Ang II-induced SMC migration. The potentiation of SMC migration by ET peptides was clearly inhibited by the ETA receptor antagonist BG-123 in a concentration-dependent manner. These results suggest that the ET family of peptides, especially ET-1 and ET-2, can induce human coronary artery SMC migration in combination with PDGF-BB or Ang II, probably via ETA receptors. Taken together with the finding that the concentrations of ET, PDGF-BB and Ang II are locally increased at sites of endothelial injury, this indicates that ET may be an initial stimulus for human coronary artery medial SMC recruitment during coronary atherosclerosis, possibly in combination with PDGF-BB or Ang II.
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PMID:Effect of the endothelin family of peptides on human coronary artery smooth-muscle cell migration. 959 8

The endothelium regulates vascular function by releasing the vasodilator autacoid nitric oxide (NO) and the vasoconstrictor peptide endothelin-1 (ET-1). Impaired activity of NO as well as excessive activity of ET-1 have been demonstrated in hypercholesterolemia and atherosclerosis. Because dietary L-arginine can restore NO function and improve abnormal endothelium-dependent relaxation in hypercholesterolemic rabbits, we examined the effects of dietary supplementation with L-arginine in cholesterol-fed rabbits on endothelium-dependent vascular relaxation and ET-1-induced vascular contraction, as well as the systemic synthesis of ET-1. Rabbits were initially fed a diet enriched with 1% cholesterol for 4 weeks, followed by 0.5% cholesterol alone or supplemented with 2% L-arginine in drinking water during the next 12 weeks. Cholesterol feeding impaired endothelium-dependent relaxation of rabbit aortic rings ex vivo and increased urinary immunoreactive ET-1 excretion, along with decreased urinary nitrate excretion, an index of NO production. L-Arginine partially restored endothelium-dependent relaxation in parallel to increased urinary nitrate excretion and decreased urinary immunoreactive ET-1 excretion. Selective inhibition of ET-A receptors with BQ123 partially restored endothelium-dependent relaxation in hypercholesterolemic rabbits but had no effect on arterial rings from rabbits supplemented with L-arginine or from control animals. The contractile vascular response of aortic rings to exogenous ET-1 was increased in rabbits fed a high-cholesterol diet; this enhanced contractility to ET-1 was completely reversed by L-arginine. These data suggest that L-arginine restores endothelial function and normalizes the synthesis and vasoconstrictor response to ET-1 in hypercholesterolemia.
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PMID:Dietary L-arginine normalizes endothelin-induced vascular contractions in cholesterol-fed rabbits. 970 Sep 94

This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content (P < 0.0001) and binding capacity for ETA receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 +/- 3 vs. 99 +/- 2%, P < 0.0001) and plasma nitrate were reduced (57.9 +/- 4 vs. 93 +/- 10 micromol/liter, P < 0.01). Treatment with the ETA receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 +/- 3 to 93 +/- 2%, P < 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 +/- 4 to 80 +/- 8.3 micromol/liter, P < 0.05). Chronic ETA receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ETA receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ETA receptor blockade may have therapeutic potential in patients with atherosclerosis.
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PMID:Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. 982 6

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.
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PMID:Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. 1046 Jun 93

The potent vasoconstrictor peptide endothelin-1 (ET-1) has been implicated in the pathophysiology of atherosclerosis and its complications. Since inflammation of the vessel wall is a hallmark of atherosclerosis, the purpose of the present study was to investigate the influence of ET-1 on cytokine production in human vascular smooth muscle cells (SMC) as a marker of inflammatory cell activation. ET-1 (100 pM - 1 microM) stimulated interleukin-6 (IL-6) secretion from human vascular SMC in a concentration-dependent manner. The ET-A-receptor antagonist BQ-123 (10 microM), but not the ET-B-receptor antagonist BQ-788, inhibited IL-6 release. ET-1 also transiently increased IL-6 mRNA compatible with regulation of IL-6 release at the pretranslational level. Electrophoretic mobility shift assays demonstrated time- and concentration-dependent activation of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in ET-1-stimulated human vascular SMC. A decoy oligodeoxynucleotide bearing the NF-kappaB binding site inhibited ET-1-stimulated IL-6 release to a great extent suggesting that this transcription factor plays a key role for cytokine production elicited by ET-1. Moreover, the antioxidant pyrrolidine dithiocarbamate (10 microM) inhibited ET-1-induced IL-6 release indicating involvement of reactive oxygen species in ET-1 signaling. ET-1-stimulated IL-6 secretion was also suppressed by diphenylene iodonium (40 microM), an inhibitor of flavon-containing enzymes such as NADH/NADPH oxidase. The results demonstrate the ability of ET-1 to induce an inflammatory response in human vascular SMC. These observations may contribute to a better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.
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PMID:Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells. 1082 1

Increased evidence has shown that endothelin-1 (ET-1) derived from the arterial cells is involved in the development of atherosclerosis. ET-1 and ET receptors are upregulated in both human and experimental animal atherosclerotic lesions. Plasma ET-1 levels are significantly elevated in hypercholestolemic subjects and cholesterol-fed animals. We hypothesized that plasma lipoproteins such as LDL and HDL retained in the arterial wall can affect ET-1 production and secretion, thereby sustaining vascular functions. Using a two-chamber culture system, we have demonstrated that endothelial cells (ECs) show a polar secretion of ET-1; the majority of ET-1 are secreted toward the basal side of the vessels. Furthermore, we found that LDL enhances whereas HDL inhibits the ET-1 secretion from ECs in a polarized pattern. In order to demonstrate ET receptor distribution in the lesion, we recently studied both human and apoE-KO mice. Our study showed that there is an increased expression of ETB receptors in foamy macrophages in the lesions. More importantly, medial smooth muscle cells (SMCs) beneath the foam cell lesions exhibited a higher intensity of ETB receptor immunoreactivity than those located in foam cell-free areas. In such an area, ET-1 immunoreactivity is also increased. These results suggest that accumulation of foamy macrophages may modulate the shift of ET receptor subtypes from ETA to ETB in SMCs and an enhanced ET system mediated by ETB receptors may play a pivotal role in the progression of atherosclerosis. This notion has been further supported by a recent finding that administration of ET receptor antagonists resulted in a significant reduction of atherosclerosis in apoE-KO mice.
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PMID:Role of endothelin-1 in atherosclerosis. 1086 28

Endothelin (ET) -1 is a potent vasoconstrictor and promitogenic peptide produced by the vascular endothelium. The ET system is activated in atherosclerosis and in most cardiovascular conditions associated with increased vascular tone and remodelling. There are two ET-receptor (ET-R) subtypes: the ETA-Rs mediate smooth muscle vasoconstriction and proliferation, and the more complex ETB-Rs have antagonistic actions - they serve a dual role of clearance and vasodilation in the endothelium, while in smooth muscle cells they also provoke vasoconstriction. Selective ETA-R and nonselective ETA/B-R antagonists are entering the clinical development phase. These agents have shown their effectiveness in the therapy of various models of heart failure, pulmonary hypertension, systemic hypertension and ischemia-reperfusion and in the prevention of restenosis. In patients with congestive heart failure, short term ET-antagonist (ET-R) therapy provides hemodynamic and symptomatic improvement. Because of the dual role of the ETB-R, nonselective antagonists may provide greater or fewer benefits than selective ETA-R antagonists: a lack of direct comparison of the two categories of agents, however, does not allow this distinction at present. In the evaluation of this new class of therapeutic agents, particular attention should be paid to potency and receptor selectivity of a compound, the alterations in ETA-R and ETB-R activity brought on by pathological conditions, the proportions of ETA versus ETB-R of the target system, and finally, the net importance of the possible protective role of the endothelial ETB versus the deleterious effects of the smooth muscle ETB-R.
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PMID:Endothelin receptor antagonists and their developing role in cardiovascular therapeutics. 1093 9


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