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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin (ET) is a novel vasoactive peptide occurring in 3 isoforms (ET1, ET2, ET3) in humans. Derived from vascular endothelium cells, ET arises from a precursor peptide and exerts diverse actions through specific receptors. ET possess a wide spectrum of activities: a potent vasoconstrictor activity but also contraction of nonvascular smooth muscles (air-way, intestinal, urinary) or mitogenic actions, renal and endocrine effects. The physiological and/or physiopathological roles of endothelin is still unclear, but ET may play a part in the genesis of some vascular diseases as atherosclerosis, forms of hypertension or may be implicated in the pathogenesis of vasospasm.
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PMID:[Endothelin. A new class of vasoactive peptides]. 152 95

We have investigated whether any of the three isoforms of endothelin (ET) ET-1, ET-2 and ET-3 or the structurally similar peptide sarafotoxin S6b is mitogenic on its own for rat vascular smooth muscle cells in culture. DNA synthesis was determined by a peroxidase-linked double antibody technique to detect bromodeoxyuridine incorporation into the nucleus and stained nuclei were counted by image analysis. None of the ET peptides or sarafotoxin S6b (up to 100 nM) was capable of initiating DNA synthesis in the absence of platelet derived growth factor (PDGF) or fetal calf serum. All the peptides potentiated the mitogenic effect of low concentrations of PDGF. ET-1 and ET-2 (10 nM) caused a 2-fold increase in the number of stained nuclei induced by 5 nM and 10 nM PDGF, whereas ET-3 and sarafotoxin S6b were less potent. These findings demonstrate that ET is a co-mitogen for rat vascular smooth muscle cells. The release of ET at sites of endothelial injury may therefore enhance the mitogenic action of locally acting PDGF on vascular smooth muscle cells and potentiate the proliferative response.
Atherosclerosis 1990 Dec
PMID:The endothelin peptides ET-1, ET-2, ET-3 and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells. 210 88

Endothelin, originally identified as a vasoconstrictive peptide derived from vascular endothelial cells, is now known to exert diverse biological effects on a wide variety of tissues and cell types through its own receptor(s). One of the outstanding actions of endothelin is a cell growth promoting activity which is demonstrated in several cell types including cultured vascular smooth muscle cells, fibroblasts, glomerular mesangial cells and osteoblasts. The mitogenic effect is likely mediated by stimulation of phospholipase C via receptor-G-protein coupling, and subsequent activation of protein kinase C. The effect of endothelin may contribute to the cell-proliferation response under various physiological and pathological conditions, such as wound healing and development of atherosclerosis and glomerulonephritis. Recently, three distinct endothelin-related genes have been cloned, suggesting that mammals, including humans, produce three members of this peptide family, endothelin (ET)-1 (the 'classical' endothelin), ET-2 and ET-3, which may act on distinct subtypes of endothelin receptor to induce different cellular responses.
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PMID:Endothelin, its diverse biological activities and mechanisms of action. 249 Dec 62

Review article informs about the physiological and pathophysiological effects of the most potent vasoconstrictor agent endothelin (ET). This vasoactive polypeptide (21-aminoacid) has three izoforms (ET-1, ET-2, ET-3) and participates on regulation of the vascular tone and on remodelling of the vascular and myocardial wall. Article is focused on the effects of endothelins on the cardiovascular system, kidney and the central nervous system with respect to their expected role in the initiation and sustaining of disorders and diseases accompanied by the local and general vasconstriction. Findings concerning the role of endothelins in the pathogenesis of arterial hypertension, myocardial infarction, congestive heart failure, atherosclerosis, shock conditions, renal failure, and vasospasm following the subarachnoidhem orrage are discussed.
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PMID:[Endothelin--a cardiovascular regulatory peptide. II. Outline of its pathophysiologic activity]. 758 20

Endothelins (ET) are a family of peptides with potent biological properties. Endothelial cells produce exclusively ET-1 while other tissues produce ET-2 and ET-3. The production of ET requires an increase in intracellular Ca2+. This increase can be induced by physical chemicals (i.e. hypoxia) or receptor-operated stimuli (i.e. thrombin, angiotensin II, arginine vasopressin, transforming growth factor beta 1, interleukin-1). Most of ET is released abluminally towards vascular smooth muscle and less luminally. The main vascular effect of ET are vasodilation (transient), profound and sustained vasoconstriction as well as proliferation of vascular smooth muscle. These biological effects are mediated by distinct receptors. Three ET receptors have been cloned, i.e. ETA-, ETB- and ETC-receptors. In vascular tissue ETA-receptors are expressed on vascular smooth muscle and responsible for vasoconstriction. ETB-receptors are expressed on endothelium and linked to nitric oxide and/or prostacyclin release. Activation of these receptors explains the transient vasodilation with intraluminal application of ET. Vascular smooth muscle cells can express ETB-receptors which contribute to ET-induced vasoconstriction particularly at lower concentrations. The role of the recently cloned ETC-receptor in the vasculature is still uncertain. ET production is increased (as judged from circulating plasma levels) in vascular disease and atherosclerosis in particular, in myocardial infarction and heart failure, pulmonary hypertension and renal disease. ET production is increased in arterial hypertension remains controversial. Non-peptidic ET antagonists have been developed which either block ETA- receptors or ETA- and ETB-receptors simultaneously. The advantage of ETA-receptors is that they leave the endothelium-dependent vasodilation to ET (via ETB-receptor) intact. However, ETB-mediated contraction remains unaffected by these antagonists. In contrast ETA-/ETB-antagonists fully prevent ET-induced vasoconstriction, however, they also inhibit the endothelial effects of the peptide. ET antagonists interfere with the effects of ET in isolated vascular tissue (including that obtained from humans) as well as in vivo. In humans, ETA as well as ETA-/ETB-antagonists inhibit endothelin-induced vasoconstriction. Hence in summary ET are a family of potent peptides with profound effects in the vasculature. Several studies suggest a role of ET in cardiovascular disease. The newly developed ET-antagonists are potent and selective tools to delineate the (patho-)physiological roles of ET and may become a new class of cardiovascular drugs.
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PMID:Endothelin and endothelin antagonists: pharmacology and clinical implications. 771 86

1. It is generally accepted that endothelial cells secrete endothelin (ET) to the underlying media which mediates the contractile effects of ET. However, there is some evidence that animal vascular smooth muscle cells (VSMCs) also secrete ET. We cultured VSMCs from human vessels representative of a number of different vascular beds to determine whether human VSMCs endogenously secrete ET. 2. VSMCs explanted from adult arterial vessels secrete picomolar quantities of immunoreactive mature ET: coronary artery 226.6 +/- 58.8 pM/10(6) cells (n = 7), thoracic aorta 169.5 +/- 105.4 pM/10(6) cells (n = 3), left internal mammary artery 102.4 +/- 23.1 pM/10(6) cells (n = 3) and saphenous vein 69.4 +/- 19.9 pM/10(6) cells (n = 3), as well as from umbilical vein (HUVSMCs) 38.3 +/- 4.3 pM/10(6) cells (n = 3). Secretion of immunoreactive big ET-1 was also detected: coronary artery 249.1 +/- 59.4 pM/10(6) cells (n = 7), thoracic aorta 120.0 +/- 13.4 pM/10(6) cells (n = 3), left internal mammary artery 170.0 +/- 68.2 pM/10(6) cells (n = 3), saphenous vein 105.1 +/- 30.7 pM/10(6) cells (n = 3) and from umbilical vein 146.3 +/- 7.4 pM/10(6) cells (n = 3). Comparable, intracellular levels of immunoreactive big ET-1 and mature ET were also detected in cultured VSMCs. 3. Since enzyme-dispersed VSMCs are thought to be more differentiated and more closely resemble their in vivo counterparts, and these enzyme-dispersed VSMCs from human umbilical vein (HUVSMCs) also secreted the greatest levels of immunoreactive peptides, they were characterized further. Reverse transcription-polymerase chain reaction assay demonstrated that HUVSMCs express ET-1 mRNA. High performance liquid chromatography coupled to radioimmunoassay revealed that HUVSMCs secrete ET-1 and ET-3, in addition to big ET-1. However, levels of ET are not altered by 100 AM phosphoramidon,an inhibitor of metalloproteases or by 100 microM pepstatin A, an aspartyl protease inhibitor.4. In concordance, KD and Bmax values for [125I]-ET-l saturation binding are not altered in HUVSMC cultures incubated for 24 h with 100 microM phosphoramidon (431 +/- 218 PM and 31.1 +/- 12.7 fmol mg-1;mean =/- s.e.mean, n = 3) or 100 microM pepstatin A (381 +/- 169PM and 19.9 +/- 7.8 fmol mg-1, n = 3) as compared to controls (355 +/- 99 pM and 33.3 +/- 9.3 fmol mg-1; n = 3). This observation indicates the absence of an autocrine 'unmasking' effect for ET receptors.5. HUVSMCs synthesize and secrete immunoreactive ET-1, ET-3 and big ET-1, and possess intracellular levels of immunoreactive mature ET and big ET-1. There is some evidence of common cellular mechanisms between growth factors and vasoconstrictor peptides, suggesting a close relationship between contraction and proliferation. Since the development of various vascular pathologies such as atherosclerosis, hypertension and after vessel injury has been attributed to alterations in the normal growth pattern of VSMCs, the role of ET in these diseases may be of significance.
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PMID:Secretion of endothelin-1 and endothelin-3 by human cultured vascular smooth muscle cells. 788 55

Endothelin (ET) 1 is a powerful vasoconstrictor of coronary arteries and may play a role in coronary spasm, atherosclerosis, and myocardial infarction. Previous studies have demonstrated that intracoronary ET caused marked vasoconstriction of the coronary circulation; however, it remains unclear which ET receptor types are present and which of these receptors mediate this vasoconstriction. To characterize the ET receptors present in dog coronary arteries, competition binding assays with radiolabeled ET-1 using ET-1, ET-3, ETA receptor antagonist BQ-123, and sarafotoxin S6c were performed. Three binding sites were apparent in the left circumflex coronary artery: an ETA receptor, a high-affinity ETB receptor, and a lower-affinity ETB receptor. To investigate the in vivo effects of ETB receptor stimulation, intracoronary sarafotoxin S6c, a highly selective ETB agonist, was administered in anesthetized open-chest dogs in a constant-pressure coronary artery perfusion model. Sarafotoxin S6c doses of 0.1 and 0.3 microgram caused a transient pronounced decrease in coronary resistance. Doses of 1.0 and 3.0 micrograms caused marked decreases in coronary diameter and blood flow, as well as myocardial segmental shortening. These effects of sarafotoxin S6c were not inhibited by constant infusion of BQ-123. The present study demonstrates the presence of ETB receptors in the canine coronary circulation that can mediate both vasodilation and vasoconstriction. These findings have important implications for an understanding of the pathophysiological function of ET in the coronary vasculature and for the development of therapeutically effective ET antagonists.
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PMID:Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries. 826 83

An endothelium-derived vasoactive peptide, endothelin (ET)-1, is a potent constrictor and mitogen for vascular smooth muscle cells (VSMC). To determine whether vascular ET receptor subtypes phenotypically change during in vitro culture conditions, we studied the expression of ET receptor subtypes, ET-induced phosphoinositide breakdown, and DNA synthesis in cultured rat VSMCs during serial passages. Binding studies using [125I]ET-1 as a radioligand revealed that the early passage (10th-15th) VSMCs possess predominantly ETA receptors, whereas the late passage (30th-35th) VSMCs possess predominantly ETB receptors in addition to ETA receptors. Northern blot analysis using cDNAs for rat ETA and ETB receptors as probes also demonstrated the predominant expression of ETA receptor mRNA in the early passage and ETB receptor mRNA in the late passage, whereas only ETA receptor mRNA was expressed in intact medium of rat aorta. ET-1 had a greater effect than ET-3 in stimulating inositol 1,4,5-trisphosphate formation, whereas ET-1 and ET-3 almost equipotently stimulated insitol 1,4,5-trisphosphate formation in the late passage VSMC even in the presence of an ETA receptor antagonist. ET-1-induced DNA synthesis was almost completely inhibited by an ETA receptor antagonist in the early passage VSMC. In contrast, ET-1, ET-3, and an ETB receptor agonist remarkably stimulated DNA synthesis in the late passage VSMC, which was completely inhibited by a nonselective ET receptor antagonist, but not by an ETA receptor antagonist. Our data provide the first evidence that a phenotypic change in VSMC in culture is concomitantly associated with a change in the ET receptor subtype that potentiates mitogenic activity and suggest that switching the ET receptor subtype from ETA to ETB during phenotypic change may in part contribute to the development of vascular lesions, such as in atherosclerosis.
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PMID:Phenotypic change of endothelin receptor subtype in cultured rat vascular smooth muscle cells. 827 37

Endothelins are produced by endothelial and epithelial cells, macrophages, fibroblasts, and many other types of cells. Their receptors are present in numerous cells, including smooth muscle cells, myocytes, and fibroblasts. Evidence now suggests that the three isoforms of endothelins (ET-1 and the other two related isopeptides, ET-2 and ET-3) regulate growth in several of these cells. Endothelin-1 influences DNA synthesis, the expression of protooncogenes, cell proliferation, and hypertrophy. The participation of ET in mitogenesis involves activation of multiple transduction pathways, such as the production of second messengers, the release of intracellular pools of calcium, and influx of extracellular calcium. Moreover, ET-1 acts in synergism with various factors, such as EGF, PDGF, bFGF, TGFs, insulin, etc., to potentiate cellular transformation or replication. Several of these factors may in turn stimulate the synthesis and/or the release of endothelins. The production and release of endothelins are also increased in acute and chronic pathological processes, e.g., atherosclerosis, postangioplastic restenosis, hypertension, and carcinogenesis. It is postulated that endothelins act in a paracrine/autocrine manner in growth regulation and play an important role mediating vascular remodeling in some cardiovascular diseases. The present review analyses the implication of endothelins (ET-1, -2, and -3) in physiopathology related to their growth regulatory properties.
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PMID:Growth regulatory properties of endothelins. 848 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


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