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)

We previously found that human chymase cleaves big endothelins at the Tyr31-Gly32 bond and produces 31-amino-acid endothelins, endothelins(1-31). Endothelin-1(1-31) has been isolated from a number of human organs, including the heart and lungs. As endothelin-1 has been shown to play a significant role in the paracrine regulation of cardiovascular functions in humans, it is possible that endothelin-1(1-31) may also exhibit biological activity on human tissues. We previously reported that synthetic endothelin-1(1-31) exhibits a number of physiological actions on cultured cells in vitro. In the present study, we investigated the plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and compared them with those in patients with cardiovascular diseases. Endothelin-1(1-31) and endothelin-1 in human plasma was measured using a sandwich-enzyme-immunoassay system, which was recently described for measurement of endothelin-1(1-31). The plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy volunteers were 19.24 +/- 5.70 and 15.54 +/- 4.45 pg/ml (n = 5), respectively. We also measured plasma concentrations of endothelin-1(1-31) and endothelin-1 before and after surgery in patients with abdominal aortic aneurysms. Before surgery, plasma concentrations of endothelin-1(1-31) and endothelin-1 in these patients were higher than those in healthy individuals. After surgery, both endothelin-1(1-31) and endothelin-1 in plasma decreased to levels similar to those of healthy subjects. This suggests that endothelin-1(1-31) may have similar physiological significance to endothelin-1 in patients with atherosclerosis.
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PMID:Determination of plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and patients with atherosclerosis. 1268 3

Endothelin-1 (ET-1) is a potent vasoconstrictor that increases vascular tone in the resistance vessels of subjects with hypertension. It is unclear whether endogenous ET-1 affects resistance-vessel function equally in patients with other cardiovascular risk factors. Vasoconstriction to ET-1 is mediated principally via the endothelin-A (ETA) receptor on vascular smooth muscle cells. Accordingly, we used an ETA-specific antagonist, BQ-123, to test the hypothesis that endogenous ET-1 increases vascular resistance selectively in subjects with hypertension compared with other risk factors. BQ-123 was infused at 100 nmol/min for 80 minutes into the brachial artery of 10 subjects with hypertension (mean+/-SEM arterial pressure, 106+/-5 mm Hg), 12 subjects with hypercholesterolemia (mean+/-SEM total cholesterol, 7.1+/-0.2 mmol/L), 10 active smokers (mean+/-SEM, 42+/-11 pack-years), and 11 healthy, age-matched individuals. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. BQ-123 dilated resistance arterioles in hypertensive subjects, with FBF's increasing by 46+/-7% from baseline (P<0.001). BQ-123 increased FBF to a lesser extent in hypercholesterolemic (24+/-5%, P<0.001) and healthy (20+/-8%, P=0.007) individuals but did not affect FBF significantly in smokers (10+/-8%, P=0.185). The vasodilator response in hypertensive subjects, but not in hypercholesterolemic patients or smokers, was significantly greater than that in healthy individuals (P=0.012). Endogenous ET-1, acting via the ETA receptor, increases resistance-vessel tone in subjects with hypertension more than in subjects with hypercholesterolemia or in smokers. These results indicate that ET-1 contributes more to the pathophysiology of hypertension than of other risk factors in subjects without overt atherosclerosis.
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PMID:Endothelin-1 and vascular tone in subjects with atherogenic risk factors. 1275 18

Endothelin-1 (ET-1) is a pleiotropic hormone produced primarily by the endothelium. Synthesis of ET-1 is stimulated by the major signals of cardiovascular stress, such as vasoactive agents (angiotensin II, norepinephrine, vasopressin, and bradykinin), cytokines (e.g., tumor necrosis factor alpha and transforming growth factor beta), and other factors, including thrombin and mechanical stress. ET-1 induces vasoconstriction, is proinflammatory, promotes fibrosis, and has mitogenic potential, important factors in the regulation of vascular tone, arterial remodeling, and vascular injury. These effects are mediated via two receptor types, ETA and ETB. The role ET-1 plays in normal cardiovascular homeostasis and in mild essential hypertension in humans is unclear. However, certain groups of essential hypertensive patients may have ET-1-dependent hypertension, including blacks (subjects of African descent), salt-sensitive hypertensives, patients with low renin hypertension, and those with obesity and insulin resistance. ET-1 has also been implicated in severe hypertension, heart failure, atherosclerosis, and pulmonary hypertension. In all of these conditions, plasma immunoreactive ET levels are elevated and tissue ET-1 expression is increased. Accordingly, it is becoming increasingly apparent that ET-1 plays an important role in cardiovascular disease and in some forms of hypertension in humans. Data from clinical trials using combined ETA-ETB receptor blockers have already demonstrated significant blood-pressure-lowering effects. Thus, targeting the endothelin system may have important therapeutic potential in the treatment of hypertension, particularly by contributing to the prevention of target organ damage and the management of cardiovascular disease.
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PMID:Role of endothelin in human hypertension. 1283 65

Endothelin-1 (ET-1) is a potent vasoconstrictor and growth-promoting mediator that is involved in the maintenance of vascular tone within the healthy circulation. However, a pathogenic role has been implicated by its overproduction in a number of cardiovascular diseases, which include pulmonary hypertension, congestive heart failure, atherosclerosis, and coronary vasospasm. ET-1 mRNA expression and peptide production in human vascular smooth muscle cells (HVSMCs) are markedly increased by exposure to tumor necrosis factor-alpha and interferon-gamma. The intracellular signaling mechanism involved in this pathway is not known. Because the transcription factors nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription 1 (STAT1), and interferon regulatory factor-1 (IRF-1) often mediate the effects of cytokines in target cells the aim of this study was to determine whether the production of ET-1 after exposure of HVSMCs to cytokines depends upon synergism between NF-kappaB and STAT1/IRF-1. Immunoblotting showed that cytokine-stimulation of ET-1 release in VSMCs involves nuclear translocation of NF-kappaB and STAT1. Cytokines also induced an increase in IRF-1 protein expression. Antisense oligonucleotides to NF-kappaB, STAT1, and IRF-1 significantly inhibited cytokine induced ET-1 release. In conclusion, NF-kappaB, STAT1, and IRF-1 activation are involved in the stimulation by cytokines of ET-1 release from HVSMCs. However, nuclear run-on assays would provide definitive proof that ET-1 is regulated transcriptionally by cytokines. Because up-regulated production of ET-1 within VSMCs may underlie the causative role of ET-1 in a number of disease states, this finding indicates that NF-kappaB, STAT1, and IRF-1 within HVSMCs could be central to a number of vascular pathologies and that inhibition of this pathway could be of therapeutic benefit.
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PMID:Role for nuclear factor-kappaB and signal transducer and activator of transcription 1/interferon regulatory factor-1 in cytokine-induced endothelin-1 release in human vascular smooth muscle cells. 1450 Jul 49

Endothelin-1 is an endothelium-derived compound that exerts a variety of hemodynamic and structural alterations in the cardiovascular and pulmonary circuits. The endothelin system is activated in an assortment of disorders and disease states, such as systemic hypertension, pulmonary hypertension, atherosclerosis, acute coronary syndromes, and congestive heart failure. The actions of endothelin are mediated by two types of receptors: ETA and ETB, which are widely distributed in the cardiovascular system. The complexity of biophysical effects mediated by these two types of receptors dictates the therapeutic implications, that is, selective (ETA) versus dual (ETA/ ETB) receptor antagonism. Preliminary experimental and clinical studies reveal a role played by endothelin as a pathogenetic substance and, conversely, a possible role for endothelin antagonism in clinical medicine.
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PMID:Possible therapeutic role of endothelin antagonists in cardiovascular disease. 1462 76

Endothelin-1 is a potent vasoconstrictor and exhibits a mitogenic activity on vascular smooth muscle cells (SMCs). Endothelin-converting enzyme (ECE) is the final key enzyme of endothelin-1 processing. We studied the immunolocalization of ECE in human coronary atherosclerotic lesions with different disease stages. Frozen sections of normal coronary arteries with diffuse intimal thickening (n=13) and those of coronary arteries with early (n=10) or advanced atherosclerotic plaques (n=13) were studied. Monoclonal antibodies used were directed against SMCs, macrophages, endothelial cells, and ECE. For the identification of cell types that express ECE, double immunostaining analysis was also used. In normal coronary arteries, ECE immunoreactivity was observed in luminal endothelial cells and medial SMCs. Early atherosclerotic plaques, which consisted predominantly of SMCs, showed enhanced ECE expression in luminal endothelial cells and intimal SMCs. In advanced atherosclerotic plaques, distinct ECE expression was found in accumulated macrophages and in endothelial cells of intraplaque microvessels, while luminal endothelial cells showed relatively weak immunoreactivity for ECE. In conclusion, the present study demonstrates that the major cell types expressing ECE within the plaques are different between early and advanced stages of human coronary atherosclerosis. Enhanced ECE expression and possible endothelin-1 generation may contribute to SMC proliferation and vasoconstriction in early atherosclerotic stages, and may promote plaque destabilization in advanced atherosclerotic stages.
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PMID:Alterations of endothelin-converting enzyme expression in early and advanced stages of human coronary atherosclerosis. 1506 64

Reactive oxygen species (ROS) have been shown to mediate the effects of several growth factors and vasoactive peptides, such as epidermal growth factor, platelet-derived growth factor, and angiotensin II (AII). Endothelin-1 (ET-1) is a vasoactive peptide which also exhibits mitogenic activity in vascular smooth muscle cells (VSMCs), and is believed to contribute to the pathogenesis of vascular abnormalities such as atherosclerosis, hypertension, and restenosis after angioplasty. However, a possible role for ROS generation in mediating the ET-1 response on extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB), and protein tyrosine kinase 2 (Pyk2), key components of the growth-promoting and proliferative signaling pathways, has not been examined in detail. Our aim was to investigate the involvement of ROS in ET-1-mediated activation of ERK1/2, PKB, and Pyk2 in A-10 VSMCs. ET-1 stimulated ERK1/2, PKB, and Pyk2 phosphorylation in a dose- and time-dependent manner. Pretreatment of A-10 VSMCs with diphenyleneiodonium (DPI), an inhibitor of reduced nicotinamide adenine dinucleotide phosphate oxidase, attenuated ET-1-enhanced ERK1/2, PKB, and Pyk2 phosphorylation. In addition, in parallel with an inhibitory effect on the above signaling components, DPI also blocked ET-1-induced protein synthesis. ET-1 was also found to increase ROS production, which was suppressed by DPI treatment. N-Acetylcysteine, a ROS scavenger, exhibited a response similar to that of DPI and inhibited ET-1-stimulated ERK1/2, PKB, and Pyk2 phosphorylation. These results demonstrate that ROS are critical mediators of ET-1-induced signaling events linked to growth-promoting proliferative and hypertrophic pathways in VSMCs.
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PMID:Reactive oxygen species mediate Endothelin-1-induced activation of ERK1/2, PKB, and Pyk2 signaling, as well as protein synthesis, in vascular smooth muscle cells. 1520 92

The role of chronic inflammation in the pathogenesis of the acute coronary syndromes has received increasing attention since active plaques rich in macrophages (Mphi's) are more prone to rupture whereas plaques rich in myofibroblasts are considered to be stable. Functionally, active plaques show a locally enhanced vasoreactivity. Endothelin-1 (ET-1) a potent vasoconstrictor acts in a paracrine fashion to regulate vascular tone. ET-1 is also produced by inflammatory cells suggesting a role for ET-1 in inflammation. Additionally, ET-1 is a mitogen. Endothelin converting enzyme-1 (ECE-1) activates ET-1 and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis. We evaluated the presence of ECE-1 and big ET-1/ET-1 and the activity of ECE-1 in different plaque types. Together with ET-1, ECE-1 is present in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and Mphi's. ECE-1 activity and ET-1-immunoreactivity (IR) both are upregulated during the progression of atherosclerosis from a non-inflammatory to an inflammatory stage. Thus, enhanced production of active ET-1 may contribute to cell growth and regulation of vascular tone in advanced plaques and also in very early stages of atherosclerosis. Furthermore, we examined the presence of ET-1 in coronary plaque tissue obtained by directional coronary atherectomy. ET-1 IR localized to plaque components indicative of chronic inflammation. Semiquantitative analysis of ET-1 IR revealed significantly higher staining grades in active coronary lesions compared with nonactive lesions. The increased ET-1 content in active coronary lesions may be beneficial to the stabilization of the vessel wall after plaque rupture and disadvantageous because it may lead to vasospasm and to the progression of atherosclerosis.
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PMID:Endothelin-1 and endothelin converting enzyme-1 in human atherosclerosis--novel targets for pharmacotherapy in atherosclerosis. 1532 Aug 23

There is increasing evidence that oxidized low-density lipoproteins (Ox-LDL) might be involved in the pathogenesis of atherosclerosis and it has been reported that polyphenols inhibit LDL peroxidation and atherosclerosis. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide isolated from endothelial cells and it induces smooth muscle cell proliferation. ET-1 secretion is increased in atheroma and induces deleterious effects such as vasospasm and atherosclerosis. The goal of this study was to test the effect of four natural phenolic compounds against copper-oxidized LDL (Cu-LDL)-induced ET-1 liberation by bovine aortic endothelial cells (BAEC). The tested compounds were phenylpropanoid glycosides previously isolated from the aerial parts of Marrubium vulgare L. (acteoside 1, forsythoside B 2, arenarioside 3 and ballotetroside 4). ET-1 secretion increased when cells were incubated with Cu-LDL but the compounds 1-4 inhibited this increase. These results were confirmed by quantitative-polymerase chain reaction (QPCR) analysis. Since ET-1 plays an important role in atherosclerosis development, our work suggests that the tested phenylpropanoids could have a beneficial effect in inhibiting atherosclerosis development.
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PMID:Natural phenylpropanoids inhibit lipoprotein-induced endothelin-1 secretion by endothelial cells. 1556 69

In patients on chronic hemodialysis hypotensive episodes are frequently encountered during the course of treatment and the prevalence of atherosclerosis is increased. Endothelin-1 (ET-1), an endothelium-derived peptide with vasoconstrictive and mitogenic effects on smooth muscles, is involved in vascular tone regulation and in the pathogenesis of atherosclerosis. The aim of the present study was to investigate plasma ET-1 during hemodialysis treatment and to explore the probable influence of pre-existing hypertension. Forty-seven hemodialysis patients (21 females, mean age 62 +/- 12 years) were evaluated and hypertensive patients (n = 33) were compared to normotensive patients (n = 14). Relative blood volume changes (hemoglobinometry) and blood pressure were measured. Samples were taken before, every hour during and after hemodialysis. Plasma ET-1 was measured by enzyme-linked immunosorbent assay and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration rate of 2224 +/- 933 mL was performed. Total blood volume at the end of hemodialysis was 89.4 +/- 8.2% of the pretreatment volume. The fall in blood pressure (137/74 +/- 22/11 mmHg vs 127/73 +/- 30/14 mmHg) correlated with the decrease in blood volume (mean blood pressure: r = 0.33). Plasma ET-1 increased from 1.29 +/- 0.47 pg/mL before to 1.46 +/- 0.56 pg/mL (reference range 0.3-0.9) at the end of hemodialysis (P < 0.05). This rise was more pronounced in patients with hypertension than in normotensive individuals (P < 0.05). The change in blood volume (r = 0.41) and blood pressure (mean blood pressure: r = 0.34) correlated with plasma ET-1 at the end of hemodialysis (P < 0.05). Plasma ET-1 was enhanced in hemodialysis patients compared to normal subjects. During the hemodialysis session an increase in ET-1 was encountered, which was more pronounced in hypertensive than in normotensive patients and paralleled the hemodynamic changes. Apart from pre-existing hypertension, further factors potentially influencing ET-1 include local endothelial injury (arteriovenous fistula) and generalized bioincompatibility reactions (e.g. foreign surface contact) occurring during hemodialysis.
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PMID:Plasma endothelin-1 in hemodialysis treatment - the influence of hypertension. 1583 40


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