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)

Calcium antagonists are useful for the management of patients with ischaemic heart disease, particularly when used prophylactically. At the cellular level, these drugs act primarily by limiting calcium ion (Ca++) entry through the voltage-sensitive Ca(++)-selective channels, an effect that contributes markedly to their 'energy sparing' properties. However, the long term use of these drugs has additional advantages, particularly with respect to their ability to slow Ca(++)-dependent processes involved in the formation of atherogenic lesions, partially antagonise the effects of the raised levels of circulating endothelin-1 encountered during ischaemia-induced heart failure and hypertension, and trap and immobilise oxyradicals. Prolonged episodes of ischaemia result in an irreversible loss of homeostasis with respect to Ca++. However, the increase in myocardial cytosolic Ca++ caused by relatively short periods of ischaemia is small, reversible, and markedly attenuated by the prophylactic use of calcium antagonists. In the isolated, perfused rat heart, verapamil pretreatment produces statistically significant inhibition of the increase in cytosolic Ca++ during 20-minute global ischaemia. This stereospecific effect is associated with a decrease in the rise in total tissue Ca++ during reperfusion and amelioration of the adenosine triphosphate depletion caused by ischaemia. In general, discussion relating to the molecular basis of the use of calcium antagonists in the management of patients with ischaemic heart disease needs to take into account the duration of the ischaemic event, the workload on the myocardium, the need for prophylactic therapy, and the presence of exacerbating factors such as atherosclerosis and tobacco smoking. The early rise in cytosolic Ca++, the source of which remains uncertain, appears to be an important focus for anti-ischaemic drug therapy.
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PMID:The molecular basis for the use of calcium antagonists in ischaemic heart disease. 137 84

In cultured rat aortic smooth cells, endothelin-1 induced tyrosine phosphorylation of at least five proteins with molecular masses of about 79, 77, 73, 45 and 40 kDa in dose- and time-dependent manners. Platelet-derived growth factor also induced tyrosine phosphorylation of the same set of proteins in addition to other proteins including platelet-derived growth factor receptors. This growth factor markedly stimulated DNA synthesis and an increase in cell number in this cell type, but endothelin-1 failed to stimulate these responses under the same conditions. These results demonstrate for the first time that endothelin-1 induces tyrosine phosphorylation of some proteins but suggest that these reactions are not enough to stimulate proliferation of vascular smooth muscle cells.
Atherosclerosis 1992 Jan
PMID:Stimulation of protein-tyrosine phosphorylation by endothelin-1 in cultured vascular smooth muscle cells. 157 17

Endothelial cells can produce contracting factors; endothelin, a 21-amino acid peptide that can control local vascular tone, is the most potent of these factors. Of the three isoforms of endothelin, endothelial cells appear to release primarily endothelin-1. The peptide is formed from its precursor big endothelin via the activity of the endothelin converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and the calcium ionophore A23187. In vascular smooth muscle cells, endothelin binds to a specific receptor that activates phospholipase C and leads to the formation of inositol trisphosphate, diacylglycerol, and increased intracellular calcium levels. In certain blood vessels, the endothelin receptor is linked to a voltage-operated calcium channel via a Gi protein. This may explain why calcium antagonists inhibit endothelin-induced contractions only in certain blood vessels. In the human forearm circulation, calcium antagonists of different classes prevent endothelin-induced contractions. In hypertension, the circulating endothelin levels appear to be normal, whereas the vascular sensitivity to the peptide is reduced in most vascular tissues, but normal and enhanced responses have also been reported. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are augmented, a phenomenon that may be related to an increased formation of the peptide induced by modified forms of low-density lipoproteins.
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PMID:Endothelin. 172 99

The distribution of endothelin-1 (ET-1) receptors on human vascular tissue has been studied. High- and low-resolution autoradiography was used to determine the distribution of [125]ET binding sites in human blood vessels and ventricular myocardium. Dense, displaceable [125I]ET binding was associated with cardiac myocytes and the smooth muscle layer of all vessels were examined. There was also dense binding to vasa vasora. There was increased [125I]ET binding to atheromatous coronary arteries and vein graft, which was associated with the tunica media and vasa vasora or regions of neovascularization. Vasoconstrictor and positive inotropic activity of ET-1 has been established in vitro. The vasoconstrictor effect of ET-1 is likely to be mediated via the binding sites identified on vascular smooth muscle. The striking perivascular [125I]ET-1 binding suggests that ET-1 may also have constrictor activity on vasa vasora. There is experimental evidence that ET-1 has mitogenic activity on vascular smooth muscle cells in culture. The increased binding to both smooth muscle and regions of neovascularization in atheromatous vessels suggests that ET-1 may play a role in atherosclerosis.
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PMID:Autoradiographic localization of [125I]endothelin binding sites in human blood vessels and coronary tissue: functional correlates. 172 12

This study examined the influence of hypercholesterolemia on the concentration of plasma immunoreactive (ir) endothelin-1 in rats. Plasma ir-endothelin-1, total cholesterol, triglycerides, and lipoprotein fraction concentrations were measured in three groups of rats; ie, fed a standard diet, a high cholesterol diet, or a high cholesterol diet supplemented with the antihypercholesterolemic drug clinofibrate for 4 and 8 weeks. In the rats fed cholesterol for 8 weeks, morphological changes in thoracic and abdominal aortas were examined. Plasma total cholesterol, low density lipoprotein (LDL), very low density lipoprotein (VLDL) and ir-endothelin-1 concentrations increased significantly in the cholesterol-fed rats after both 4 and 8 weeks. In the clinofibrate-treated rats, these lipid parameters and plasma ir-endothelin-1 levels after 4 and 8 weeks were significantly lower than in the cholesterol-fed rats. The plasma ir-endothelin-1 concentration was correlated with plasma total cholesterol, LDL, and VLDL concentrations in the three study groups after 4 and 8 weeks. Morphologically, neither foam cells formation nor intimal thickening was observed in rats fed the high cholesterol diet for 8 weeks. These observations indicate that hypercholesterolemia without atherosclerosis elevates the plasma ir-endothelin-1 level in rats. The observed increase in plasma ir-endothelin-1 associated with hypercholesterolemia may play a role in the initiation or development of atherosclerotic vascular lesions.
Atherosclerosis 1991 Aug
PMID:Increased plasma immunoreactive endothelin-1 concentration in hypercholesterolemic rats. 179 51

The endothelium is increasingly recognized as a modulator of vascular tone, and evidence also is accumulating for an important role of the endothelium in humans in vivo. Endothelial release of prostacylin appears to regulate hyperemic blood flow after ischemia and muscle exercise, and the potent vasodilating properties of endothelium-derived relaxing factor (EDRF) are well established. Tonic release of EDRF plays an important role in the regulation of vascular tone in normal subjects, and a reduction of EDRF release in response to muscarinergic stimulation has been described in subjects with uncomplicated hypertension and also in hyperlipidemic patients. These observations point toward an early disturbance of endothelial function in disorders known as risk factors for the development of atherosclerosis. Furthermore, altered EDRF release and responsiveness to stimuli may be involved in the disturbed regulation of peripheral vascular tone in congestive heart failure. The physiological role of the vasoconstricting peptide endothelin-1 is not yet defined, but the study of the vascular actions of the peptide in humans has shown a vasodilating effect (for low dosages or when the vasconstricting effects are blocked), as well as a marked and long-lasting vasoconstricting effect. Although the mechanisms leading to vasodilation are not clear in humans, endothelin-1-induced vasoconstriction appears to be completely dependent on the activity of voltage-operated calcium channels and can be blocked by organic calcium antagonists but not by nitrovasodilators or EDRF. Further clarification of the role of the endothelium will provide a better understanding of circulatory physiology and pathophysiology and eventually may lead to the development of new therapeutic modalities.
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PMID:Endothelial function in humans. Studies of forearm resistance vessels. 191 1

We have investigated the effect of glucose on the release of endothelin-1-like immunoreactivity (ET-1-LI) from cultured bovine aortic endothelial cells. Elevation of glucose concentrations in cultured media from 5.5 to 11.1 or 22.2 mM significantly stimulated ET-1-LI release from cultured endothelial cells. An aldose reductase inhibitor did not affect the high glucose-induced ET-1-LI release. These findings suggest the possibility that hyperglycemia in diabetic patients enhances ET-1-LI release at the local site of vascular endothelium, which might be involved in the developments of vascular complications and atherosclerosis.
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PMID:Enhanced secretion of endothelin-1 by elevated glucose levels from cultured bovine aortic endothelial cells. 211 22

The effect of endothelin-1 (ET-1) on proliferation of aortic vascular smooth-muscle cells (VSMCs) from spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) rats was assessed by the measurement of [3H]-thymidine incorporation into DNA. ET-1 stimulated DNA synthesis in a concentration-dependent manner. Half-maximal stimulation occurred at a concentration of 7 x 10(-11) M. Three separate administrations of ET-1 to the cell cultures resulted in a half-maximal stimulation at 3 x 10(-12) M in of VSCMs from SHRs. VSMCs from SHRs responded to a far greater extent compared with WKY rats. The stimulatory effect of ET-1 was significantly attenuated by atrial natriuretic peptide (ANP). Repeated administration of ANP led to exacerbation of the inhibitory effect. Serum-stimulated DNA synthesis was not influenced by ANP. The proliferative action of ET-1 and the inhibition by ANP are discussed with respect to the development of vascular disease in atherosclerosis and hypertension.
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PMID:Inhibition by atrial natriuretic peptide of endothelin-1-stimulated proliferation of vascular smooth-muscle cells. 750 59

The distribution of [125I]-endothelin-1 (ET-1) binding sites on human and porcine vessels was studied with in vitro receptor autoradiography. Binding to normal human saphenous veins was compared to atheromatous veins used as coronary artery bypass grafts. Binding to porcine vessels, from an experimental model of intimal hyperplasia, was also studied. There was dense binding of [125I]-ET-1 to smooth muscle of all vessels examined, as well as to the vasa vasorum and regions of neovascularization of diseased vessels. Binding to microvasculature (vasa vasorum and regions of neovascularization) is of particular interest, because ET-1 has been shown to have mitogenic activity on vascular smooth-muscle cells in culture and microvessels are extremely sensitive to the constrictor effect of ET-1. Binding of [125I]-ET-1 to vasa vasorum of normal blood vessels and to regions of neovascularization of atheromatous vessels suggests that ET-1 plays a pathophysiologic role in atherosclerosis.
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PMID:[125I]-endothelin-1 binding to vasa vasorum and regions of neovascularization in human and porcine blood vessels: a possible role for endothelin in intimal hyperplasia and atherosclerosis. 750 83

Key discoveries in the past decade have revealed that the vascular endothelium is an important regulatory organ that is involved in maintaining cardiovascular homeostasis in health and contributes significantly to the pathomechanism of several cardiovascular diseases. Occupying a strategically important location between circulating blood and tissues and having the ability to respond to changes in its physical, chemical, and humoral environment by the production of a host of biologically active substances, the normal endothelium modulates the tone of underlying vascular smooth muscle, maintains a nonadhesive luminal surface, and mediates hemostasis, cellular proliferation, and inflammatory and immune mechanisms in the vascular wall. Modulation of smooth-muscle tone is mediated by the synthesis release of endothelium-derived relaxing [PGI2, EDRF(NO), and EDHF] and contracting factors (arachidonic acid metabolites, endothelin-1, and angiotensin II). Anticoagulant, fibrinolytic, and antithrombotic properties contribute to the maintenance of the fluidity of blood. Injury or activation (by cytokines) of endothelial cells disrupts these normal regulatory mechanisms and results in morphologic and functional alterations (phenotypic changes) commonly defined as endothelial dysfunction. Clinically, the "syndrome" of endothelial cell dysfunction can be described as generalized or localized vasospasm, thrombosis, atherosclerosis, and restenosis. Although its importance is clearly established, no drugs used today were originally targeted for the treatment of endothelial dysfunction. Recent studies, however, showed that some existing therapies (e.g., angiotensin-converting enzyme inhibitors) may protect the endothelium. Novel diagnostic techniques and innovative therapeutic strategies, based on the already known molecular mechanisms of endothelial dysfunction, are briefly outlined. Further knowledge of the pathobiology of the impaired endothelium will contribute to unraveling some of the remaining mysteries of many cardiovascular diseases and will enable us to design novel therapies to prevent and treat them.
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PMID:The role of endothelium in cardiovascular homeostasis and diseases. 752 67


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