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)

Hypercholesterolemia is an important risk factor for the development of atherosclerosis. Late vein graft failure has been attributed to a combination of both intimal hyperplasia and atherosclerosis. This study examines the effect of hypercholesterolemia on the early morphology and vasomotor function of experimental vein grafts. Forty New Zealand White rabbits received either a 1% cholesterol diet (n = 24; HC) or a standard diet (n = 16; CON) for 4 weeks before operation and thereafter until harvest. All animals underwent a reversed vein common carotid artery bypass. The vein grafts and contralateral veins were harvested at 2 and 4 weeks after operation in both groups for either histological and morphometric analysis (n = 8 for each group) or for in vitro isometric tension studies using serotonin (5-HT), norepinephrine (NE), bradykinin (BK), and endothelin-1 (ET) and following NE precontraction, relaxation in response to acetylcholine (ACh) and sodium nitroprusside (SNP). Serum cholesterol levels were measured after 4, 6, and 8 weeks of the cholesterol diet. Serum cholesterol concentrations were 20 to 30 times higher than controls in the hypercholesterolemic animals at all times. The intimal area of the grafts in the HC group increased by twofold at 2 weeks and threefold at 4 weeks compared to corresponding controls. In contrast to the CON vein grafts, the intima of the vein grafts from HC consisted mainly of lipid-laden smooth muscle cells with scattered interspersed macrophages and occasional lipid plaques between the intima and the media. Medial areas were similar in all grafts. HC grafts became progressively more sensitive to 5-HT at 2 and 4 weeks. A supersensitivity to NE and BK developed at 4 weeks in HC grafts. There was no change in sensitivity to ET. While no graft relaxed to ACh, HC grafts contracted at low doses. All grafts responded to SNP in a dose-dependent manner. In contrast to CON veins, HC veins demonstrated an increase in sensitivity to NE and a contractile response to 5-HT (at 4 weeks only). HC veins did not relax in a dose-dependent manner in response to ACh. No changes in the morphology of HC veins were noted. HC produces changes in the structure and associated vasomotor abnormalities of vein grafts. Closely related functional changes also occur in contralateral veins. HC appears to induce intrinsic changes in smooth muscle cells which are linked to a greater proliferative and abnormal vasomotor capability. Clinically, applications of vigorous anti-HC regimens perioperatively may be beneficial in maintaining patency over the longer term.
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PMID:Hypercholesterolemia and experimental vein grafts: accelerated development of intimal hyperplasia and an increase in abnormal vasomotor function. 836 Nov 71

Studies on such injury processes as atherosclerosis, angioplasty, and restenosis, have shown an impairment of relaxations mediated by endothelium-derived relaxing factor (EDRF). Increasingly, the rabbit carotid artery is being used as the vessel of choice in such studies, but a definite protocol for the assessment of endothelial dysfunction or denudation has not been developed. Using isolated carotid artery rings, we have obtained reproducible dose-response curves in endothelially intact and denuded vessels from normally fed rabbits to a variety of vasoconstrictors and endothelium-dependent and -independent vasodilators. Endothelium-dependent vasodilators (acetylcholine (1 x 10(-8)-1 x 10(-6) M), carbachol (1 x 10(-8)-5 x 10(-6) M), substance P (0.01-100 nM), and A23187 (1 x 10(-8)-1 x 10(-7) M) relaxed the arteries in a concentration-dependent manner but produced no relaxation in denuded vessels. Endothelium-independent nitric oxide (NO) donors [Sin-1 (1 x 10(-8)-1 x 10(-6) M)] and sodium nitroprusside (1 x 10(-8)-1 x 10(-6) M)) relaxed both intact and denuded vessels to a similar degree (slight augmentation of the relaxation induced in denuded vessels was not significant), demonstrating that denuded vessels did not have an impaired reactivity to NO. Concentration response curves to the vasoconstrictors [5-HT (1 x 10(-7)-1 x 10(-4) M) and KCl (15-60 mM)] were produced in intact vessels and it was shown that similar contraction was produced by 1 x 10(-6) M 5-HT in intact and denuded vessels. This indicated that the vessels retained contractile ability following denudation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the responses of isolated rings of rabbit left carotid artery. A potential protocol for the assessment of pathologically induced functional changes. 840 Apr 14

Accelerated atherosclerosis is commonly observed in diabetes mellitus as well as in some kidney diseases. This may be partly due to platelet hyperactivity. Serotonin (5-HT) is thought to play a role in platelet/vessel wall interactions and to be implicated in the pathogenesis of atherosclerosis. The aim of the study was to evaluate platelet aggregation and peripheral serotonergic system in patients with diabetic nephropathy. The studies were performed in 37 patients with diabetic nephropathy (age 53.5 +/- 14.9) and healthy volunteers (age 44.2 +/- 12.3). Platelet aggregation (in PRP according to Born) induced by collagen (2 micrograms/ml), ADP (5 microM), epinephrine (10 microM) arachidonic acid (0.25 mM) and 5-HT (1 microM) was found to be significantly enhanced in diabetic relative to controls. Whole blood 5-HT was significantly lower in diabetics patients, whereas plasma 5-HT was significantly higher in diabetic patients when compared to controls. Since serotonin can amplify platelet aggregatory responses to various agonists, platelet hyperactivity in diabetes may be in part due to an enhanced availability of this amine. Disturbances in peripheral serotonergic system together with platelet hyperaggregability may be associated with an increased incidence of cardiovascular complications in diabetes.
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PMID:[Blood platelet function, plasma serotonin and lipid metabolism in patients with diabetic nephropathy]. 852 96

Serotonin (5-HT, 5-hydroxytryptamine) is a mitogen in vascular smooth muscle and vascular reactivity to 5-HT is significantly enhanced in hypertension and atherosclerosis. We have tested the hypothesis that tyrosine kinases, enzymes important for mitogenesis, may play a role in 5-HT-induced vascular smooth muscle contractility. Helical strips of rat carotid artery and aorta denuded of endothelium were mounted in tissue baths for measurement of contractile force. The tyrosine kinase inhibitor genistein (5 x 10(-6) M) decreased the potency of 5-HT approximately 4-fold and reduced maximal contraction to 5-HT in carotid arterial strips denuded of endothelium (58% control). Genistein's inactive congener daidzein (5 x 10(-6) M) did not reduce maximal contraction to 5-HT in carotid arteries but did shift the 5-HT concentration response curve 3-fold to the right. Tyrphostin 23 (5 x 10(-5) M), another tyrosine kinase inhibitor, decreased the potency of 5-HT 4-fold and reduced the maximal contraction to 5-HT in the carotid artery (10% control). Contractions induced by phorbol-12,13-dibutyrate (10(-9) to 10(-5) M) were not reduced or shifted by either tyrosine kinase inhibitor, indicating that phorbolester-sensitive protein kinase C isoforms were not affected. KCl-induced contraction was shifted 2-fold and the maximum significantly inhibited by tyrphostin 23 (38.6% control) but not genistein or daidzein, indicating that tyrphostin 23 but not genistein may inhibit voltage-gated calcium channels to reduce contractility. Western blot analysis using antiphosphotyrosine antibody confirmed that 5-HT produced a time- and concentration-dependent increase in the phosphotyrosine immunoreactivity of a 42-kD protein in cultured aortic smooth muscle cells. Lysate immunoprecipitation with an antimitogen-activated-protein (MAP)-kinase antibody indicated that the 42-kD protein was most likely a MAP kinase. 5-HT (10(-5) M) stimulated contraction and increased antiphosphotyrosine immunoreactivity in whole aorta mounted in tissue baths. Importantly, aortic contraction to 5-HT was shifted (5-fold rightward) and reduced (69% control) by genistein but not daidzein. These findings demonstrate that (1) tyrosine kinase activation may partially mediate contractility to 5-HT in arterial smooth muscle, (2) tyrphostin 23 is somewhat nonselective and (3) 5-HT stimulates tyrosine kinase as documented by increased tyrosyl phosphorylation of proteins in cultured aortic smooth muscle cells and aortic tissue in active contraction of 5-HT. These findings have significant implications not only in understanding a novel pathway of 5-HT signal transduction but also in vascular diseases in which growth and/or contractility to 5-HT is increased (e.g. hypertension, atherosclerosis).
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PMID:Serotonin stimulates protein tyrosyl phosphorylation and vascular contraction via tyrosine kinase. 869 53

Serotonin induces platelet activation. Purified apoprotein E of 300 micrograms/ml prevented morphological alterations of blood platelets stimulated with serotonin (5 microM). Lower concentrated apoprotein E showed no such clear effects. These findings suggest that apoprotein E may liter atherosclerosis by suppressing agonist-induced platelet activation.
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PMID:Influence of purified apoprotein E on platelet activation induced by serotonin. 870 53

Intimal thickening predisposes to atherosclerosis and is often associated with alterations of the vascular reactivity of the artery. We investigated whether dexamethasone inhibited the intimal thickening and reactivity changes induced by a silicone collar placed around the left rabbit carotid artery for 2 weeks. The sham-operated, right artery served as control. Dexamethasone (1 mg/kg/day), given in the drinking water (n = 10) or by a subcutaneous minipump (n = 10), abolished intimal thickening compared to that of both placebo groups (n = 10). Both dexamethasone and the collar suppressed the isometric force development of isolated segments elicited by KCl in organ chamber experiments. The collar raised the sensitivity to serotonin (5-hydroxytryptamine, 5-HT) and the maximum force development (Emax) after normalization for the KCl responses. Dexamethasone exerted complex effects on 5-HT contractions in sham arteries: the curves often became biphasic, and sensitivity and Emax of the first phase were depressed by dexamethasone. In contrast, dexamethasone raised the hypersensitivity of collared arteries to 5-HT even further. Collar and dexamethasone did not influence endothelium-dependent relaxations elicited by acetylcholine or the calcium ionophore A-23187. It is concluded that dexamethasone interfered with neo-intima formation in the collar model, presumably by inhibition of smooth muscle cell migration and/or proliferation, without restoring contractile behaviour. Therefore, the collar-induced alterations in the reactivity of the smooth muscle cells in the media appear to be unrelated to the process of intimal thickening.
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PMID:Dexamethasone influences intimal thickening and vascular reactivity in the rabbit collared carotid artery. 875 Jul 42

Noradrenaline (NA)-containing nerves, mainly originating in the sympathetic superior cervical ganglia, supply large and small cerebral arteries. In large cerebral arteries, nerves containing serotonin (5-hydroxytryptamine, 5-HT) may represent neuronal uptake of circulating 5-HT by sympathetic nerves. 5-HT-containing nerves supplying small pial vessels probably have a central origin in the dorsal raphe nucleus. In most species, NA is a weak vasoconstrictor (alpha 1- or alpha 2-adrenoceptors), while 5-HT is a potent vasoconstrictor (5-HT2 or 5-HT1-like receptors) of large cerebral arteries. In contrast, both NA and 5-HT tend to cause vasodilatation in small pial vessels and arterioles. Adrenergic and serotonergic transmission can be modulated by pH, a range of putative neurotransmitters and neuromodulators, and by the endothelium. Sumatriptan, a 5-HT1-like receptor agonist, has been shown to be effective in the treatment of migraine. Changes in NA- or 5-HT-containing nerves and/or in the responses of cerebral vessels to NA and 5-HT have been observed in a variety of vascular disorders, including cerebral vasospasm following subarachnoid haemorrhage, hypertension, and atherosclerosis.
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PMID:Innervation of cerebral arteries by nerves containing 5-hydroxytryptamine and noradrenaline. 878 67

The lipoxygenase product 15-hydroxyeicosatetraenoic acid (15-HETE) was shown to be the most important eicosanoid formed in the atherosclerotic rabbit aorta. The aim of the present study was to compare the effects of 15-HETE and its hydroperoxy precursor 15-HpETE with those of other vasoconstrictor and vasodilator agents in arteries from rabbits fed either a control or a cholesterol-rich diet for 16 and 30 weeks. 5-Hydroxytryptamine (5-HT) aggregated platelets and thrombin caused contractions of isolated rabbit aortas. The contractile responses elicited by platelets from control animals were similar to those evoked by platelets from atherosclerotic rabbits. After 16 weeks of hypercholesterolemia, the contractile responses were either augmented (5-HT), unchanged (platelets) or reduced (thrombin). After 30 weeks of hypercholesterolemia, the responses to all contractile agents used had decreased. In both aortas and pulmonary arteries the endothelium-dependent relaxations to the calcium ionophore, A23167, and to acetylcholine were progressively lost and the endothelium-independent relaxations to nitroglycerin were reduced by the progressing hypercholesterolemia. The 15-lipoxygenase metabolites contracted the isolated thoracic aorta and pulmonary artery from control rabbits and to a lesser extent those of the cholesterol-fed rabbits. After raising the tone in these vessels with prostaglandin F2 alpha PGF2 alpha) or noradrenaline, 15-HpETE induced relaxations which were not significantly influenced by the development of fatty streaks. Our data illustrate that the contractions of the blood vessel wall to 15-HETE, like those to other vasoconstrictors, are markedly reduced by developing atherosclerosis. In contrast, the relaxations to 15-HpETE in the rabbit arteries remain unaltered after 16 to 30 weeks of hypercholesterolemia. This is unlike the reactions to other vasodilators, which are markedly reduced.
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PMID:Influence of hypercholesterolaemia on the reactivity of isolated rabbit arteries to 15-lipoxygenase metabolites of arachidonic acid: comparison with platelet-derived agents and vasodilators. 884 33

A comprehensive study on platelet aggregation, hemostasis, fibrinolysis and serum lipids in relation to peripheral serotonergic system has been performed on 41 nephrotic patients. Enhanced platelet aggregatory responses in both whole blood and in platelet rich plasma (PRP) were found upon stimulation with different agonists when compared to healthy volunteers. Increased levels of fibrinogen, fibrin monomers, and protein C activity were observed in nephrotic patients. Euglobulin clot lysis time was significantly prolonged in nephrotic patients. Activity of tissue plasminogen activator (tPA) inhibitor was higher in nephrotic syndrome, whereas tPA activity was significantly lower in these patients when compared to controls. Urokinase concentration, lipoprotein (a), cholesterol, LDL and VLDL levels were significantly higher in nephrotic patients over controls. Whole blood serotonin was significantly lower, whereas plasma serotonin was significantly higher in nephrotic patients relative to controls. Serotonin uptake and its release from platelets were markedly diminished in patients with nephrotic syndrome. Disequilibrium in the coagulolytic system, platelet hyperactivity, hyperfibrinogenemia, disturbances in peripheral serotonergic system together with lipid abnormalities may contribute to the progression and development of atherosclerosis and an enhanced risk of thromboembolic complications in nephrotic syndrome.
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PMID:Comprehensive study on platelet function, hemostasis, fibrinolysis, peripheral serotonergic system and serum lipids in nephrotic syndrome. 911 50

Plasma and platelet serotonin (5-HT) concentrations, and resting and collagen-induced 5-HT release in platelet-rich plasma were studied in normal and familial hypercholesterolaemic (FH) subjects. Platelet 5-HT concentrations were significantly reduced (-37%, P < 0.01) in FH patients whilst mean plasma concentrations, although increased, were not significantly different from those in normal subjects. Platelet 5-HT correlated negatively with plasma cholesterol when the data for normal subjects and FH, patients were combined (r = -0.48, P = 0.005). It also correlated negatively with low-density lipoprotein (LDL) (FH data, r = -0.59, P = 0.03; normal and FH data, r = -0.49, P = 0.004) but positively with high-density lipoprotein (HDL) (FH r = 0.79, P = 0.001; normal and FH, r = 0.37, P = 0.03). Collagen (5-160 micrograms/ml) stimulated platelet 5-HT release occurred in a concentration-dependent manner. In FH patients stimulated 5-HT release was reduced (10 micrograms/ml collagen, -40%, P < 0.05) and accompanied by increased collagen EC50 values (P < 0.02). Resting 5-HT release was increased substantially in FH patients but not significantly. Our data provide evidence for a relationship between circulating cholesterol and platelet serotonergic mechanisms. It is proposed that abnormalities relating to platelet-plasma 5-HT dynamics, perhaps due to enhanced platelet activity or decreased platelet uptake, may contribute to the cardiovascular complications in FH.
Atherosclerosis 1997 Apr
PMID:Reduced platelet serotonin content and release in familial hypercholesterolaemia. 912 51


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