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)

A decrease in the formation of prostacyclin (PGI2), a potent vasodilating and platelet antiaggregatory substance, has been implicated in the pathogenesis of diabetic vasculopathy. This defect, as well as others, may contribute to imbalances in the thrombo-regulatory system resulting in enhanced platelet aggregability, accelerated atherosclerosis, and subsequent vessel injury. Until recently the major thrust of relevant literature has been directed toward abnormalities in PGI2 quantity or function in vascular tissue from experimentally induced diabetic animal models. For the past 2 years our laboratory has studied prostaglandin metabolism in human diabetic and nondiabetic blood vessels. We determined prostacyclin synthetase (PGI2ase) activity in saphenous veins of diabetic and nondiabetic patients (HSV-D and HSV-ND) undergoing coronary artery bypass grafts and in tibial arteries and tibial veins of diabetic patients (HTA-D and HTV-D) and nondiabetic patients (HTA-ND and HTV-ND) undergoing limb amputation for arterial disease of the lower extremity. Carbon 14-labeled prostaglandin endoperoxide (PGH2) was incubated for 2 minutes with vascular microsomal protein. The products were separated via thin-layer chromatography and quantified by radiochromatographic scan. PGI2ase activity was determined by the formation of 6-keto-PGF1 alpha, the stable breakdown product of PGI2. Results of this study indicate that the microsomal fractions of all vascular tissues studied contain an active PGI2ase capable of forming PGI2; formation is enzymatic, as the amount of product increased with increasing microsomal protein concentration; there is no significant difference in PGI2ase activity between HSV-D and HSV-ND; PGI2ase activity in HTA-D and HTV-D is less than in HSV-D and HSV-ND.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostacyclin synthetase activity in human diabetic and nondiabetic vascular tissue. 352 43

This report describes measurements of 50 variables in adult, female, reproductively inactive Vervet monkeys during prolonged nutrition realistic for westernized people. Dietary treatments consisted of an atherogenic Western diet (WD) and a prudent Western diet (PD). Ingredients were normal foods for man and no extra cholesterol was added. Fortification of both diets with vitamin C after cooking was necessary to prevent deficiency. Randomised groups of Vervet monkeys received either the PD or WD for 47 months, while a third group was fed WD for 20 months and then PD for 27 months (WD-PD). Before the dietary treatments nourishment was by a high carbohydrate diet (HCD) and baseline and reference values (RV) apply to this nutritional status. Plasma total cholesterol (mg/dl) was increased from 147 (HCD) to 174 (PD) and 376 (WD). Individual cholesterolaemio response ranged from mild to severe and was stable (PD and WD). Dietary reversal (WD-PD) reduced cholesterolaemia promptly. Statistically significant increases in calcium, zinc and vitamin E and decreased vitamin B6 were associated with the WD relative to the PD (in serum and plasma). Two cholesterol metabolising microsomal enzymes in liver were notably increased and one unchanged (WD). There were no dietary effects on triglycerides, vitamin A and glucose in plasma; insulin, glucagon, electrolytes, copper, magnesium or enzymes reflecting liver, muscle or brain cell damage in serum. Red blood cells, platelets and directly associated parameters increased (WD), haemoglobin was the same and haemoglobin per red cell decreased. Bleeding time was not affected. Bivariate correlations across the diets confirmed that Western nutrition promoted inherent individual susceptibility to cholesterolaemia. There were notable differences from RVs in total cholesterol, calcium, packed cell volume and haemoglobin, which emphasise excesses and deficiencies of the WD and PD.
Atherosclerosis 1987 Aug
PMID:Diets realistic for westernized people significantly effect lipoproteins, calcium, zinc, vitamins C, E, B6 and haematology in vervet monkeys. 363 58

Ro 16-0521 is a newly synthesized benzodiazepine derivative which is devoid of reactivity with the brain benzodiazepine receptor. The effects of this drug on plasma lipids and lipoproteins and hepatic cholesterol metabolism have been examined in the cholesterol-fed rat. Drug therapy was associated with dose-related falls in plasma cholesterol concentration, liver cholesterol content, and the activity of the liver enzyme Acyl-CoA cholesterol acyltransferase. Drug therapy abolished the lipid and lipoprotein changes induced by cholesterol feeding, including those associated with a diet supplemented with olive oil to facilitate cholesterol loading. Drug therapy was also associated with an increased activity of the enzyme HMG-CoA reductase and reduced hepatic microsomal cholesterol content. It is suggested that the cholesterol-fed rat will be a suitable model for further mechanistic studies.
Atherosclerosis 1986 Jun
PMID:Effects of Ro 16-0521 on cholesterol metabolism in the rat. 373 45

The hypothesis was examined that arterial microsomal membrane fluidity is decreased in atherosclerosis. To investigate this hypothesis, the fluorescence anisotropy (r) of 1,6-diphenylhexa-1,3,5-triene was measured in aortic microsomes isolated from normal and atherosclerotic rabbits. A decrease in membrane fluidity, as indicated by a significant increase in r, was observed in microsomes from atherosclerotic rabbits. Notably, the increase in r occurred prior to macroscopic lesion development. The data support the hypothesis that membrane fluidity is decreased in atherosclerosis and indicate that this decrease occurs early in the atherogenic process. The hypothesis that decreased microsomal membrane fluidity contributes to the increased activity of acyl-CoA:cholesterol acyltransferase (ACAT) in atherosclerosis was also investigated. The hypothesis was rejected on the basis that enrichment of microsomes from normal rabbits with exogenous cholesterol to achieve r values equal to that of microsomes from atherosclerotic rabbits did not result in comparable ACAT activity.
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PMID:Decreased microsomal membrane fluidity in the development of cholesterol-induced atherosclerosis in the rabbit. 379 13

Clinical observations have shown that hypercholesterolemia is associated with abnormal androgen metabolism, viz. an increased excretion of etiocholanolone (E) relative to androsterone (A). Substances which restore the A/E ratio to normal likewise lower serum cholesterol. Postulating that the abnormal steroid and sterol metabolism may be either causally related or dependent on the same metabolic defect, we have developed in vitro and in vivo models to select drugs which favorably effect the ratio of A to E produced from [4-14C]androst-4-ene-3,17-dione [4-14C]A-dione). The in vitro model employs a mixture of rat liver microsomal delta 4-3-ketosteroid-5 alpha-reductase and cytosolic 3 alpha-hydroxysteroid dehydrogenase and delta 4-3-ketosteroid-5 beta-reductase. Kinetic and mechanistic studies have been performed on active compounds using this in vitro assay. The in vivo model employs i.v. injection of [4-14C]A-dione followed by collection of bile in anesthetized, hypophysectomized female rats. Many compounds preselected in the in vitro assay likewise reduced the A/E ratio in vivo. One of these compounds (CGS 10614A) also lowered serum cholesterol and reduced the incidence and severity of atherosclerotic lesions in aortas of cholesterol-fed rabbits.
Atherosclerosis 1985 Jan
PMID:Identification of potential antiatherosclerotic/hypolipidemic agents by their effect on hepatic conversion of androst-4-ene-3,17-dione to etiocholanolone and androsterone. 385 15

We describe herein the effects of Marek's disease herpesvirus (MDV) on cholesterol and cholesteryl ester metabolism in cultured chicken arterial smooth muscle cells. Infection of arterial smooth muscle cells from specific pathogen-free chickens with MDV, but not a virus control, herpesvirus of turkeys led to a 7-10-fold increase in the accumulation of free and esterified cholesterol and a 2-fold increase in phospholipids. The cellular lipid changes observed in the MDV-infected arterial smooth muscle cells resulted, in part, from the following: decreased low-density lipoprotein-cholesteryl ester hydrolysis due to decreased lysosomal (acid) cholesteryl ester hydrolytic activity; increased de novo synthesis of cholesterol; decreased excretion of free cholesterol; and, both increased cholesteryl ester synthetic activity and decreased cytoplasmic (neutral) cholesteryl ester hydrolytic activity which resulted in increased incorporation of oleic acid into cholesteryl ester. Other changes noted in the MDV-infected cells as compared to uninfected cells included a 2-fold increase in both total protein synthesis and lysosomal and microsomal marker enzyme activities. These alterations in lipid and protein metabolism in MDV-infected arterial smooth muscle cells may explain in part our in vivo findings that herpesvirus (MDV) infection of specific pathogen-free chickens fed a normocholesterolemic diet will induce arterial thickening and lipid accumulation resembling human atherosclerosis.
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PMID:Altered cholesteryl ester cycle is associated with lipid accumulation in herpesvirus-infected arterial smooth muscle cells. 399 16

The effect of the beta-blocker propranolol and of bensonal, a barbituric acid derivative stimulating microsomal oxidation of the liver monooxygenase, was evaluated using the model of experimental myocardial infarction (EMI) in the presence of 3-month cholesterol atherosclerosis. Using light and electron microscopy, polarography and weight planimetry atherosclerosis was shown to complicate considerably the course of EMI analyzed 1, 3, 7, 15 and 30 days after the coronary artery ligation. The drugs given at the same intervals improved the structure and metabolism of different myocardial zones while limiting necrotic areas for 7 days of EMI.
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PMID:[Experimental myocardial infarction in atherosclerosis--various methods of pharmacological correction]. 400 54

Chromium ions (Cr3+)evoked a biphasic curve of changes of rat liver microsomal cholesterol biosynthesis using [14C]acetate and/or [14C]mevalonate as precursors. While for the lower range of Cr3+ concentrations the rate of cholesterol biosynthesis rises, at concentrations above 8 X 10(-6) M they evoke a decrease in the cholesterol biosynthesis, up to 50% down on its control value at a concentration of 8 X 10(-4) M. Differences were more pronounced when using [14C]mevalonate instead of [14C]acetate as precursor. The activity of the microsomal enzyme biphenyl-4-hydroxylase showed an equally intense rise to that of cholesterol biosynthesis up to a 8 X 10(-6) M Cr3+ concentration. Above this concentration, however, the activity of the enzyme starts to drop. NADPH-cytochrome c reductase and NADPH-oxidase were decreased at all Cr3+ concentrations used, which cover a 100-fold range. Lineweaver-Burk plots of the cytoplasmic glucose-6-phosphate dehydrogenase demonstrated an uncompetitive mechanism of inhibition by Cr3+ ions. The results are discussed in terms of the possible significance of the Cr3+ concentration-dependent effects on cholesterol biosynthesis, with the observed atherosclerosis in Cr-deficient humans.
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PMID:Rat liver microsomal cholesterol biosynthesis and drug oxidase activity are affected by chromium ions (Cr3+) in vitro. 643 2

Carnitine ester hydrolysis was observed in homogenates of normal rabbit (Oryctolagus cuniculus) aortas and in intact aortas from normal and cholesterol-fed rabbits using [14C]palmitoylcarnitine as a substrate. Hydrolytic activity was decreased approximately 50% in arterial tissue from cholesterol-fed rabbits and may account for the observation that carnitine esters accumulate in arteries of animals fed atherogenic diets. Long-chain acylcarnitines (C14-C18) were found to be moderate inhibitors of microsomal acylCoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26); short-chain acylcarnitine (C2-C10) and carnitine itself were not inhibitors. The data suggest that the increase in activity of arterial ACAT that characteristically parallels the development of atherosclerosis does not occur as a result of carnitine ester accumulation.
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PMID:Carnitine ester hydrolysis in arteries from normal and cholesterol-fed rabbits and the effects of carnitine esters on arterial microsomal ACAT. 650 6

Forty-eight menopausal women taking exogenous estrogen were compared with 246 postmenopausal women not on estrogen. The estrogen users had significantly higher total high density lipoprotein (HDL) (76.0 vs 61.4 mg/dl) and HDL2 (36.7 vs 23.0 mg/dl) cholesterol than the controls. There was a similar concentration of HDL3 cholesterol for the two groups (39.2 for the estrogen users and 38.4 for the controls). A dose-response was evident between the amount of daily estrogen and HDL-total and HDL2 cholesterol. The significant differences between the two groups remained after adjusting for body composition, alcohol intake, cigarette smoking and physical activity. There was a significant difference between the two groups in liver function as measured by the liver enzymes, SGOT, SGPT, with liver enzyme concentrations lower in the estrogen users. The results indicate that the increase in the total HDL cholesterol as a result of menopausal estrogen is primarily the result of increased HDL2. The increase could not be explained by alterations in hepatic microsomal activity as measured by liver enzymes since estrogen users had lower concentrations of liver enzymes than non-estrogen users.
Atherosclerosis 1983 Oct
PMID:Menopausal estrogen use, high density lipoprotein cholesterol subfractions and liver function. 665 11


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