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)

Aryl 4-monooxygenase [aniline, reduced-flavoprotein:oxygen oxidoreductase (4-hydroxylating); EC 1.14.14.1] activity was searched for and found in homogenates of aorta walls from rabbits, rhesus monkeys, and humans. Specific activities were comparable to activities observed in several other extrahepatic tissues of rabbits and monkeys and in epidermal tissues from mice, but were one to two orders of magnitude lower than those observed in corresponding preparations of hepatic tissues. Cytochrome P-450 also could be detected in low concentrations in microsomal fractions of aortic wall homogenates. The monooxygenase activity found in the aorta could play a significant role in the etiology and pathogenesis of atherosclerosis in humans by catalyzing the conversion of environmental promutagens to mutagenic initiators and/or cytotoxic factors, thus leading to development of benign, smooth muscle tumors of the inner lining of artery walls.
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PMID:Aryl 4-monooxygenase and cytochrome P-450 in the aorta: possible role in atherosclerosis. 82 48

Microsomal fractions from arterial walls of pigs and rabbits and fundus of rat stomach generate from prostaglandin endoperoxides (PGG2 or H2) an unstable substance, prostaglandin X (PGX) which is a potent inhibitor of platelet aggregation induced by several different substances. Other microsomal fractions including corpus of stomach, lung and ram seminal vesicles generate smaller amounts of PGX from PGG2 or PGH2. Incubation of microsomes from arterial wall or fundus of stomach with platelet-rich plasma under various conditions shows that the enzyme which generates PGX can utilize endoperoxides liberated from platelets or added to the cuvette, thereby preventing, interrupting or reversing the process of platelet aggregation. The generation of PGX is strongly inhibited (IC50 0.43 mug/ml) by 15-hydroperoxy arachidonic acid. These observations are important in the interpretation of vascular diseases such as atherosclerosis and thrombosis and provide a rational basis for the use of anti-oxidants in the prevention and treatment of these diseases.
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PMID:A lipid peroxide inhibits the enzyme in blood vessel microsomes that generates from prostaglandin endoperoxides the substance (prostaglandin X) which prevents platelet aggregation. 82 86

Strong clinical and experimental evidence suggests that chronic latent vitamin C deficiency leads to hypercholesterolaemia and the accumulation of cholesterol in certain tissues. Ascorbic acid supplementation of the diet of hypercholesterolaemic humans and animals generally results in a significant reduction in plasma cholesterol concentration. While most studies relating ascorbic acid to atherosclerosis have used the rabbit as a model, those concerned with elucidating the role of ascorbic acid in the regulation of cholesterol metabolism have generally used the guinea pig. Comparatively little use has been made of the non-human primates. A significant advance in recent years has been the development of a model of chronic latent scurvy in the guinea pig. Chronic dietary inadequacy of vitamin C may influence the pathogenesis of atherosclerosis as it affects not only plasma cholesterol and triglyceride concentrations but also the integrity of the vascular wall. Ascorbic acid is involved in the regulation of cholesterol metabolism in several ways. Dietary inadequacy of vitamin C is associated indirectly with a lowering of cholesterol absorption, this effect resulting from a reduction in the availability of bile acids, monoglycerides and fatty acids. The excretion of cholesterol as neutral steroids, however, appears not to be affected by ascorbic acid. Although much of the evidence for the involvement of ascorbic acid in cholesterol synthesis is equivocal, it seems likely that cholesterol synthesis is decreased in vitamin C deficiency. A series of studies using guinea pigs with chronic latent vitamin C deficiency has provided clear evidence that bile acid synthesis is reduced in this condition. Indirect evidence strongly suggests that this results from a decrease in the activity of the microsomal enzyme cholesterol 7 alpha-hydroxylase. However, some evidence suggests that the mitochondrial reactions of bile acid synthesis require ascorbic acid. The role of ascorbic acid in the regulation of steroidogenesis appears to involve selective inhibitory and stimulatory effects on the desmolase, hydroxylase and dehydrogenase reactions which lead to the formation of pregnenolone and its subsequent conversion to steroid hormones.
Atherosclerosis
PMID:The role of ascorbic acid in the regulation of cholesterol metabolism and in the pathogenesis of artherosclerosis. 94 15

The cholesterol-7alpha-hydroxylase activity of hepatic microsomal preparations of hypothalamic hypercholesterolemic rats and normal rats was assayed in rats fed diets high and low in cholesterol, and in rats killed at the supposed height and at the nadir of the diurnal cycle of enzyme activity. The activity of this enzyme system appeared to be unimpaired in the hypothalamic hypercholesterolemic rat.
Atherosclerosis 1976 Sep
PMID:Hepatic cholesterol-7alpha-hydroxylase activity in neurogenic hypercholesterolemia. 97 42

Cholesteryl ester hydrolase activity was measured in the microsomal and supernatant fractions of the aorta of atherosclerosis-susceptible White Carneau and atherosclerosis-resistant Show Racer pigeons while on their normal cholesterol-free diets. Enzyme activities from both fractions showed fatty acid specificities for the hydrolysis of different cholesteryl esters in the following decreasing order: Linoleate greater than oleate greater than palmitate. At 9 months of age (the period of lipid accumulation) the microsomal enzyme activity in the Show Racer breed was significantly higher (P less than 0.001) than in the White Carneau breed, while the supernatant enzyme was slightly higher (P less than 0.05) in the White Carneaux at this age. In older birds (3 years of age) these differences in enzyme activities disappeared.
Atherosclerosis 1976 Sep
PMID:On the cholesteryl ester hydrolase activity in the microsomal and supernatant fractions of pigeon aorta. 97 53

In Rhesus monkeys, nicotinic acid given daily by subcutaneous injection for 5 weeks brought about a reversible decrease in total cholesterol concentration in skeletal muscle and skin to about half the normal value. The decrease in cholesterol concentration was due to a net loss of cholesterol from muscle, since the treatment had no effect on the water content or on the percentage of DNA or protein in fresh tissue. In muscle, free cholesterol was lost in preference to esterified cholesteol, but in skin both cholesterol fraction were affected to about the same extent. Analysis of the cholesterol content of subcellular fractions of homogenates of muscle showed that loss of cholesterol occurred mainly from the soluble fraction and the 800-g sediment, with no significant loss from the mitochondrial or microsomal fractions.
Atherosclerosis
PMID:Loss of cholesterol from muscle and skin of monkeys treated with nicotinic acid. 113 7

The activity of fatty acyl CoA synthetase and fatty acyl CoA:cholesterol acyltransferase was determined in microsomal fractions from normal and atherosclerotic rabbit aortic tissue. No change in fatty acyl CoA synthetase activity was observed as a result of cholesterol feeding in contrast to the several-fold increase in the activity of fatty acyl CoA:cholesterol acyltransferase seen in atherosclerotic tissue. Inhibition of both enzymes was observed when clofibrate, or the tetrahydronapthyl analog of this drug were added in vitro. The inhibitory effects were most pronounced on the fatty acyl CoA:cholesterol acyltransferase.
Atherosclerosis
PMID:Fatty acyl CoA synthetase activity in normal and atherosclerotic rabbit aortic tissue. 120 Nov 48

Male rats were fed a semi-purified diet containing oat bran or wheat bran with or without a marine fish oil to investigate the effects of such combinations on lipid metabolism. Oat bran alone and wheat bran plus fish oil gave lower plasma cholesterol concentrations than wheat bran alone while oat bran plus fish oil gave the lowest. Oat bran increased plasma triacylglycerols compared with wheat bran but oat bran plus fish oil gave concentrations similar to those seen with wheat bran plus fish oil. Oat bran gave higher hepatic cholesterol synthesis rates and a higher activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase compared to wheat bran. The addition of fish oil to either bran diet decreased cholesterol synthesis but HMG CoA reductase activity was not reduced. Oat bran increased hepatic acyl coenzyme A:cholesterol acyl transferase (ACAT) activity and increased the ratio of esterified to unesterified cholesterol in hepatic microsomal membranes compared with wheat bran. Fish oil decreased hepatic LDL receptor activity and increased HDL binding activity when added to the wheat bran diet but these effects were not seen with oat bran. Oat bran also had no effect on hepatic lipoprotein receptor activity compared with wheat bran. These results show that fish oil and oat bran have complementary cholesterol lowering effects in the rat.
Atherosclerosis 1992 Oct
PMID:Fish oil and oat bran in combination effectively lower plasma cholesterol in the rat. 133 53

1. The relationship between atherosclerosis development and changes in arterial fatty acid binding protein (FABP) activity was investigated in the aortas of New Zealand rabbits which were fed an atherogenic diet containing 1% cholesterol and 3% peanut oil for 16 weeks. 2. At 4-week intervals, FABP activity, cholesterol and microsomal acylCoA:cholesterol acyltransferase (ACAT) activity were determined in aortic tissue and serum cholesterol was measured; age-matched normal rabbits served as control comparators. 3. Serum cholesterol increased from 35 mg/dl in the normal rabbits to 2290 mg/dl in the 16-week cholesterol-fed rabbits. 4. The microsomal fraction isolated from cholesterol-fed rabbit aortas exhibited a progressive elevation in ACAT activity as time on the diet increased. By 12-16 weeks, ACAT activity had increased approximately 10-fold relative to normal activity. 5. Arterial cholesterol content of the cholesterol-fed animals increased from less than 2 mg/g wet weight to greater than 10 mg/g wet weight at 12 and 16 weeks. In contrast, arterial FABP activity gradually decreased with time on the cholesterol diet; a significant decrease (P less than 0.05) was observed at 16 weeks, where palmitoyl CoA binding was decreased from 61.0 to 36.3 pmol/mg protein. 6. In the cholesterol-fed rabbits, total arterial cholesterol and ACAT activity showed a significant (P less than 0.05) inverse correlation to FABP activity with correlation coefficients of -0.93 and -0.95, respectively. 7. Additionally, FABP activity increased significantly (P less than 0.05) in the 16-week normal rabbit as compared to the 4-week normal rabbit, suggesting an age-dependent interaction.
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PMID:Temporal evaluation of fatty acid-binding protein (FABP) activity in association with the development of atherosclerosis in the rabbit. 135 84

A potent, bioavailable ACAT inhibitor may have beneficial effects in the treatment of atherosclerosis by (i) reducing the absorption of dietary cholesterol, (ii) reducing the secretion of very low density lipoproteins into plasma from the liver, and (iii) preventing the transformation of arterial macrophages into foam cells. We have found that a mevalonate derivative 2, which contains a 4,5-diphenyl-1H-imidazol-2-yl moiety, inhibits rat hepatic microsomal ACAT in vitro and produces a significant hypocholesterolemic effect in the cholesterol-fed rat. Structure-activity relationships for analogues of 2 demonstrate that the 4,5-diphenyl-1H-imidazole moiety is a pharmacophore for inhibition of rat microsomal ACAT.
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PMID:Acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors. 1. 2-(Alkylthio)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. 144 39


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