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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis, coronary artery disease and elevated serum cholesterol are frequently associated with an abnormal pattern of androgen metabolites, especially an elevation of etiocholanolone (E) and/or epiandrosterone (EA) relative to androsterone (A). Therapeutic correction of these metabolic defects may lower serum cholesterol. We have attempted to reproduce this metabolic syndrome in rats by altering their endocrine status. Intact male rats excreted very little A or E in their bile; more than 80% of the [4-14C]A-dione was excreted as unknown polar compounds. Adrenalectomy, thyroidectomy or streptozotocin diabetes induced little or no change in the excretion of both E and A and did not alter the A/E ratio. Hypophysectomy (hypox), however, resulted in a huge increase in E excretion and a 10-fold decrease in the A/E ratio. Treatment of hypophysectomized males with bovine growth hormone (bGH) but not testosterone or thyroxine restored the pattern of androgen metabolites to that of intact male rats. Intact female rats excreted mainly A, and this was decreased by ovariectomy. Hypophysectomy, however, resulted in a marked increase in E and a corresponding large decrease in A excretion. Treatment of hypox females with estradiol or triiodothyronine did not correct the metabolic defects in A and E production, whereas GH resulted in a pattern of A-dione metabolism resembling that of intact males; i.e., primarily polar metabolites with low A and E. Hypophysectomy thus results in a dramatic increase in 5 beta-reductase activity in male and female rats. GH therapy restores the metabolic pathway to that seen in intact males. Our objective had been to find a model capable of detecting substances which would increase A and decrease E production. The male rat (regardless of endocrine status) has little 5 alpha-reductase activity. The intact female rat, however, has high 5 alpha-reductase activity, and retains significant 5 alpha-reductase in the absence of the ovaries. In hypox females, 5 alpha-reductase was much reduced while 5 beta-reductase was increased. Furthermore, serum cholesterol was elevated in hypox females but could be lowered by exogenous androsterone. Thus the hypox female rat appears to offer the best model for identifying non-hormonal agents which could enhance the production of A and/or decrease the production of E. Such agents might favorably influence cholesterol metabolism.
Atherosclerosis 1985 Jan
PMID:Effects of altered endocrine function on biliary metabolites of [4-14C]androst-4-ene-3,17-dione in rats. Possible utility as a model for identifying anti-atherosclerotic agents. 399 76

A light microscopy study on the localization of enzyme activity within atherosclerotic human intracranial arteries was performed on autopsy material obtained within 4 hours of death. The data suggests that the atherosclerotic process first goes through a proliferative phase and then a degenerative phase culminating in the formation of a plaque. In the proliferative phase, smooth muscle cell proliferation has formed a thickened intima. Tetrazolium reductase, adenosine triphosphatase (ATPase) and adenosine monophosphatase (AMPase) activities are present in these cells, while all dehydrogenases and acid phosphatase activities were weak or not present. As the degenerative phase commences, an area of necrosis, lipid and macrophage accumulation is formed on the lumen side of the elastica. This area increases in size until a plaque is formed. Unsaturated polar and nonpolar lipid, cholesterol, alpha-glycerophosphate dehydrogenase, acid phosphatase, and AMPase activities are associated with these areas and in foam cells, which are often found in the thickened intima of the proliferative phase. Tetrazolium reductase and ATPase activities decrease in the thickened intima as the area of necrosis increases in size, while dehydrogenase activity, except that for alpha-glycerophosphate, remains low or not present. Patterns of enzyme alterations for various stages of the disease process in intracranial arteries, the aorta and coronary arteries suggest a similar, if not identical, progression of the atherosclerotic process, irrespective of known differences in the prevalence of atherosclerosis.
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PMID:A histoenzymatic study of human intracranial atherosclerosis. 426 Jul 21

Hepatic beta-hydroxy-beta-methylglutaryl CoA (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase (7 alpha-hyd), and fatty acid synthetase (FAS) activities and cholesterol levels were determined in chicks fed isonitrogenous corn- and high-protein barley flour (HPBF) based diets. HMG-CoA reductase (-27%), 7 alpha-hyd (-30%), and serum cholesterol (-13%) were reduced, whereas FAS increased (28%) in comparison to a corn-based (control) diet. fractions obtained by serial extractions of HPBF with solvents of increasing polarity were fed at levels equivalent to 20% HPBF in a corn-based diet to female White Leghorn (WHL) chickens for 3 weeks. A petroleum ether-soluble fraction of HPBF produced 3 effects: an increase in body weight (18%), a strong suppression of HMG-CoA reductase (-36%) and FAS (-40%) accompanied by decreases in serum triglyceride (-9%) and cholesterol levels (-23%). The methanol-soluble fraction produced a significant suppression of HMG-CoA reductase (-49%) and serum cholesterol level (-29%), and an increase in FAS activity (95%). These effects were duplicated in 7-week-old broiler chickens which also showed a significant decrease in chol-LDL (low density lipoprotein) levels by these fractions. The factor(s) lowering serum cholesterol concentration was about equally divided between the polar and nonpolar fractions, and each was significantly more effective than the 20% HPBF in the corn-based diet. The observed effects on lipogenesis and cholesterogenesis might be attributed to a number of chemical constituents of HPBF, but cannot be attributed to the water-insoluble plant fibers.
Atherosclerosis 1984 Apr
PMID:Suppression of cholesterol biosynthesis by constituents of barley kernel. 672 4

AMO 1618 (2-isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine carboxylate methyl chloride) was added to corn-soy based diets and fed to 9-week-old female chickens for 3 weeks to measure the inhibition of hepatic beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase. Dose-related decreases in the activities of these two enzymes were obtained (2.5--15 ppm) of AMO 1618. Decreases in plasma total cholesterol, chol-HDL, and chol-LDL levels were observed, but the decreases in chol-LDL were substantially larger than those of chol-HDL in both chicken and rat. Assays of livers from rats fed 20 ppm AMO 1618 for 3 days had 24% less HMG-CoA reductase activity and 67% less cholesterol 7 alpha-hydroxylase activity than the controls. Plasma cholesterol in these animals was reduced 26%; the ratio of total cholesterol : chol-HDL was reduced from 3.27 to 2.67 and the chol-LDL : chol-HDL ratio was reduced from 1.96 to 1.14 as a result of the relatively brief treatment. Fatty acid synthetase (FAS) and other key lipogenic enzymes increased 1.5--4-fold in both the chicken and rat. The inhibition of HMG-CoA reductase and the induction of FAS by AMO 1618 were tested in vitro, using 10--100 micrograms (28--280 mumoles) for 15 min with isolated hepatocytes from chicken and rat. Linear responses in activity were dose-dependent and increased with duration of incubation (30 micrograms or 85 mumoles AMO 1618, 5--120 min) in both species. The results suggest the compound acts at the cellular level and AMO 1618 appears to possess several properties which recommend it for testing as a cholesterol-lowering agent in humans.
Atherosclerosis 1983 Feb
PMID:Effect of AMO 1618 on cholesterol and fatty acid metabolism in chickens and rats. 683

When cultured human skin fibroblasts were incubated at 37 degrees C with sonically dispersed positively charged sphingomyelin liposomes, sphingomyelin accumulated within the cell. This resulted in stimulation of cholesterol synthesis by increasing 3-hydroxy-3-methylglutaryl Coenzyme A reductase activity. Activation was rapid and was not due to the efflux of cell cholesterol or to cell growth and proliferation. Neither low density lipoprotein cholesterol nor nonlipoprotein cholesterol could suppress the sphingomyelin-induced cholesterol synthesis or activate the acyl-CoA cholesterol acyltransferase, despite an increase in cell cholesterol content. In contrast, the response to 7-ketocholesterol or 26-hydroxycholesterol was not impaired. The effect of sphingomyelin on cholesterol synthesis was temporary and reversible. Twenty-four hours after removal of sphingomyelin, cholesterol synthesis returned to normal and could be suppressed by LDL. Accumulation of sphingomyelin in the cell decreased lysosomal cholesteryl ester hydrolase but had no effect on the microsomal cholesteryl ester hydrolase. These results suggest that accumulation of sphingomyelin in the cell markedly affects cellular cholesterol homeostasis. Resultant accumulation of cholesteryl esters in the presence of extracellular cholesterol could be relevant to atherogenesis.
Atherosclerosis 1983 Mar
PMID:Effect of positively charged sphingomyelin liposomes on cholesterol metabolism of cells in culture. 684 46

The effects of ginseng root powder and of serially extracted solvent fractions of ginseng on avian hepatic cholesterol metabolism and lipogenesis and on avian serum lipoprotein cholesterol levels were examined. In one study, White Leghorn females were fed for 4 weeks a corn-based diet (control) or an experimental diet in which was incorporated 0.25% Wisconsin ginseng or an equivalent quantity of a serial solvent fraction [petroleum ether (PESF), methyl alcohol (MESF), water (WASF)] or of the residue. beta-hydroxy-beta-methylglutaryl-CoA (HMG-CoA) reductase activity was significantly lower (P less than 0.01) in each of the treatment groups (31-37% of control activity) except that fed the extracted residue (90% of control, N.S.). Cholesterol 7 alpha-hydroxylase activity was lowered in parallel (45-64% of control, P less than 0.01) by all treatments except the residue (100% of control). Also with the exception of the residue treatment, each ginseng treatment effected a lowering of the serum total cholesterol level (67-83% of control, P less than 0.01) and of serum low density lipoprotein cholesterol level (53-81% of control, P less than 0.01). Lipogenic activities and serum triglycerides levels were lowered (P less than 0.01) by two of the ginseng treatments. The PESF treatment was the most effective suppressor of each parameter, 74% and 68% respectively, of the control values. The WASF also had significant impact. Not one of the experimental diets influenced the serum high density lipoprotein level. The PESF, the potent source of suppressors, effected a change in the ratio of low to high density lipoprotein cholesterol from 1.46 (control) to 0.88. The levels of cholesterol and triglycerides in liver under these conditions showed a similar pattern as that of serum. In companion studies, broiler females were fed 0.28% Chinese red ginseng root powder or its various fractions. The results confirmed those recorded above. The factor(s) responsible for lowering the serum total and low density lipoprotein cholesterol levels were generally more concentrated in the PESF and WASF of ginseng and each was significantly more effective than was ginseng root powder. Ginsenosides (saponins) are considered to be the active agents for the suppression of cholesterogenesis and lipogenesis.
Atherosclerosis 1983 Jul
PMID:Suppression of cholesterogenesis and reduction of LDL cholesterol by dietary ginseng and its fractions in chicken liver. 688 11

It has been proposed that a platelet-derived growth factor (PDGF) may play an important role in the genesis of atherosclerosis by promoting proliferation of smooth muscle cells. The present study shows evidence that fenofibric acid inhibits the growth promoting activity of PDGF on cultured smooth muscle cells. When smooth muscle cells are in a quiescent state by feeding them a PDGF -and lipoproteins- deficient medium, addition of a platelet extract induces DNA synthesis in a synchronous fashion. A 6 hours' exposure of cells to this extract is sufficient for this effect. Fenofibric acid could inhibit this synthesis when the compound was present in the culture medium concomitantly with platelet extract. This result suggests that fenofibric acid target is a cellular event attendant on PDGF-induced growth promotion. Fenofibric acid is a hypolipidemic drug which inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCoA reductase) activity, the limiting step of endogenous cholesterol synthesis. If any endogenous cholesterol is available, smooth muscle cell cholesterol needs for proliferation can be supplied by LDL-cholesterol. As the addition of LDL to the culture medium did not overcome fenofibric acid inhibition, this demonstrates a cholesterol independent mechanism for the anti-PDGF growth promoting activity. The fact that fenofibric acid, a hypolipidemic drug, can also inhibit growth promoting activity of PDGF suggests that this drug can be effective on the prevention of atherosclerosis and cardiovascular diseases by at least two independent mechanisms.
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PMID:Evidence for the inhibition of platelet-derived growth factor induced rat smooth muscle cells DNA synthesis by fenofibric acid at the Go/G1 cell cycle level. 688 56

Mevinolin, a fungal metabolite isolated from cultures of Aspergillus terreus, is a potent competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis. In the current studies we demonstrate that mevinolin significantly lowers serum cholesterol in rabbits fed a cholesterol free, low-fat semi-synthetic diet. Rabbits maintained on this diet developed endogenous hypercholesterolemia with average cholesterol concentrations of 310 mg/dl over a 66-day period. Treatment with mevinolin for 39 days at a dose of 2 mg/kg per day lowered serum cholesterol levels by an average of 37% (P less than 0.05), while a dose of 6 mg/kg per day resulted in a 48% (P less than 0.05) decrease when compared with the control group. When the administration of mevinolin was discontinued, serum cholesterol levels of the 6 mg/kg per day group increased significantly to a maximum post-treatment value of 319 mg/dl (P less than 0.0001). The results of this study demonstrate that rabbits with endogenous hypercholesterolemia are a useful animal model for the study of cholesterol biosynthesis inhibitors like mevinolin.
Atherosclerosis 1982 Jul
PMID:The effects of mevinolin on serum cholesterol levels of rabbits with endogenous hypercholesterolemia. 692 95

Regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC: 1.1.1.34), by heterologous human lipoproteins and hormones was studied in a maintenance culture of rat hepatocytes. The liver cells were cultured under hormone and serum free conditions and maintained differentiated morphology and specific function. Under control conditions total HMG-CoA reductase increased by 50% after 24 h culture compared to 0 h values immediately after isolation. Thereafter a plateau of enzyme activity was reached lasting until 48 h, with a slight decline at 72 h. Concomitantly the "expressed" enzyme activity increased steadily, probably through dephosphorylation of latent reductase, the activation was largely complete at 48 h. During the steady state period of total reductase VLDL added to the medium at concentrations up to 50 microgram/ml protein had no effect o HMG-CoA reductase activity. In contrast, LDL suppressed the enzyme in a dose-dependent fashion to 40% of controls at 100 microgram/ml. On the other hand, HDL had the opposite effect with a significant induction up to 252% of controls at 50 microgram/ml. Insulin also caused a comparable dose-dependent stimulation of enzyme activity at 10(-8) and 10(-7)M, whereas glucagon inhibited reductase activity. Compared to the insulin action, triiodothyronine and triamcinolone prompted a minor, but still significant increase of reductase activity. Insulin and triamcinolone acted synergistically, but the combination of triamcinolone and tri-iodothyronine was only additive. All hormonal inductions of reductase could be blocked by cycloheximide. The present data establish that HMG-CoA reductase of maintenance cultured hepatocytes is subject to a complex regulation by heterologous lipoproteins as well as pancreatic, adrenal and thyroid hormones.
Atherosclerosis 1982 Jan
PMID:3-Hydroxy-3-methylglutaryl CoA reductase in cultured hepatocytes. Regulation by heterologous lipoproteins and hormones. 707 95

The effects of skim milk powder (SMP) and fluid skim milk (FSM) on plasma cholesterol (CH) and hepatic liquid concentrations, and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase activity of rats of different ages were compared. Groups of young (23 days old) and older (45 days old) rats were fed a casein -based diet and provided tap water; the casein-based diet and FSM as fluid source; or tap water and the casein diet into which SMP (25% by wt.) had been isocalorically incorporated. Plasma CH concentrations were determined at 0, 1.5, 3 and 5 wk, hepatic total lipid, triglyceride and CH at 5 wk. Half of each group were killed at wk 3 and the other half at wk 5 for determinations of HMG CoA reductase activity. Both FSM and SMP decreased plasma CH levels at 1.5 and 3 wk of feeding in the young rats; plasma CH concentrations of the older rats were not altered by either FSM or SMP. Both milk derivatives increased HMG CoA reductase activity at wk 3 and wk 5 in both ages of rat, whereas hepatic lipid levels were unchanged. In these experiments the effects of feeding FSM of SMP along with a casein-based diet were comparable and included an increase in HMB CoA reductase activity, no change in hepatic lipid levels, and a decrease in plasma CH; the latter response depended on the initial age of the rat.
Atherosclerosis 1981 May
PMID:Plasma and hepatic cholesterol and hepatic HMG CoA reductase levels in rats fed fluid or powdered skim milk. 724 1


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