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)

To assess the direct effect of androgen on the development of atherosclerosis, we investigated the effect of androgen and its receptor expression in rat vascular smooth muscle cells (VSMC) isolated from rat aorta. We detected the androgen receptor mRNA in VSMC by reverse transcription of the total RNA coupled with amplification of the resulting cDNA by polymerase chain reaction. Binding studies revealed the presence of a single class of binding sites for testosterone (Kd 7.37 nM, Bmax 10.59 fmol/mg protein) and dihydrotestosterone (DHT; Kd 4.89 nM, Bmax 11.37 fmol/mg protein) in VSMC. Measurement of 5 alpha-reductase activity suggested that testosterone is converted to DHT in VSMC (Km 0.36 microM, Vmax 623 fmol/mg protein/h). Moreover, in the present study, DHT significantly stimulated DNA synthesis of VSMC (120-160% of control). The mitogenic activity of testosterone is much less potent than that of DHT. Considering these results, we concluded that androgen may directly accelerate atherosclerosis by stimulating the proliferation of VSMC.
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PMID:Androgen receptors, 5 alpha-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells. 804 46

Recent studies demonstrated that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase lower plasma triglyceride primarily by decreasing hepatic secretion of very low density lipoproteins (VLDL). A possible mechanism is that inhibition of cholesterol synthesis interferes with the assembly of VLDL particles. Since one molecule of apolipoprotein (apo) B is required for the proper assembly and secretion of each VLDL and secretion of apo B may be regulated by various lipid components of the lipoproteins, question arises whether HMG-CoA reductase inhibitors also decrease the secretion of apo B. To address this issue, we investigated the effect of lovastatin on the secretion rate of VLDL-apo B and on the composition of VLDL in the Zucker obese rat; a model for genetic hypertriglyceridemia. Lovastatin treatment (4 mg/kg day x 13 days), as compared with placebo, decreased the concentrations of fasting plasma triglyceride (1740 +/- 170 vs. 3130 +/- 790 micrograms/ml) and VLDL-triglyceride (1379 +/- 59 vs. 3082 +/- 715 micrograms/ml). There was a small but non-significant decrease in VLDL-apo B (19 +/- 2 micrograms/ml vs. 26 +/- 7 micrograms/ml). Thus, lovastatin significantly decreased the ratio of triglyceride to apo B in VLDL (76 in lovastatin vs. 124 in placebo group). Secretion rates of VLDL-lipids and VLDL-apo B were measured after intravenous injection of Triton WR-1339.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1993 Dec
PMID:Effect of lovastatin on the secretion of very low density lipoprotein lipids and apolipoprotein B in the hypertriglyceridemic Zucker obese rat. 814 38

Previous studies have shown that both cholesterol synthesis and the activity of hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, are increased in the small intestine of a wide variety of different animal models of diabetes. In the present study, we demonstrate that the mass of HMG CoA reductase protein is increased in the small intestine of both streptozocin-induced diabetic rats (2.5-fold) and streptozocin/alloxan-induced diabetic dogs (2.4-fold). These increases in HMG CoA reductase protein mass are of a magnitude similar to the previously observed increases in either HMG CoA reductase activity and/or cholesterol synthesis in the small intestine of diabetic animals. Furthermore, mRNA levels for HMG CoA reductase in the small intestine of diabetic rats and diabetic dogs are increased 2.1- and 1.7-fold, respectively. These results suggest that the increase in HMG CoA reductase protein levels in the small intestine of diabetic animals is due to an increase in mRNA levels. In contrast, mRNA levels for HMG CoA reductase in the liver of diabetic rats are not increased. Additionally, mRNA levels for the low-density lipoprotein (LDL) receptor are also increased in the small intestine of diabetic animals (rats, 43%; dogs, 59%). The increase in small-intestinal cholesterol synthesis has the potential for adversely affecting lipoprotein metabolism and increasing the risk of atherosclerosis in diabetes.
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PMID:Diabetes increases hepatic hydroxymethyl glutaryl coenzyme A reductase protein and mRNA levels in the small intestine. 815 2

The role of mevalonate and its products (isoprenoids) in the control of cellular proliferation was examined by investigating the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (vastatins) on growth and on cholesterol biosynthesis of cultured arterial myocytes (SMC). Simvastatin (S) and fluvastatin (F), but not pravastatin (P), decreased the rate of growth of rat vascular SMC. The inhibition, evaluated as cell number, was dose-dependent with IC50 values of 2.8 and 2.2 microM for S and F, respectively; P (1-500 microM) was inactive. The inhibition of cell growth induced by 3.5 microM S (70% decrease) was prevented completely by the addition of 100 microM mevalonate, partially (70-85%) by the addition of 10 microM geraniol, 10 microM farnesol and 5 microM geranylgeraniol, but not by the addition of squalene, confirming the specific role of isoprenoid metabolites in regulating cell proliferation. All the tested vastatins inhibited the incorporation of [14C]acetate into cholesterol but P had 800 times lower potency than S and F. Similar results were obtained in SMC from human femoral artery. At least 80% inhibition of cholesterol synthesis was necessary to induce a decrease in SMC proliferation. To further investigate the relationship between cholesterol synthesis and cell growth, two enantiomers of F were investigated. The enantiomer more active on HMG-CoA reductase was 70- and 1.6-fold more potent on arterial myocyte proliferation than its antipode and the racemic mixture, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1993 Jun
PMID:Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. 821 98

Hyperlipidaemia is an invariable complication of the nephrotic syndrome. The quantitative and qualitative changes in lipoproteins which occur may accelerate atherosclerosis. The pathogenetic mechanisms of the hyperlipidaemia are complex and poorly understood. Increases in lipoprotein production are compounded by reduced lipolysis of very low density lipoprotein and impaired catabolism of low density lipoprotein. Both proteinuria and hypoalbuminaemia have been implicated in the genesis of these abnormalities. The optimum treatment of the hyperlipidaemia has not been determined. 3-Hydroxy-3-methyl-glutaryl co-enzyme A reductase inhibitors appear to be the most effective lipid-lowering drugs, although their ability to reduce ischaemic events or prevent/delay renal failure remains to be proven.
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PMID:Pathogenesis of lipid abnormalities in patients with nephrotic syndrome/proteinuria: clinical implications. 823 98

Existing evidence suggests that dyslipidemia associated with long-lasting nephrotic syndrome and with chronic renal insufficiency may favor in the long run the occurrence of cardiovascular complications, and also aggravate glomerular damage with a pathological mechanism analogous to atherosclerosis. Correction of hypercholesterolemia and hypertriglyceridemia is therefore mandatory in both clinical conditions. This goal can be achieved with the combination of dietary intervention and the administration, even for long periods of time, of hypolipemic drugs (hydroxymethylglutaryl coenzyme A, HMGCoA, reductase inhibitors, to correct hypercholesterolemia in nephrotic syndrome, and fibric acids, to correct hypertriglyceridemia in uremic and dialyzed patients are the drugs of choice). In end-stage renal failure, the choice of the type of dialysis is also important. The value of extracorporeal LDL cholesterol removal is still to be proven.
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PMID:Treatment of hyperlipidemia in human renal disease. 823 7

It has been postulated that oxidatively modified low-density lipoprotein (LDL) contributes to the genesis of atherosclerosis. Ubiquinone has been suggested to be an important physiological lipid-soluble antioxidant and is found in LDL fractions in the blood. We measured plasma level of ubiquinone using high-performance liquid chromatography and plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in 245 normal subjects (186 males, 59 females) and in 104 patients (55 males, 49 females) who had coronary artery disease not receiving pravastatin and 29 patients (12 males, 17 females) receiving pravastatin. In the normal subjects, the plasma ubiquinone levels did not vary with age. In the patient groups, the plasma total cholesterol and LDL levels were higher and the plasma ubiquinone level lower than in the normal subject group. The LDL/ubiquinone ratio was higher in the patient groups. We found that ubiquinone level, either alone or when expressed in relation to LDL levels, was significantly lower in the patient groups compared with the normal subject group. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor is thought to prevent atherosclerosis, however, it also inhibits ubiquinone production. The present study revealed that HMG CoA reductase inhibitor decreased plasma cholesterol level, and that it did not improve either the ubiquinone level or the LDL/ubiquinone ratio. From these results, the LDL/ubiquinone ratio is likely to be a risk factor for atherogenesis, and administration of ubiquinone to patients at risk might be needed.
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PMID:Coenzyme Q10 and coronary artery disease. 824 93

In 3-month-old homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits the effect of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin was studied for 9 months and related to the endothelial function of the coronary arteries of isolated hearts and rings of the distal abdominal aorta. Oral administration of pravastatin in doses up to 40 mg/kg per day significantly decreased plasma cholesterol by 51% in comparison to untreated WHHL rabbits. Basal coronary flow and bradykinin-induced increase in coronary flow in Langendorff hearts of the pravastatin-treated animals were significantly greater than the flow in the control animals, whereas the metacholine-induced relaxation of abdominal aortic rings was not different and attenuated in comparison to New Zealand white rabbits. The incidence of atherosclerotic lesions in four main coronary arteries and the aorta was significantly lower in the pravastatin treated animals (25.0% and 52.8% respectively) than in untreated WHHL rabbits (34.1% and 80.0% respectively). The mean percentage of narrowing in the aorta was also significantly lower in the pravastatin-treated group (12.0%) than in the controls (25.2%). Significant correlations were found between the extent of atherosclerotic lesions and the bradykinin-induced increase in coronary flow versus plasma total cholesterol levels. Thus, in this model, long term cholesterol lowering treatment with pravastatin starting at an early age retards the progression of plaque formation and preserves the endothelium-dependent relaxation of the coronary arteries.
Atherosclerosis 1993 Nov
PMID:The effect of cholesterol reduction on the endothelial function and progression of atherosclerosis in WHHL rabbits. 829 97

The Multicenter Anti-Atheroma Study (MAAS) is a 2 + 2-year, placebo-controlled trial to evaluate the effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitor, on progression and regression of coronary atherosclerosis in patients with established coronary artery disease. This paper describes the aims, methodology, and baseline data. Patients with at least two coronary segments visibly involved with atherosclerosis, in whom an angiogram was carried out according to the standards required for quantitative analysis, were selected provided that the serum total cholesterol was between 5.5 and 8.0 mmol/L and fasting triglycerides were lower than 4 mmol/L. Between march 1988 and October 1989, 383 eligible patients of both sexes aged 30-67 years were randomized in 11 European clinics. Patients received either 20 mg oral simvastatin or placebo daily for 2 years in addition to dietary counseling. The primary outcome measures are the change in the mean absolute width and in the mean of the minimal width of segments analyzed quantitatively by coronary angiography performed before and after 2 and 4 years of trial medication. To this end, at least 5 coronary artery segments are analyzed in each angiogram using matched view. The 2-year analysis was completed on 89% of eligible patients in February 1992. The trial was initially designed with a 2-year treatment period. To allow for the possibility to extend this, the decision was taken to keep all patients on the original medication allocation until all 2-year angiograms had been analyzed. Based on a predefined decision rule, an independent committee then recommended extension of treatment with another 2 years, to be concluded by a third angiogram. Of the patients enrolled initially, 81% continued. Four-year follow-up will be completed late 1993 and final results are expected mid 1994.
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PMID:Effect of cholesterol reduction by simvastatin on progression of coronary atherosclerosis: Design, baseline characteristics, and progress of the Multicenter Anti-Atheroma Study (MAAS). 833 51

In the rabbit, dietary cholesterol downregulates the hepatic LDL receptor and concomitant treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors partly restores its expression. The aim of this study was to determine whether the LDL receptor activity of circulating mononuclear cells would reflect the changes seen in liver. New Zealand White rabbits were fed for 3 weeks either a normal diet or diets containing 0.25% (w/w) cholesterol, 0.25% cholesterol plus 22 mg/kg per day pravastatin or 0.25% cholesterol plus 6 mg/kg per day simvastatin. Dietary cholesterol increased plasma cholesterol 8.9-fold, liver membrane cholesterol 1.8-fold and bile cholesterol saturation 2.3-fold, and decreased the LDL receptor activities of liver and mononuclear cells by 69% and 58%, respectively. In the cholesterol-fed rabbit, pravastatin decreased plasma cholesterol by 55%, liver membrane cholesterol by 29% and bile cholesterol saturation by 23%, and increased liver and mononuclear cell LDL receptor activities by 120% and 77%, respectively. Similarly, simvastatin decreased plasma cholesterol by 74%, liver membrane cholesterol by 24% and bile cholesterol saturation by 38%, and increased liver and mononuclear cell LDL receptor activities by 80% and 62%, respectively. Liver and mononuclear cell LDL receptor activities were directly correlated (r = 0.73, P < 0.005) and both activities were inversely correlated with plasma cholesterol concentration in a log-linear fashion (r = -0.70, P < 0.005 and r = -0.69, P < 0.01, respectively). The LDL receptor activity of mononuclear cells therefore reflected the hepatic LDL receptor activity in these rabbits.
Atherosclerosis 1993 Jul
PMID:Coordinate changes in the low density lipoprotein receptor activity of liver and mononuclear cells in the rabbit. 837 60


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