Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we investigated the influence of cholesterol depletion and hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibition on chemotaxis of the human monocytic cell line U937. Chemotaxis was nearly completely depressed after incubation for 24 h in the absence of lipoproteins. This was accompanied by a significant decrease in cellular cholesterol. Addition of 10 micrograms/ml low density lipoprotein (LDL) for 2 h to the cholesterol-depleted cells restored chemotaxis. Free cholesterol had no effect under these conditions. Inhibition of HMG-CoA reductase by pravastatin (0.01-1.0 mM) for 20 or 72 h also reduced chemotaxis. However, this effect was not accompanied by a decrease in cellular cholesterol when cells were grown in the presence of lipoproteins. The effect of pravastatin could be reversed by the addition of mevalonate. Addition of LDL did not change the response to pravastatin. We propose that the availability of cholesterol plays an important role in cellular chemotaxis. Furthermore, it can be suggested that other products of the mevalonate pathway apart from cholesterol may contribute to the regulation of chemotaxis.
Atherosclerosis 1991 Oct
PMID:Chemotaxis of the monocyte cell line U937: dependence on cholesterol and early mevalonate pathway products. 175 91

The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis were started from 1971. The first potent inhibitor, ML-236B (compactin), was found from the culture broth of Penicillium citrinum. Among many derivatives of ML-236B, pravastatin sodium (hereafter refer to pravastatin) was finally selected because of its potency and tissue selectivity. Since pravastatin has a hydroxyl group at 6 beta position in the skeleton of decaline of ML-236B, the microbial hydroxylation was adopted for the production of pravastatin. Streptomyces carbophilus was finally chosen as a potent converter with the formation of a lesser amount of by-products. For the sake of industrial production of pravastatin, many devices and improvements were performed for selecting high potent strains and for culturing conditions both with ML-236B and pravastatin. Pravastatin strongly inhibited the sterol synthesis in freshly isolated rat hepatocytes, but only weakly inhibited in the cells from nonhepatic tissues. This selective inhibition of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments by using rats and mice. Pravastatin markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. Pravastatin showed the preventive effect on the development of coronary atherosclerosis and xanthoma in young WHHL rabbits in consequence of maintaining the serum cholesterol levels low. In the clinical trials, pravastatin significantly reduced serum cholesterol and low density lipoprotein cholesterol levels, whereas inversely increased high density lipoprotein cholesterol levels.
 ...
PMID:[Research and development of pravastatin]. 176 49

Epidemiological observations, experimental and clinical researches have laid special stress on the importance of hypercholesterolemia in the natural development of the atherosclerotic disease and its cardiovascular complications. Primary and secondary trials have demonstrated the benefits of cholesterol-lowering therapy to modify the evolution of atherosclerotic disease. In particular, it was observed a significant reduction of incidence and mortality due to coronary heart disease, that is the most common complication of atherosclerosis. At the present time, we have a new class of cholesterol-lowering drugs which is able to inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, the enzyme limiting the endogenous pathway of cholesterol synthesis. The HMGCoA reductase inhibitors, according to the chemical structure, can be divided into two groups. The first includes inactive lactone prodrugs, as Lovastatin and Simvastatin, that are enzymatically hydrolyzed to the corresponding ring-opened active forms in the liver, where the HMGCoA reductase inhibitors must chiefly reduce cholesterol synthesis. To the other group belongs the Pravastatin, a drug that is administered in its active open hydroxyacid form. Several clinical studies seem to demonstrate a greater cholesterol-lowering effect of the active form of Simvastatin, probably because of its more affinity for the HMGCoA reductase enzyme. Up to now, no inhibitor of HMGCoA reductase has showed serious toxic effects in man. The remarkable therapeutic efficacy showed by Simvastatin to reduce the serum concentrations of total and LDL-cholesterol, associated with moderate side-effects, ascribes to this molecule an important role in the therapeutic approach of familial and polygenic hypercholesterolemia.
 ...
PMID:[Hypercholesterolemia: therapeutic approach]. 183 10

Serum lipoproteins and key hepatic and intestinal enzymes regulating cholesterol synthesis, esterification and catabolism, namely 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, acyl coenzyme A: cholesterol-o-acyltransferase (ACAT) and cholesterol 7 alpha-hydroxylase respectively, were compared in two hypercholesterolaemic rabbit models - the cholesterol-fed animal and the hypercholesterolaemic diabetic animal. Hypercholesterolaemia in the cholesterol-fed animals was reflected in the VLDL and LDL fractions, whereas VLDL and HDL2 cholesterol levels were elevated in the diabetic animals. The lipoproteins of the cholesterol-fed animals were enriched with cholesterol but the lipoprotein fractions in the diabetic animals were enriched with triacylglycerol. While hepatic HMGCoA reductase activity was significantly reduced in both groups, the activities of hepatic ACAT and cholesterol 7 alpha-hydroxylase were significantly increased in the cholesterol-fed animals and significantly reduced in the diabetic animals compared with controls. In the intestine, the activity of HMGCoA reductase was increased and ACAT reduced in the diabetic animals. By contrast, in the cholesterol-fed group. HMGCoA reductase activity was lower and ACAT activity was higher in comparison with the control group. These differences in lipoproteins and cellular cholesterol metabolism between the hypercholesterolaemic rabbit models may explain the differences in susceptibility to atherosclerosis, previously reported in these two animal models.
 ...
PMID:Serum lipoproteins and cholesterol metabolism in two hypercholesterolaemic rabbit models. 188 84

A study was made on the effect of simvastatin (the generic name of MK-733), a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on coronary atherosclerosis in cholesterol-fed rabbits with focus on the serum lipids and morphology. Twenty-seven Japanese white rabbits were divided according to dosage of simvastatin into four groups as follows, group P (placebo, 5 rabbits), group MK 1 (simvastatin 1mg/kg, 5 rabbits), group MK 3 (simvastatin 3mg/kg, 6 rabbits) and group MK 5 (simvastatin 5mg/kg, 5 rabbits). They were placed on a 0.5% cholesterol atherogenic diet for 16 weeks and measurements were made of the concentration of serum lipids weekly. After sacrifice, the degree of surface involvement (SI) of aorta stained with Sudan III and the degree of coronary stenosis (CS) of the left circumflex artery were measured using an image-processing system. Serum total cholesterol (TC) level and beta-lipoprotein level decreased dose-dependently in MK groups compared with group P. High density lipoprotein cholesterol level increased in groups MK 3 and MK 5 slightly. Triglyceride level decreased in groups MK 3 and MK 5. The progressions of SI and CS were suppressed in MK groups dose-dependently. Integrated TC, that is, sum of the serum TC values obtained at each week multiplied by 7 corresponded more closely to CS than SI. Intimal thickening constructed from large foam cells originated from macrophages and proliferating smooth muscle cells included lipid droplets in MK groups was almost similar in group P. But it was likely that lipid droplets in each smooth muscle cell in MK groups were less than in group P. In conclusion, the development of coronary atherosclerosis in cholesterol-fed rabbits was suppressed dose-dependently by simvastatin and it was suggested that this preventive effect was due to reducing the integrated TC and local action to vessel walls by simvastatin. (Fukuoka Acta Med.)
 ...
PMID:[Preventive effect of simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on coronary atherosclerosis in cholesterol-fed rabbits]. 202 60

Available data on results of lipid-acting drug trials investigating the prevention or treatment of atherosclerotic cardiovascular disease have conclusively shown that: (a) The beneficial results may not be specific for a given pharmacological group of drugs (i.e., niacin, resins, fibrates, reductase inhibitors). (b) For lipid-acting drugs, the extent of cardiovascular benefit may be related to the extent of the effect on blood lipids. (c) Some drugs may be acting by affecting factors not necessarily related to blood lipid levels (i.e., calcium channel blockers and antioxidants of low-density lipoproteins. (d) The differences in endpoints begin to appear after the second year of intervention. (e) The effects on atherosclerosis can be measured objectively by modern angiographic techniques. (f) Patient's signs and symptoms of disease can be beneficially modified. (g) The long-term safety record of the tested drugs seems adequate. (h) The risk-benefit ratio justifies long-term drug treatment of dyslipidemias in patients not responding to life-style intervention.
 ...
PMID:Drug intervention trials in dyslipidemia: the past and the future. 204 59

In 6 normal rabbits, the aortic arch, the descending thoracic and the abdominal aorta were tested for non proteic thiol compounds, selenium-dependent and selenium-independent glutatione peroxidase, glutatione reductase, glutatione transferase and thiobarbituric acid reactive substances. The aortic arch showed the greatest content of non proteic thiol compounds and thiobarbituric acid reactive substances, associated to the highest activities of glutathione-related enzymes. However, not significant differences were detectable between aortic arch and descending thoracic aorta, except for the glutathione transferase activity (0.395 +/- 0.031 vs 0.330 +/- 0.053 U/mg protein, p less than 0.05). Furthermore, both aortic arch and descending thoracic aorta showed significantly higher values of non proteic thiol compounds (46.05 +/- 10.15% and 33 +/- 13.5%, p less than 0.05), selenium-dependent glutathione peroxidase activity (70.35 +/- 26% and 54.3 +/- 9.5%, p less than 0.05), glutathione reductase activity (25.4 +/- 7% and 18.4 +/- 4.5%, p less than 0.05) and thiobarbituric acid reactive substances (65.8 +/- 18% and 47.2 +/- 17%, p less than 0.05) with respect to the abdominal aorta. The selenium-independent glutathione peroxidase activity was not detectable. In conclusion, a biochemical gradient in glutathione-related antioxidant defences and thiobarbituric acid reactive substances proceeding from the proximal to the distal segments seems to exist in the normal rabbit aorta. These results could contribute to explain the non homogeneous distribution of experimental atherosclerosis in the rabbit aorta.
 ...
PMID:Regional distribution of glutathione-related antioxidant defences in the normal rabbit aorta. 204 54

In 1973, studies with cultured human fibroblasts by Brown, Goldstein, and colleagues showed that receptor-mediated endocytosis of low-density lipoprotein (LDL) is the regulatory principle in cellular cholesterol homeostasis. The complete sequence of metabolic events associated with the binding, uptake, and degradation of these cholesterol-rich lipoprotein particles by mammalian cells has been termed the LDL receptor pathway. This important process has two main tasks. First, it supplies cells with cholesterol, thereby mediating the removal of cholesterol-rich lipoproteins from the circulation. Second, it protects cells from over-accumulation of cholesterol, because the cholesterol derived from lysosomal hydrolysis of LDL cholesterylesters exerts a series of feedback control mechanisms designed to maintain a constant level of cholesterol within the cell. Thus, high extracellular concentrations of LDL reduce cellular synthesis of cholesterol (by suppression of the activities of 3 hydroxy-, 3-methyl-glutaryl-CoA synthase and reductase, rate-limiting enzymes in cholesterol synthesis), stimulate its re-esterification, and decrease the number of LDL receptors, preventing further cellular entry of cholesterol. The suppression of LDL receptor activity by high plasma levels of LDL is beneficial for most cells, but the consequences caused by reduction of LDL receptor activity in the liver can be devastating. This is best documented in familial hypercholesterolemia (FH), in which defects in the LDL receptor gene disrupt the normal functions of the LDL receptor pathway. The clinical manifestation of the failure to remove LDL from the bloodstream at normal rates includes severe hypercholesterolemia and premature atherosclerosis. Some of the important findings that emerged from studies on structure/function relationships of the key player in the process, the LDL receptor itself, are described.
 ...
PMID:Familial hypercholesterolemia: dissection of a receptor disease. 209 41

Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia.
 ...
PMID:Management of dyslipidemia in NIDDM. 219 Jul 70

Pharmacologic intervention for altering plasma lipoproteins is aimed principally at reducing atherogenesis and thereby preventing coronary artery disease. These drugs should be prescribed only after nonpharmacologic interventions (reduction of saturated fat and cholesterol consumption, weight reduction, aerobic exercise, cessation of cigarette smoking) have failed to achieve an adequate effect. The plasma concentration of the atherogenic low-density lipoprotein (LDL) may be reduced in hypercholesterolemic patients by increasing hepatic LDL receptor synthesis (bile acid sequestering resins, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors) or by reducing hepatic very low density lipoprotein synthesis (gemfibrozil, nicotinic acid). LDL concentration may also be reduced by treatment with one of the fibrates (e.g., fenofibrate). Several classes of lipid-lowering drugs also increase the plasma high-density lipoprotein (HDL) cholesterol concentration. In the case of the fibrates, this appears to be principally mediated through an increase in lipoprotein lipase activity. Gemfibrozil additionally stimulates apolipoprotein AI synthesis. The increase in HDL cholesterol produced by nicotinic acid is due primarily to decreased clearance of HDL particles from the circulation. The increase in HDL concentration produced by gemfibrozil was shown in the Helsinki Heart Study to make a major contribution to a reduced incidence of coronary artery disease, independently of that made by the decrease in LDL. The Cholesterol-Lowering Atherosclerosis Study demonstrated that combined therapy with a resin (colestipol) and nicotinic acid can reduce the progression of coronary atherosclerosis and the development of graft lesions in patients who have undergone coronary artery bypass graft surgery.
 ...
PMID:Pharmacotherapy of disorders of plasma lipoprotein metabolism. 220 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>