Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme A reductase, on the growth of human Ito cells.

Mavier P.

Unite INSERM-99, Hopital Henri Mondor, Creteil, France.

During hepatic fibrogenesis, Ito cells proliferate, acquire a myofibroblastlike phenotype and synthesize increased amounts of extracellular matrix components. In this study, we have assessed the effects of simvastatin, an inhibitor of hydroxy-methylglutaryl-coenzyme A reductase, on the growth of human myofibroblastlike Ito cells. Cells were grown from explants of normal human liver and characterized by a positive staining for desmin and smooth muscle alpha-actin. Simvastatin (0.1 to 10 mumol/L) induced a marked dose-dependent decrease of [3H]thymidine incorporation in human Ito cells, whether stimulated by human serum or by purified growth factors. Simvastatin-induced inhibition of DNA synthesis was confirmed by nuclear autoradiography and was not explained by a cytotoxic effect. The growth inhibitory effect of simvastatin was specifically due to inhibition of hydroxy-methylglutaryl-coenzyme A reductase because it was overcome by addition of mevalonic acid, the product of the enzymatic reaction. The reduction in [3H]thymidine incorporation was not affected by supplementation of culture medium with purified cholesterol-low-density lipoprotein or isopentenyl adenine. It was partially reversed by addition of farnesol. These results show that simvastatin decreases the growth of human Ito cells, independently of its effect on cholesterol synthesis. This decrease may be due in part either to reduced farnesylation of proteins involved in growth factor signaling pathway or to inhibition of N-linked protein glycosylation. Whether this effect exists in vivo and could thus lead to a parallel decrease of fibrosis deposition within the liver requires further study.

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Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors.

Eisenberg S.

Department of Medicine B, Hadassah University Hospital, Jerusalem, Israel.

To test the possibility that HMG-CoA reductase inhibitors reduce LDL mass by an increased VLDL catabolism, we determined the effect of simvastatin therapy on cellular metabolism of VLDL in 18 patients with primary hypercholesterolaemia. Six months of simvastatin therapy was followed by 26%, 31% and 21% reduction of plasma total cholesterol, LDL-cholesterol and plasma triglyceride levels, respectively. Before therapy, patients' VLDL metabolism in cultured human normal skin fibroblasts was similar to control VLDL. Six months after therapy was initiated, a remarkable 2-5-fold increase in VLDL cell metabolism was found. These effects were even more marked when the VLDL was enriched with exogenous recombinant apo E-3. A comparison of the metabolism of the patients' VLDL to control VLDL and LDL, revealed that simvastatin increased metabolic ratios of 60-70% and 45-95%, respectively. Simvastatin therapy was associated with a decrease of VLDL cholesteryl ester content of 19% and increase of the phospholipid content of 13%. The data strongly indicate that simvastatin therapy stimulates VLDL: cell interactions and catabolism, possibly reflecting alterations of the physico-chemical properties of the particle. It is proposed that in addition to other previously described pathways, HMG-CoA reductase inhibitors decrease LDL mass through a novel mechanism of enhanced VLDL catabolism prior to the conversion to LDL.

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Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine.

De Geest H.

Department of Cardiology, University Hospital Gasthuisberg, University of Leuven, Belgium.

Hyperlipidemia is common in heart transplant patients. Lipid-lowering therapy poses special problems, yet may be important because accelerated graft atherosclerosis is the major factor limiting long-term survival. Simvastatin 5 mg/day was started > 6 months after surgery in 26 consecutive cardiac transplant recipients with a total serum cholesterol level of > 250 mg/dl. The dose of simvastatin was increased in 5-mg increments until total serum cholesterol fell below 220 mg/dl or until side effects developed or up to a maximal dose of 20 mg/day. The final average daily dose was 10 mg. Changes in serum lipid levels after 6 months of therapy were compared with data from a matched and concurrent control group of heart transplant patients not taking simvastatin. Immunosuppression for both groups consisted of CsA, AZA, and corticosteroids. In the simvastatin-treated group, the serum level of total cholesterol decreased by 27% from 315 +/- 53 to 230 +/- 38 mg/dl (P < 0.0001), low density lipoprotein cholesterol decreased by 40% from 205 +/- 30 to 123 +/- 32 mg/dl (P < 0.0001), and triglycerides decreased by 21% from 177 +/- 89 to 140 +/- 49 mg/dl (P < 0.01). There was no significant change in high density lipoprotein cholesterol level. Body weight and CsA blood levels remained stable. Steroid intake decreased during the study period to a similar extent in both the treated and the control groups. In the control group, no significant changes in serum lipid levels were observed. Two patients experienced a mild form of myotoxicity. In one other patient simvastatin treatment was stopped after an acute pancreatitis of uncertain etiology developed. Low dose simvastatin effectively lowers total serum cholesterol, low density lipoprotein cholesterol, and triglycerides in heart transplant patients. With due precautions, the safety profile of the drug in this patient population seems reasonable.

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Electrical myotonia of rabbit skeletal muscles by HMG-CoA reductase inhibitors.

Osame M.

Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan.

HMG-CoA reductase (HCR) inhibitors are effective cholesterol-lowering agents in the treatment of hypercholesterolemia. Using intracellular microelectrodes, we studied the pathomechanism of myotonia experimentally induced in rabbits by HCR inhibitors, simvastatin, and pravastatin. The external intercostal muscle of rabbits showed some electrophysiologic characteristics of myotonia including repetitive firing after administration of simvastatin (50 mg/kg per day, for 4 weeks). The relative chloride conductance, though reduced in both, was more affected in simvastatin-administered muscles. In normal muscles perfused with a solution containing the inhibitors, both simvastatin and pravastatin produced membrane hyperexcitability with repetitive firing similar to that seen in simvastatin-administered rabbits. The minimum concentrations required to cause repetitive firing was 0.3 mg/L for simvastatin and 30 mg/L for pravastatin. These results indicate that HCR inhibitors induce some characteristics of myotonia by blocking the chloride channel in the muscle membrane.

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Cytosolic Ca2+ increase and cell damage in L6 rat myoblasts by HMG-CoA reductase inhibitors.

Osame M.

Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan.

Acute rhabdomyolysis is caused by HMG-CoA reductase (HCR) inhibitors clinically and experimentally. To study the mechanism of muscle cell damage, we investigated the change in the cytosolic free Ca2+ concentration ([Ca2+]i) in L6 rat myoblasts stimulated with three kinds of HCR inhibitors: simvastatin, simvastatin-acid form and pravastatin. Simvastatin and simvastatin-acid form induced an increase in [Ca2+]i through two different pathways, namely, the Ca2+ release from intracellular stores and the Ca2+ influx from extracellular solution. They also caused cell puncture either in the presence or absence of extracellular Ca2+. Pravastatin induced little or no change in [Ca2+]i and no cell damage resulted. Simvastatin was 10-fold more potent than simvastatin-acid form. These results suggest that the mechanism of cell damage may relate to the [Ca2+]i elevation by these drugs and may be dependent on the lipophilicity of the inhibitors.

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Effects of simvastatin, a cholesterol synthesis inhibitor, on phosphatidylcholine synthesis in HepG2 cells.

Sakai T.

Department of Applied Biological Sciences, Saga University, Japan.

The effects of the addition of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to the medium on sterol synthesis and phosphatidylcholine (PC) synthesis were studied in HepG2 cells. The cells were cultured with simvastatin at concentrations of 10(-7) and 10(-6) mol/L for 6 hours, and radioactive lipid precursors were added 1 hour before harvesting. Simvastatin inhibited cholesterol synthesis from [14C]acetate in a dose-dependent manner. It also decreased the incorporation of [14C]choline into PC by 30%; this decrease was accompanied by a decrease in phosphocholine cytidylyltransferase activity in cell homogenates. Simvastatin had no significant effects on the incorporation of [3H]glycerol into phospholipids. These data indicate that simvastatin has two different functions: inhibition of HMG-CoA reductase and depression of de novo synthesis of PC via the cytidine diphosphate-choline pathway, which, in turn, may result in a decrease in plasma lipid levels.

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