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Direct vascular effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

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1. We have examined the effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on porcine endothelial cell (EC) injury induced by xanthine (X)/xanthine oxidase (XO), a source of superoxide anion. Furthermore, the effects of HR780 on platelet-derived growth factor (PDGF)-induced migration and fetal calf serum (FCS)-induced proliferation of rabbit smooth muscle cells (SMC) were investigated.

2. Probucol, at 10 µmol/L, significantly (P < 0.001) and completely suppressed lactate dehydrogenase leakage induced by X/XO. At 10 µmol/L, HR780 significantly (P = 0.010) inhibited X/XO-induced EC injury.

3. HR780 dose-dependently inhibited PDGF-induced SMC migration and FCS-induced SMC proliferation. The addition of mevalonate completely abolished the inhibitory effect of HR780 on SMC proliferation. Another HMG-CoA reductase inhibitor, simvastatin (0.1–100 µmol/L), also inhibited the migration and proliferation responses as potently as HR780. In contrast, pravastatin (0.1–100 µmol/L) did not show any effects.

4. This in vitro study provides the first evidence that HR780 protects the vascular endothelium from oxidant stress and inhibits the migration and proliferation of SMC.
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Keywords: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; HR780; cell injury; endothelial cell; migration; proliferation; smooth muscle cell

Document Type: Research Article

Affiliations: Pharmacology, Aventis Pharma Ltd, Minamidai, Kawagoe, Saitama, Japan

Publication date: December 1, 2003

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