EFFECT OF THE NEW HMG-COA REDUCTASE INHIBITOR CERIVASTATIN (BAY W-6228) ON MIGRATION, PROLIFERATION AND CHOLESTEROL-SYNTHESIS IN ARTERIAL MYOCYTES

The major relation existing between cell growth, migration and cholest erol homeostasis prompted us to investigate the effect of the new 3-hy droxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ceriva statin (BAY W 6228) on these cellular events. The molecule inhibited i n a dose-dependent manner the migration and the replication (evaluated as cell number and nuclear incorporation of H-3-thymidine) of rat art erial SMC with IC50 values of 2.7 mu M and 0.5 mu M, respectively. Amo ng the tested statins BAY W 6228 resulted to be the most potent inhibi tor of cholesterol synthesis and cell proliferation. Conditions produc ing 80-90% inhibition of cholesterol synthesis correlate with approxim ately 50% inhibition of cell growth. Similar results were obtained in SMC from human femoral artery. The in vitro inhibition of cell migrati on and proliferation induced by BAY W 6228 (80% decrease) was complete ly prevented by the addition of mevalonate and partially prevented (60 -80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites-probably through a prenylated protein(s)-in re gulating these cellular events. The present results provide evidence t hat BAY W 6228 interferes, at least in vivo, with smooth muscle cells migration and proliferation, major processes involved in atherogenesis . (C) 1996 The Italian Pharmacological Society