DIRECT VASCULAR EFFECTS OF HMG-COA REDUCTASE INHIBITORS

Several studies have demonstrated that any beneficial effect of 3-hydr oxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statin s) on coronary events are linked to their hypocholesterolemic properti es. However, since mevalonic acid (MVA), the product of the enzyme rea ction, is the precursor of numerous metabolites, inhibition of HMG-CoA reductase has the potential to result in pleiotropic effects. MVA and other intermediates of cholesterol synthesis (isoprenoids) are necess ary for cell proliferation and other important cell functions, hence e ffects other than cholesterol reduction may help to explain the antiat herosclerotic properties of statins. Recently, we provided in vitro ev idence that fluvastatin, simvastatin, lovastatin, cerivastatin, but no t pravastatin, dose-dependently decrease smooth muscle cells (SMC) mig ration and proliferation, independently of their ability to reduce pla sma cholesterol. Moreover, statins are able to reduce the in vitro cho lesterol accumulation in macrophages, by blocking cholesterol esterifi cation and endocytosis of modified lipoproteins. This in vitro inhibit ion was completely prevented by the addition of mevalonate and partial ly by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites-probably through a prenylated protein(s)-in regulating these cellular events. The inhibitory effect of lipophilic statins on SMC proliferation has been recently shown in different models of proliferating cells such as cultured arterial myo cytes and rapidly proliferating carotid and femoral intimal lesions in rabbits. Finally, ex vivo studies recently showed that sera from fluv astatin-treated patients interfere with smooth muscle cell proliferati on. These results suggest that HMG-CoA reductase inhibitors exert a di rect antiatherosclerotic effect in the arterial wall, beyond their eff ects on plasma lipids, that could translate into a more significant pr evention of cardiovascular disease. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.