Several studies have demonstrated that any beneficial effect of 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) reductase inhibitors (statins) on coronary events are linked to their
hypocholesterolemic properties. However, since mevalonic acid (MVA), the product of
the enzyme reaction, 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 necessary for cell proliferation and other
important cell functions, hence effects other than cholesterol reduction may help
to explain the antiatherosclerotic properties of statins. Recently, we provided in
vitro evidence that fluvastatin, simvastatin, lovastatin, cerivastatin, but not pravastatin,
dose-dependently decrease smooth muscle cells (SMC) migration and proliferation, independently
of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce
the in vitro cholesterol accumulation in macrophages, by blocking cholesterol esterification
and endocytosis of modified lipoproteins. This in vitro inhibition was completely
prevented by the addition of mevalonate and partially 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 myocytes and rapidly proliferating
carotid and femoral intimal lesions in rabbits. Finally, ex vivo studies recently
showed that sera from fluvastatin-treated patients interfere with smooth muscle cell
proliferation. These results suggest that HMG-CoA reductase inhibitors exert a direct
antiatherosclerotic effect in the arterial wall, beyond their effects on plasma lipids,
that could translate into a more significant prevention of cardiovascular disease.