Lipophilic statins induce apoptosis of human vascular smooth muscle cells

Background. The accumulation of vascular smooth muscle cells (VSMC) in the intima is an early feature of atherosclerosis that results from a balance o f migration from the media, proliferation, an eventual death (including pro grammed cell death) of VSMC. Several reports have described that HMG-CoA re ductase inhibitors (statins) attenuate both the migration and proliferation of VSMC. However, the potential effect of statins on VSMC programmed cell death has received little attention. Methods. Human and rat VSMC were incubated with different concentration of statins in the presence of fetal bovine serum as a survival factor. The pre sence of apoptosis was evaluated by morphological criteria, Bow cytometry a nd DNA electrophoresis. Results. Lipophilic statins induced, in a dose-dependent manner the appeara nce of VSMC apoptosis. The effect of statins was fully reversed by mevalona te, farnesylpyrophosphate. and geranylgeranypyrophosphate, but not by chole sterol or other mevalonate metabolites, suggesting a role for isoprenoids i n VSMC apoptosis. In addition, the induction of apoptosis by statins was as sociated with the inhibition of prenylation of Rho B. Conclusions. The present results suggest that protein prenylation inhibitio n by statins may be involved in statin-induced VSMC apoptosis, These data p rovide a new potential mechanism by which statins may modulate the evolutio n of atherosclerotic lesions.