3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation

Abstract

The mechanism by which 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) induce apoptosis in vascular smooth muscle cells (VSMCs) is unknown. In this work, we demonstrate that treatment of VSMCs with simvastatin and atorvastatin inhibited Bcl-2 expression in a time and dose-dependent manner, while Bax expression was not modified. This effect was reversed by mevalonate (100 micromol/l), farnesylpyrophosphate (5 micromol/l) or geranylgeranylpyrophosphate (5 micromol/l), suggesting the involvement of protein prenylation. The treatment of VSMCs with lipophilic statins was associated with decreased prenylation of p-21 Rho A and mevalonate, farnesyl pyrophosphate (F-PP) and geranylgeranyl pyrophosphate (G-PP) reversed prenylation to basal levels. In addition, overexpression of constitutively active Q63L Rho A prevented, at least in part, apoptosis induced by statins and downregulation of Bcl-2. We also investigated the participation of caspases (proteases) in the apoptosis induced by statins. The treatment of VSMCs with lipophilic statins induced activation of the caspase 9, the first caspase of the mitochondrial pathway. Coincubation of VSMCs with the caspase inhibitor ZVAD-fmk (100 micromol/l) significantly inhibited lipophilic statin-induced apoptosis. These findings indicate that the downregulation of Bcl-2 by Rho GTPases mediates statin-induced apoptosis and suggest a new potential mechanism of action for these drugs on the regulation of cell number in the atherosclerotic lesions.