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
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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.