3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE AND ISOPRENYLATION INHIBITORS INDUCE APOPTOSIS OF VASCULAR SMOOTH-MUSCLE CELLS IN CULTURE

Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesio ns. 3-Hydroxy-3-methylglutalyl coenzyme A (HMG-CbA)reductase inhibitor s have been reported to induce apoptosis in a variety of tumor cell li nes. To evaluate whether these agents also induce apoptosis of VSMCs, cultured rat VSMCs were treated with increasing doses of atorvastatin in the presence of FBS as a survival factor. The presence of apoptosis was evaluated by morphological criteria, annexin V binding, and DNA f ragmentation and quantified as the proportion of hypodiploid cells by flow cytometry. Atorvastatin induced apoptosis in a dose-dependent man ner, an effect also seen with simvastatin and lovastatin, but not with the hydrophilic drug pravastatin. The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterol s was >95% and was fully reversed by mevalonate, farnesyl pyrophosphat e, and geranylgeranyl pyrophosphate but not by isopentenyl adenosine, ubiquinone, or squalene, suggesting a role for prenylated proteins in the regulation of VSMC apoptosis. To further assess the role of protei n prenylation, VSMCs were exposed to the prenyl transferase inhibitors perillic acid and manumycin A. Both agents induced VSMC apoptosis as evaluated by the above-mentioned criteria. Finally, VSMC treatment wit h lipophilic statins was associated with decreased prenylation of p21- Rho B, further supporting the role of protein prenylation inhibition i n statin-induced VSMC apoptosis. The present data suggest that interfe rence with protein prenylation by HMG-CoA reductase inhibitors or othe r agents may provide new strategies for the prevention of neointimal t hickening.