Perillyl alcohol, an inhibitor of geranylgeranyl transferase, induces apoptosis of immortalized human vascular smooth muscle cells in vitro

The isoprenoids geranylgeraniol and farnesol are required for lipid modific ation of several important cellular proteins. In this study the effect of p erillyl alcohol (PA), an inhibitor of geranylgeranyl transferase, was exami ned on proliferation and apoptosis of immortalized human vascular smooth mu scle cells (HVSMCs) derived from saphenous vein. PA induced a time- and con centration-dependent inhibition of cell proliferation over 3 days and 48 h exposure to PA inhibited [methyl-H-3]-thymidine incorporation induced by 10 % fetal calf serum in a concentration-dependent manner. Flow cytometry anal ysis indicated that PA reduced the proportion of cells in S phase and incre ased apoptosis. PA-induced apoptosis was confirmed by terminal deoxynucleot idyl transferase (TdT) reagent-based immunocytochemistry. In contrast, the selective inhibitors of farnesyl transferase B581 and BZA-5B were without e ffect, In view of the proposed role of proliferation and apoptosis in myoin timal hyperplasia, inhibitors of geranylgeranyl transferases may have thera peutic potential in cardiovascular disease.