Simvastatin enhanced sodium nitroprusside-induced apoptosis of smooth muscle cells - An involvement of geranylgeraniol

A decrease in serum cholesterol is one of the most beneficial effects in an ti-atherogenesis. Nitric oxide is also an anti-atherogenic substance, induc ing vasodilation and inhibits proliferation of smooth muscle cells (SMC). T herefore, we examined sodium nitroprusside (SNP)-induced apoptosis of vascu lar SMC with respect to cholesterol metabolism. Cultured vascular SMC from bovine carotid arteries and rat aorta were used. Apoptosis was determined b y propidium iodide assay. Treatment of the SMC with SNP(100 mu mol/l-l mmol /l) for 6 h induced a little nuclear fragmentation. SNP (1 mmol/l) elicited apoptosis in 4.4 +/- 2.2% of cells. Pretreatment of SMC with simvastatin ( 1 mu g/ml, 2 days), a hydroxymethylglutaryl Coenzyme A (HMG CoA) reductase inhibitor. synergistically enhanced SNP-induced apoptosis (% apoptosis = 15 .9 +/- 3.3%). Either mevalonate (100 mu mol/l) or geranylgeraniol (30 mu mo l/l) recovered the simvastatin (1 mu g/ml)-enhanced SMC apoptosis induced b y SNP. Neither squalene (10 mmol/l) nor farnesol (30 mu mol/l) had a recove ry effect on the simvastatin-enhanced SMC apoptosis induced by SNP. Pretrea tment with simvastatin (1 mu g/ml) reduced total cholesterol content in SMC . Mevalonate (100 mu mol/l) restored a decrease in total cholesterol conten t. However, incubation with LDL deficient serum did not enhance SNP-induced apoptosis of SMC, although treatment with LDL deficient serum decreased th e total cholesterol content in SMC. These data suggested that decrease in H MG CoA reductase metabolites, especially geranylgeraniol might enhance the SNP-induced apoptosis of SMC, and that, apoptosis was not involved in a dec rease in cholesterol of SMC. (C) 2000 Elsevier Science Ireland Ltd. All rig hts reserved.