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 anti-atherogenesis. Nitric oxide is also an anti-atherogenic substance, inducing vasodilation and inhibits proliferation of smooth muscle cells (SMC). Therefore, we examined sodium nitroprusside (SNP)-induced apoptosis of vascular SMC with respect to cholesterol metabolism. Cultured vascular SMC from bovine carotid arteries and rat aorta were used. Apoptosis was determined by propidium iodide assay. Treatment of the SMC with SNP(100 micromol/l-1 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 microg/ml, 2 days), a hydroxymethylglutaryl Coenzyme A (HMG CoA) reductase inhibitor, synergistically enhanced SNP-induced apoptosis (% apoptosis =15. 9+/-3.3%). Either mevalonate (100 micromol/l) or geranylgeraniol (30 micromol/l) recovered the simvastatin (1 microg/ml)-enhanced SMC apoptosis induced by SNP. Neither squalene (10 mmol/l) nor farnesol (30 micromol/l) had a recovery effect on the simvastatin-enhanced SMC apoptosis induced by SNP. Pretreatment with simvastatin (1 microg/ml) reduced total cholesterol content in SMC. Mevalonate (100 micromol/l) restored a decrease in total cholesterol content. However, incubation with LDL deficient serum did not enhance SNP-induced apoptosis of SMC, although treatment with LDL deficient serum decreased the total cholesterol content in SMC. These data suggested that decrease in HMG CoA reductase metabolites, especially geranylgeraniol might enhance the SNP-induced apoptosis of SMC, and that, apoptosis was not involved in a decrease in cholesterol of SMC.
Fujita
H
H
Second Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, Japan.
Shimotsuura
S
S
Yanagisawa
A
A
Morita
I
I
Murota
S
S
Ishikawa
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology*
D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D002784:Cholesterol; D019821:Simvastatin; C017338:geranylgeraniol