Abstract-In vitro and in vivo evidence of a decrease in vascular smooth muscle cell (SMC) migration induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been reported. When added to SMC cultures for 6 hours, the HMG-CoA reductase inhibitors fluvastatin, simvastatin, and pravastatin at 1 mol/L resulted in a 48%, 50%, and 16% suppression, respectively, of human coronary SMC migration; these reductions mirrored the suppression in oxidative stress induced by 1 mol/L lysophosphatidylcholine (lyso-PC) of 50%, 53% and 19%, respectively. The hydroxylated metabolites of fluvastatin, M 2 and M 3 , at 1 mol/L also suppressed the enhancement of SMC migration by 58% and 45% and the increase in oxidative stress induced by lyso-PC of 58% and 49%, respectively. Lyso-PC activated phospholipase D and protein kinase C (PKC), and this activation was also suppressed by HMG-CoA reductase inhibitors. The inhibition of phospholipase D and PKC was reversed by 100 mol/L mevalonate, its isoprenoid derivative, farnesol, and geranylgeraniol but not by 10 mol/L squalene. Antisense oligodeoxynucleotides at 5 mol/L to PKC-␣, but not those to the PKC- isoform, suppressed the lyso-PC-mediated increases in SMC migration and oxidative stress. These findings suggest that HMG-CoA reductase inhibitors have direct antimigratory effects on the vascular wall beyond their effects on plasma lipids and that they might exert such antimigratory effects via suppression of the phospholipase D-and PKC (possibly PKC-␣)-induced increase in oxidative stress, which might in turn prevent significant coronary artery disease. Key Words: lipids Ⅲ atherosclerosis Ⅲ smooth muscle Ⅲ coronary disease C linical and experimental studies have shown that a reduction of plasma cholesterol, particularly LDL cholesterol, reduces the risk of cardiovascular events in both primary and secondary prevention. 1,2 The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), which are cholesterol-reducing drugs, can achieve a relatively large reduction in plasma cholesterol. 3 The beneficial effects of HMG-CoA reductase inhibitors are usually assumed to result from their ability to reduce cholesterol synthesis. 4 However, a variety of experimental findings suggest that statins can interfere with major events involved in the formation of atherosclerotic lesions, independent of their hypocholesterolemic properties. [4][5][6] Vascular smooth muscle cell (SMC) migration in the arterial wall is an important mechanism in atherogenesis and is a possible determinant of restenosis after angioplasty. 7 In addition, increased oxidative stress is reported to play an important role in SMC migration, 8 suggesting a relation between oxidative stress and SMC migration. Because there exists in vitro and in vivo evidence of decreased SMC proliferation after administration of fluvastatin, simvastatin, or lovastatin, 6,9 it is possible that statins have the potential to decrease oxidative stress and SMC migration.Therefore, we examined whether suppressi...
