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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:937.)
© 2001 American Heart Association, Inc.

Vascular Biology

HMG-CoA Reductase Inhibitors Prevent Migration of Human Coronary Smooth Muscle Cells Through Suppression of Increase in Oxidative Stress

Kenichi Yasunari; Kensaku Maeda; Mieko Minami; Junichi Yoshikawa

From the Department of Cardiology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Correspondence to Kenichi Yasunari, MD, Department of Cardiology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail yasunari{at}osaka.med.or.jp

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 µmol/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 µmol/L lysophosphatidylcholine (lyso-PC) of 50%, 53% and 19%, respectively. The hydroxylated metabolites of fluvastatin, M₂ and M₃, at 1 µmol/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 µmol/L mevalonate, its isoprenoid derivative, farnesol, and geranylgeraniol but not by 10 µmol/L squalene. Antisense oligodeoxynucleotides at 5 µmol/L to PKC-, but not those to the PKC-ß 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 • atherosclerosis • smooth muscle • coronary disease

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