HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress

In vitro and in vivo evidence of a decrease in vascular smooth muscle cell (SMC) migration induced by 3-hydroxy-3-merhylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been reported. When added to SMC cultures for 6 ho urs, the HMG-CoA reductase inhibitors fluvastatin, simvastatin, and pravast atin at I mu mol/L resulted in a 48%, 50%, and 16% suppression, respectivel y, of human coronary SMC migration: these reductions mirrored the suppressi on in oxidative stress induced by I mu mol/L lysophosphatidylcholine (lyso- PC) of 50%, 53% and 19%, respectively. The hydroxylated metabolites of fluv astatin, M-2 and M-3, at 1 mu mol/L also suppressed the enhancement of SMC migration by 58% and 45% and the increase in oxidative stress induced by ly se-PC of 58% and 49%, respectively. Lyse-PC activated phospholipase D and p rotein kinase C (PKC), and this activation was also suppressed by HMG-CoA r eductase inhibitors. The inhibition of phospholipase D and PKC was reversed by 100 mu mol/L mevalonate. its isoprenoid derivative, farnesol, and geran ylgeraniol but not by 10 mu mol/L squalene. Antisense oligodeoxynucleotides at 5 mu mol/L to PKC-alpha, but not those to the PKC-P isoform, suppressed the lyse-PC-mediated increases in SMC migration and oxidative stress. Thes e findings suggest that HMG-CoA reductase inhibitors have direct antimigrat ory effects on the vascular wall beyond their effects on plasma lipids and that they might exert such antimigratory effects via suppression of the pho spholipase D- and PKC (possibly PKC-alpha)-induced increase in oxidative st ress, which might in turn prevent significant coronary artery disease.