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

Abstract

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...

Carvedilol Inhibits Pressure-Induced Increase in Oxidative Stress in Coronary Smooth Muscle Cells.

“…These findings suggest that pressure increased oxidative stress through PLD and PKC activation, consistent with previous findings (14). Since it has been reported that the PKC pathway plays a role in increasing oxidative stress (15,20), increase in oxidative stress may play a role in increasing the rate of migration (21).…”

Role of protein kinase C in pitavastatin-induced human paraoxonase I expression in Huh7 cells

“…We reported that depletion of farnesyl pyrophosphate by pitavastatin was associated with pitavastatin-increased PON1 promoter activity in HepG2 cell [13]; moreover, it was recently reported that pitavastatin also induced PON1 expression through activation of the p44/42 mitogen-activated protein kinase signaling cascade in Huh7 cells [33]. To our best knowledge, it was only one report to refer the association with statins-influenced PKC activity and isoprenoids, which fluvastatin-decreased PKC activity was reversed by isoprenoids [30]. However, we determined that pitavastatin-activated PKCζ was not reversed by supplement of isoprenoids, such mevalonic acid, farnesyl pyrophosphate and geranylgeranyl pyrophosphate in this study (data not shown).…”

Endothelial Lipase is Increased by Inflammation and Promotes LDL Uptake in Macrophages

“…Because statins have also been reported to attenuate oxidative stress 30,31) , we next examined if simvastatin inhibits the LPS-induced production of ROS and uptake of LDL in macrophages. The lucigenin-chemiluminescence assay revealed that simvastatin inhibited LPS-induced NADPH …”