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-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 micromol/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 micromol/L lysophosphatidylcholine (lyso-PC) of 50%, 53% and 19%, respectively. The hydroxylated metabolites of fluvastatin, M(2) and M(3), at 1 micromol/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 micromol/L mevalonate, its isoprenoid derivative, farnesol, and geranylgeraniol but not by 10 micromol/L squalene. Antisense oligodeoxynucleotides at 5 micromol/L to PKC-alpha, but not those to the PKC-beta 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-alpha)-induced increase in oxidative stress, which might in turn prevent significant coronary artery disease.
Yasunari
K
K
Department of Cardiology, Graduate School of Medicine, Osaka City University, Osaka, Japan. yasunari@osaka.med.or.jp
Maeda
K
K
Minami
M
M
Yoshikawa
J
J
D000975:Antioxidants / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000188:drug therapy; D003331:Coronary Vessels / Q000166:cytology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010739:Phospholipase D / Q000502:physiology; D017035:Pravastatin / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology
D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008244:Lysophosphatidylcholines; D016376:Oligonucleotides, Antisense; D000077340:Fluvastatin; D019821:Simvastatin; D011505:Protein-Tyrosine Kinases; C496628:PRKCA protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D010739:Phospholipase D; D017035:Pravastatin; D008798:Mevalonic Acid