title: Pitavastatin inhibits lysophosphatidic acid-induced proliferation and monocyte chemoattractant protein-1 expression in aortic smooth muscle cells by suppressing Rac-1-mediated reactive oxygen species generation.
abstract: Lysophosphatidic acid (LPA), a product generated during oxidative modification of low-density lipoprotein (LDL) and a major lipid extracted from human atherosclerotic plaques, has been shown to elicit smooth muscle cell (SMC) proliferation and inflammation, thereby being involved in atherogenesis. Recently, statins, an inhibitor of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, have been reported to reduce the risk of cardiovascular events and slows the progression of atherosclerosis, at least partly, via pleiotropic effects. However, the effect of statin on the LPA-signaling in SMCs remains to be elucidated. In this study, we investigated whether and how pitavastatin could inhibit the LPA-induced proliferation and monocyte chemoattractant protein-1 (MCP-1) expression in cultured human aortic SMCs. LPA dose-dependently increased intracellular reactive oxygen species (ROS) generation in SMCs, which was blocked by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase or pitavastatin. The anti-oxidative property of pitavastatin was prevented by simultaneous treatment of geranylgeranyl pyrophosphate. Furthermore, overexpression of dominant negative Rac-1 mutant was found to inhibit the LPA-induced ROS generation in SMCs. LPA induced Rac-1 activation in SMCs, which was suppressed by pitavastatin or LPA receptor antagonist. Pitavastatin, DPI, and an anti-oxidant N-acetylcysteine inhibited the LPA-induced proliferation and MCP-1 gene expression in SMCs. These results suggest that pitavastatin could block the LPA-induced proliferation and MCP-1 expression in SMCs by suppressing Rac-1-mediated NADPH oxidase-dependent ROS generation. Our present study provides a novel beneficial aspect of pitavastatin; pitavastatin may act as a blocker of the LPA-signaling in SMCs.
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
authors.forename: Utako
authors.initials: U
authors.lastname: Kaneyuki
authors.forename: Seiji
authors.initials: S
authors.lastname: Ueda
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Seiya
authors.initials: S
authors.lastname: Kato
authors.forename: Toshiko
authors.initials: T
authors.lastname: Fujimura
authors.forename: Ryo
authors.initials: R
authors.lastname: Shibata
authors.forename: Ayako
authors.initials: A
authors.lastname: Hayashida
authors.forename: Junko
authors.initials: J
authors.lastname: Yoshimura
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kojiro
authors.forename: Koichi
authors.initials: K
authors.lastname: Oshima
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008246:Lysophospholipids; D011804:Quinolines; C107953:RAC1 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D049368:Receptors, Lysophosphatidic Acid; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; C108475:pitavastatin; C032881:lysophosphatidic acid