PMID- 17178255
OWN - NLM
STAT- MEDLINE
DCOM- 20070330
LR  - 20171116
IS  - 1537-1891 (Print)
IS  - 1537-1891 (Linking)
VI  - 46
IP  - 4
DP  - 2007 Apr
TI  - 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.
PG  - 286-92
AB  - 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.
FAU - Kaneyuki, Utako
AU  - Kaneyuki U
AD  - Division of Nephrology, Department of Medicine, Kurume University School of 
      Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
FAU - Ueda, Seiji
AU  - Ueda S
FAU - Yamagishi, Sho-ichi
AU  - Yamagishi S
FAU - Kato, Seiya
AU  - Kato S
FAU - Fujimura, Toshiko
AU  - Fujimura T
FAU - Shibata, Ryo
AU  - Shibata R
FAU - Hayashida, Ayako
AU  - Hayashida A
FAU - Yoshimura, Junko
AU  - Yoshimura J
FAU - Kojiro, Masamichi
AU  - Kojiro M
FAU - Oshima, Koichi
AU  - Oshima K
FAU - Okuda, Seiya
AU  - Okuda S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061114
PL  - United States
TA  - Vascul Pharmacol
JT  - Vascular pharmacology
JID - 101130615
RN  - 0 (Antioxidants)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Lysophospholipids)
RN  - 0 (Quinolines)
RN  - 0 (RAC1 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Lysophosphatidic Acid)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
RN  - M5681Q5F9P (pitavastatin)
RN  - PG6M3969SG (lysophosphatidic acid)
SB  - IM
MH  - Antioxidants/*pharmacology
MH  - Aorta/drug effects/metabolism
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Lysophospholipids/*pharmacology
MH  - Muscle, Smooth, Vascular/drug effects/metabolism
MH  - Myocytes, Smooth Muscle/*drug effects/metabolism
MH  - NADPH Oxidases/metabolism
MH  - Quinolines/*pharmacology
MH  - RNA, Messenger/metabolism
MH  - Reactive Oxygen Species/*metabolism
MH  - Receptors, Lysophosphatidic Acid/drug effects
MH  - Signal Transduction/*drug effects
MH  - Transfection
MH  - rac1 GTP-Binding Protein/metabolism
EDAT- 2006/12/21 09:00
MHDA- 2007/03/31 09:00
CRDT- 2006/12/21 09:00
PHST- 2006/10/29 00:00 [received]
PHST- 2006/11/07 00:00 [revised]
PHST- 2006/11/07 00:00 [accepted]
PHST- 2006/12/21 09:00 [pubmed]
PHST- 2007/03/31 09:00 [medline]
PHST- 2006/12/21 09:00 [entrez]
AID - S1537-1891(06)00648-3 [pii]
AID - 10.1016/j.vph.2006.11.002 [doi]
PST - ppublish
SO  - Vascul Pharmacol. 2007 Apr;46(4):286-92. doi: 10.1016/j.vph.2006.11.002. Epub 
      2006 Nov 14.