Kaneyuki Utako, Ueda Seiji, Yamagishi Sho-ichi, Kato Seiya, Fujimura Toshiko, Shibata Ryo, Hayashida Ayako, Yoshimura Junko, Kojiro Masamichi, Oshima Koichi, Okuda Seiya
Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Vascul Pharmacol. 2007 Apr;46(4):286-92. doi: 10.1016/j.vph.2006.11.002. Epub 2006 Nov 14.
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.
溶血磷脂酸（LPA）是低密度脂蛋白（LDL）氧化修饰过程中产生的一种产物，也是从人类动脉粥样硬化斑块中提取的主要脂质，已被证明可引发平滑肌细胞（SMC）增殖和炎症，从而参与动脉粥样硬化的发生发展。最近，他汀类药物作为3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的抑制剂，已被报道可降低心血管事件风险，并至少部分地通过多效性作用减缓动脉粥样硬化的进展。然而，他汀类药物对平滑肌细胞中LPA信号传导的影响仍有待阐明。在本研究中，我们调查了匹伐他汀是否以及如何抑制培养的人主动脉平滑肌细胞中LPA诱导的增殖和单核细胞趋化蛋白-1（MCP-1）表达。LPA剂量依赖性地增加了平滑肌细胞内活性氧（ROS）的生成，这被二苯基碘鎓（DPI）（一种NADPH氧化酶抑制剂）或匹伐他汀所阻断。同时用香叶基香叶基焦磷酸处理可阻止匹伐他汀的抗氧化特性。此外，发现显性负性Rac-1突变体的过表达可抑制平滑肌细胞中LPA诱导的ROS生成。LPA诱导平滑肌细胞中Rac-1活化，这被匹伐他汀或LPA受体拮抗剂所抑制。匹伐他汀、DPI和抗氧化剂N-乙酰半胱氨酸抑制了平滑肌细胞中LPA诱导的增殖和MCP-1基因表达。这些结果表明，匹伐他汀可通过抑制Rac-1介导的NADPH氧化酶依赖性ROS生成来阻断平滑肌细胞中LPA诱导的增殖和MCP-1表达。我们目前的研究揭示了匹伐他汀一个新的有益作用；匹伐他汀可能作为平滑肌细胞中LPA信号传导的阻断剂。
