Simvastatin induces heme oxygenase-1 - A novel mechanism of vessel protection

被引：238

作者：

Lee, TS ^{[1
]}

Chang, CC ^{[1
]}

Zhu, Y ^{[1
]}

Shyy, JYJ ^{[1
]}

机构：

[1] Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA

来源：

CIRCULATION | 2004年 / 110卷 / 10期

关键词：

vasculature; statins; muscle; smooth;

D O I：

10.1161/01.CIR.0000140694.67251.9C

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Evidence from experimental and clinical studies indicates that statins can protect the vessel wall through cholesterol-independent mechanisms. The "pleiotropic" effects include the prevention of inflammation and proliferation of vascular cells. Here, we studied whether heme oxygenase-1 (HO-1), an important cytoprotective molecule, is induced by simvastatin and the role of HO-1 in the pleiotropic effects of simvastatin. Methods and Results-Human and rat aortic smooth muscle cells treated with simvastatin showed an elevated level of HO-1 for up to 24 hours. The induction of HO-1 by simvastatin was not found in cultured endothelial cells and macrophages. Injecting C57BL/6J mice intraperitoneally with simvastatin increased the level of HO-1 in vascular SMCs (VSMCs) in the tunica media. Treating VSMCs with zinc protoporphyrin, an HO-1 inhibitor, or HO-1 small interfering RNA (siRNA) blocked the antiinflammatory effect of simvastatin, including the inhibition of nuclear factor-kappaB activation and nitric oxide production. Blockade of HO-1 also abolished the simvastatin-induced p21(Waf1) and the associated antiproliferative effect. Simvastatin activated p38 and Akt in VSMCs, and the respective inhibitor of p38 and phosphoinositide 3-kinase (PI3K) greatly reduced the level of simvastatin-induced HO-1, which suggests the involvement of p38 and the PI3K-Akt pathway in HO-1 induction. Conclusions-Simvastatin activates HO-1 in VSMCs in vitro and in vivo. The antiinflammatory and antiproliferative effects of simvastatin occur largely through the induced HO-1.

引用

页码：1296 / 1302

页数：7

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