Published online before print August 30, 2004, doi: 10.1161/01.CIR.0000140694.67251.9C
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(Circulation. 2004;110:1296-1302.)
© 2004 American Heart Association, Inc.
Original Articles |
Simvastatin Induces Heme Oxygenase-1
A Novel Mechanism of Vessel Protection
From the Division of Biomedical Sciences, University of California, Riverside.
Correspondence to John Y.-J. Shyy, PhD, Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121. E-mail john.shyy{at}ucr.edu
Received December 4, 2003; de novo received April 7, 2004; revision received June 4, 2004; accepted June 7, 2004.
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-
B activation and nitric oxide production. Blockade of HO-1 also abolished the simvastatin-induced p21Waf1 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.
Key Words: vasculature • statins • muscle, smooth
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Circulation 2004 110: 1177.
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