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(Circulation Research. 2007;101:1113.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway

Xiaomei Guo^*, Kuang-Hueih Chen^*, Yanhong Guo, Hua Liao, Jian Tang, Rui-Ping Xiao

From the Laboratory of Cardiovascular Science (X.G., K.-H.C., R.-P.X.), National Institute on Aging, NIH, Baltimore, Md; Institute of Cardiovascular Science (K.-H.C., Y.G., J.T.), Peking University, Beijing, People’s Republic of China; and Center for Molecular Cardiology (X.G., H.L.), Department of Cardiology, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, People’s Republic of China.

Correspondence to Kuang-Hueih Chen, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail chenku{at}grc.nia.nih.gov

Previous studies have shown that mitofusin 2 (Mfn-2) (or hyperplasia suppressor gene [HSG]) inhibits vascular smooth muscle cell (VSMC) proliferation. Here, we demonstrate that Mfn-2 is a primary determinant of VSMC apoptosis. First, oxidative stress with H₂O₂, inhibition of protein kinase C with staurosporine, activation of protein kinase A with forskolin, and serum deprivation concurrently elevate Mfn-2 expression and induce VSMC apoptosis. Second, overexpression of Mfn-2 also triggers apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries, thus contributing to Mfn-2–mediated prevention of neointima formation after angioplasty. Third, Mfn-2 silencing protects VSMCs against H₂O₂ or Mfn-2 overexpression–induced apoptosis, indicating that upregulation of Mfn-2 is necessary and sufficient for oxidative stress–mediated VSMC apoptosis. The Mfn-2 proapoptotic effect is independent of its role in mitochondrial fusion but mainly mediated by inhibition of Akt signaling and the resultant activation of the mitochondrial apoptotic pathway, as manifested by decreased Akt phosphorylation, increased mitochondrial Bax/Bcl-2 ratio, cytochrome c release, and activation of caspases-9 and caspase-3. Furthermore, Mfn-2–induced apoptosis was blocked by overexpression of an active phosphoinositide 3-kinase mutant or Bcl-xL or inhibition of caspase-9 but not caspases-8. Thus, in addition to its antiproliferative effects, Mfn-2 constitutes a primary determinant of VSMC apoptosis.

Key Words: PI3K-Akt • apoptosis • HSG • Mfn-2 • vascular smooth muscle cells

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