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(Circulation Research. 2009;104:842.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Activation of NAD(P)H:Quinone Oxidoreductase 1 Prevents Arterial Restenosis by Suppressing Vascular Smooth Muscle Cell Proliferation

Sun-Yee Kim^*, Nam Ho Jeoung^*, Chang Joo Oh, Young-Keun Choi, Hyo-Jeong Lee, Han-Jong Kim, Joon-Young Kim, Jung Hwan Hwang, Surendar Tadi, Yong-Hyeon Yim, Ki-Up Lee, Keun-Gyu Park, Seung Huh, Ki-Nam Min, Kyeong-Hoon Jeong, Myoung Gyu Park, Tae Hwan Kwak, Gi Ryang Kweon, Kouichi Inukai, Minho Shong, In-Kyu Lee

From the Department of Internal Medicine (S.-Y.K., N.H.J., C.J.O., Y.-K.C., H.-J.L., H.-J.K., J.-Y.K., I.-K.L.), Department of Surgery (S.H.), Kyungpook National University School of Medicine, Daegu, South Korea; Department of Internal Medicine (J.H.H., S.T., M.S.), Department of Biochemistry (G.R.K.), Chungnam National University School of Medicine, Daejeon, South Korea; Korea Research Institute of Standard and Science (Y.-H.Y.), Daejeon, South Korea; Department of Internal Medicine (K.-U.L.), University of Ulsan College of Medicine, Seoul, South Korea; Department of Internal Medicine (K.-G.P.), Keimyung University School of Medicine, Daegu, South Korea; Mazence Inc R&D Center (K.-N.M., K.-H.J., M.G.P., T.H.K.), Suwon, South Korea; and Division of Endocrinology and Diabetes (K.I.), Department of Medicine, Saitama Medical School, Saitama, Japan.

Correspondence to In-Kyu Lee, Department of Internal Medicine, Kyungpook National University School of Medicine, 50 Samduck-2 ga, Jung-gu, Daegu, 700-721, South Korea. E-mail leei{at}knu.ac.kr

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are important pathogenic mechanisms in atherosclerosis and restenosis after vascular injury. In this study, we investigated the effects of β-lapachone (βL) (3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione), which is a potent antitumor agent that stimulates NAD(P)H:quinone oxidoreductase (NQO)1 activity, on neointimal formation in animals given vascular injury and on the proliferation of VSMCs cultured in vitro. βL significantly reduced the neointimal formation induced by balloon injury. βL also dose-dependently inhibited the FCS- or platelet-derived growth factor-induced proliferation of VSMCs by inhibiting G₁/S phase transition. βL increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase 1 in rat and human VSMCs. Chemical inhibitors of AMPK or dominant-negative AMPK blocked the βL-induced suppression of cell proliferation and the G₁ cell cycle arrest, in vitro and in vivo. The activation of AMPK in VSMCs by βL is mediated by LKB1 in the presence of NQO1. Taken together, these results show that βL inhibits VSMCs proliferation via the NQO1 and LKB1-dependent activation of AMPK. These observations provide the molecular basis that pharmacological stimulation of NQO1 activity is a new therapy for the treatment of vascular restenosis and/or atherosclerosis which are caused by proliferation of VSMCs.

Key Words: vascular smooth muscle cell • β-lapachone • AMPK • NQO1 • restenosis

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