Published online before print February 19, 2009, doi: 10.1161/CIRCRESAHA.108.189837
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Submitted on October 22, 2008
Revised on February 5, 2009
Accepted on February 10, 2009
Activation of NAD(P)H:Quinone Oxidoreductase 1 Prevents Arterial Restenosis by Suppressing Vascular Smooth Muscle Cell Proliferation
Sun-Yee Kim ;
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.
* To whom correspondence should be addressed. E-mail: iklee{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 
-lapachone (L) (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. L significantly reduced the neointimal formation induced by balloon injury. L also dose-dependently inhibited the FCS- or platelet-derived growth factor–induced proliferation of VSMCs by inhibiting G1/S phase transition. L 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 L-induced suppression of cell proliferation and the G1 cell cycle arrest, in vitro and in vivo. The activation of AMPK in VSMCs by L is mediated by LKB1 in the presence of NQO1. Taken together, these results show that L 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 •
-lapachone •
AMPK •
NQO1 •
restenosis
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