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

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Author(s)
박근규이인규
Alternative Author(s)
Park, Keun GyuLee, In Kyu
Publication Year
2009
Abstract
—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. (Circ Res. 2009;
104:842-850.)
Key Words: vascular smooth muscle cell -lapachone AMPK NQO1 restenosis
Department
Dept. of Internal Medicine (내과학)
Publisher
School of Medicine
Citation
Circulation Research, Vol.104(7) : 842-850, 2009
Type
Article
ISSN
0009-7330
DOI
10.1161/CIRCRESAHA.108.189837
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/35435
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