Activation of NAD(P)H:Quinone Oxidoreductase 1 Prevents
Arterial Restenosis by Suppressing Vascular Smooth Muscle
Cell Proliferation
- Author(s)
- 박근규; 이인규
- Alternative Author(s)
- Park, Keun Gyu; Lee, 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
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