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Cardiovascular Research 2007 76(2):331-339; doi:10.1016/j.cardiores.2007.06.030
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Copyright © 2007, European Society of Cardiology

Role of NAD(P)H:quinone oxidoreductase 1 on tumor necrosis factor-{alpha}-induced migration of human vascular smooth muscle cells

Syng-Ook Leea, Young-Chae Changb, Key Whanga, Cheorl-Ho Kimc,* and In-Seon Leea,*

aDepartment of Food Science and Technology and The Center for Traditional Microorganism Resources (TMR), Keimyung University, Daegu 704-701, Republic of Korea
bDepartment of Pathology, Catholic University of Daegu School of Medicine, Daegu 705-034, Republic of Korea
cMolecular and Cellular Glycobiology Unit, Department of Biological Science, Sungkyunkwan University, Suwon City, Kyunggi 440-746, Republic of Korea

*Corresponding authors. Lee is to be contacted at The Center for Traditional Microorganism Resources (TMR), Keimyung University, 1000 Sindang-Dong, Dalseo-Gu, Daegu 704-701, Republic of Korea. Tel./fax: +82 53 580 5538. Kim, Department of Biological Science, Sungkyunkwan University, Chunchun-Dong 300, Jangan-Gu, Suwon City, Kyunggi-Do 440-746, Republic of Korea. Tel.: +82 31 290 7002; fax: +82 31 290 7015. chkimbio{at}skku.edu inseon{at}kmu.ac.kr

Objectives In a preliminary study, NAD(P)H:quinone oxidoreductase 1 (NQO1) was found to be highly expressed in cultured human aortic smooth muscle cells (HASMC) and dicumarol, a NQO1 inhibitor and a coumarin-derived natural anticoagulant, suppressed tumor necrosis factor (TNF)-{alpha}-induced HASMC migration. Therefore, it was hypothesized that NQO1 plays an important role in the regulation of vascular smooth muscle cells (VSMC) migration activated by TNF-{alpha}.

Methods and results Gelatin zymography, reporter gene, electrophoretic mobility shift and Western blotting assays showed that dicumarol, but not other coumarin-derived anticoagulants, inhibited TNF-{alpha}-induced HASMC migration and suppressed TNF-{alpha}-induced matrix metalloproteinase (MMP)-9 expression and secretion in a dose-dependent manner. In addition, down-regulation of NQO1 by transfection of its small interfering RNA similarly inhibited TNF-{alpha}-induced MMP-9 secretion, indicating that dicumarol-mediated inhibition of MMP-9 expression is due in large part to inhibition of NQO1. Down-regulation of NQO1 inhibits MMP-9 gene expression by suppressing activation of nuclear factor-kappa B (NF-{kappa}B) and activator protein-1 (AP-1), well-known key elements mediating MMP-9 gene expression in its promoter, via the p38 MAPK and JNK pathways.

Conclusion The results of the present study demonstrate that down-regulation of NQO1 effectively suppresses TNF-{alpha}-induced HASMC migration through inhibition of MMP-9 expression, suggesting that NQO1 may be a potential target for the prevention of vascular disorders related to migration of VSMC.

KEYWORDS Vascular smooth muscle cells; Migration; TNF-{alpha}; NAD(P)H:quinone oxidoreductase 1; Dicumarol; Matrix metalloproteinase-9


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