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Title 

Enhanced activation of NAD(P)H: Quinone oxidoreductase 1 attenuates spontaneous hypertension by improvement of endothelial nitric oxide synthase coupling via tumor suppressor kinase liver kinase B1/adenosine 5′-monophosphate-activated protein kinase-medi

Authors 

Yong-Hoon KimJung Hwan HwangKyoung Shim KimJung Ran NohGil Tae GangW K OhK H JeongT H KwakH S ChoiI K LeeChul Ho Lee

Publisher 

Lippincott, Williams & Wilkins

Issue Date 

2014

Citation 

Journal of Hypertension, vol. 32, no. 2, pp. 306-317

Keywords 

endothelial nitric oxide synthaseguanosine 5′-triphosphate cyclohydrolase-1hypertensionNAD(P)H:quinone oxidoreductase 1tumor suppressor kinase liver kinase B1/adenosine 5′-monophosphateactivated protein kinase

Abstract 

Aims: Guanosine 5′-triphosphate cyclohydrolase-1 (GTPCH-1) is a rate-limiting enzyme in de-novo synthesis of tetrahydrobiopterin (BH 4), an essential cofactor for endothelial nitric oxide synthase (eNOS) coupling. Adenosine 5′-monophosphate-activated protein kinase (AMPK) is crucial for GTPCH-1 preservation, and tumor suppressor kinase liver kinase B1 (LKB1), an upstream kinase of AMPK, is activated by NAD +-dependent class III histone deacetylase sirtuin 1 (SIRT1)-mediated deacetylation. β-Lapachone has been shown to increase cellular NAD +/NADH ratio via NAD(P)H:quinone oxidoreductase 1 (NQO1) activation. In this study, we have evaluated whether β-lapachone-induced NQO1 activation modulates blood pressure (BP) through preservation of GTPCH-1 in a hypertensive animal model. Methods and results: Spontaneously hypertensive rats (SHRs), primary aortic endothelial cells, and endothelial cell line were used to investigate the hypotensive effect of β-lapachone and its action mechanism. β-Lapachone treatment dramatically lowered BP and vascular tension in SHRs and induced eNOS activation in endothelial cells. Consistent with these effects, β-lapachone treatment also elevated levels of both aortic cGMP and plasma nitric oxide in SHRs. Meanwhile, β-lapachone-treated SHRs showed significantly increased levels of aortic NAD+, LKB1 deacetylation, and AMPK Thr172 phosphorylation followed by increased GTPCH-1 and tetrahydrobiopterin/dihydrobiopterin ratio. In-vitro study revealed that AMPK inhibition by overexpression of dominant-negative AMPK nearly abolished GTPCH-1 protein conservation. Enhanced LKB1 deacetylation and AMPK activation were also elicited by β-lapachone in endothelial cells. However, inhibition of LKB1 deacetylation by blocking of NQO1 or SIRT1 blunted AMPK activation by β-lapachone. Conclusion: This is the first study demonstrating that eNOS coupling can be regulated by NQO1 activation via LKB1/AMPK/GTPCH-1 modulation, which is possibly correlated with relieving hypertension. These findings provide strong evidence to suggest that NQO1 might be a new therapeutic target for hypertension.

ISSN 

0263-6352

Link 

http://dx.doi.org/10.1097/HJH.0000000000000018

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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