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Activation of NAD(P)H:quinone oxidoreductase ameliorates spontaneous hypertension in an animal model via modulation of eNOS activity.

Authors: Kim, YH  Hwang, JH  Noh, JR  Gang, GT  Kim do, H  Son, HY  Kwak, TH  Shong, M  Lee, IK  Lee, CH 
Citation: Kim YH, etal., Cardiovasc Res. 2011 Aug 1;91(3):519-27. doi: 10.1093/cvr/cvr110. Epub 2011 Apr 18.
Pubmed: (View Article at PubMed) PMID:21502369
DOI: Full-text: DOI:10.1093/cvr/cvr110

AIMS: Hypertension is one of the most common human diseases worldwide, and extensive research efforts are focused upon the identification and utilizing of novel therapeutic drug targets. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important regulator of blood pressure (BP). beta-Lapachone (betaL), a well-known substrate of NAD(P)H:quinone oxidoreductase (NQO1), increases the cellular NAD(+)/NADH ratio via the activation of NQO1. In this study, we evaluated whether betaL-induced activation of NQO1 modulates BP in an animal model of hypertension. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR), primary human aortic endothelial cells (HAEC), and endothelial cell lines were used to investigate the hypotensive effect of betaL and its mode of action. betaL treatment stimulated endothelium-dependent vascular relaxation in response to acetylcholine in aorta of SHR and dramatically lowered BP in SHR, but the hypotensive effect was completely blocked by eNOS inhibition with omega-nitro-l-arginine methyl ester. Aortic eNOS phosphorylation and eNOS protein expression were significantly increased in betaL-treated SHR. In vitro studies revealed that betaL treatment elevated the intracellular NAD(+)/NADH ratio and concentration of free Ca(2+) ([Ca(2+)]i), and resulted in Akt/AMP-activated protein kinase/eNOS activation. These effects were abolished by NQO1 siRNA and [Ca(2+)]i inhibition through a ryanodine receptor blockade. CONCLUSION: This study is the first to demonstrate that NQO1 activation has a hypotensive effect mediated by eNOS activation via cellular NAD(+)/NADH ratio modulation in an animal model. These results provide strong evidence suggesting NQO1 might be a new therapeutic target for hypertension.

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RGD Object Information
RGD ID: 11035215
Created: 2016-02-11
Species: All species
Last Modified: 2016-02-11
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.