NAD(P)H:Quinone oxidoreductase 1 activation reduces blood pressure through regulation of endothelial nitric oxide synthase acetylation in spontaneously hypertensive rats

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Title
NAD(P)H:Quinone oxidoreductase 1 activation reduces blood pressure through regulation of endothelial nitric oxide synthase acetylation in spontaneously hypertensive rats
Author(s)
Yong-Hoon KimJung Hwan HwangKyoung Shim KimJung Ran Noh; Gil Tae Gang; Youngwon SeoKi Hoan Nam; T H Kwak; Hee Gu LeeChul Ho Lee
Bibliographic Citation
American Journal of Hypertension, vol. 28, no. 1, pp. 50-57
Publication Year
2015
Abstract
BACKGROUND Endothelial nitric oxide synthase (eNOS) is involved in blood pressure (BP) regulation through the production of nitric oxide. Sirtuin I (SIRT1), an NAD-dependent protein deacetylase, promotes vascular relaxation through deacetylation and activation of eNOS. β-Lapachone (βL) increases the cellular NAD+/NADH ratio by activating NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, we verified whether activation of NQO1 by βL modulates BP through regulation of eNOS acetylation in a hypertensive animal model. METHODS Spontaneously hypertensive rats (SHRs) and an endothelial cell line (bEnd.3 cells) were used to investigate the hypotensive effect of βL and its mechanism of action. RESULTS βL treatment significantly lowered the BP in SHRs, but this hypotensive effect was completely blocked by eNOS inhibition with ω-nitro-l-arginine methyl ester. In vitro studies revealed that βL activated eNOS, which was accompanied by an increased NAD+/NADH ratio. Moreover, βL significantly decreased acetylation of eNOS; however, this reduced eNOS acetylation was completely precluded by inhibition of SIRT1 in the bEnd.3 cells and in the aorta of the SHRs. Consistent with these effects, βL-induced reduction in BP was also abolished by SIRT1 inhibition in the SHRs. CONCLUSIONS To the best of our knowledge, this is the first study to demonstrate that eNOS acetylation can be regulated by NQO1 activation in an SIRT1-dependent manner, which is correlated with the relief of hypertension. These findings provide strong evidence that NQO1 might be a new therapeutic target for hypertension.
Keyword
Blood pressureENOSHypertensionNQO1SIRT1
ISSN
0895-7061
Publisher
Oxford Univ Press
DOI
http://dx.doi.org/10.1093/ajh/hpu116
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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