NAD(P)H:Quinone Oxidoreductase 1 Activation Reduces Blood Pressure Through Regulation of Endothelial Nitric Oxide Synthase Acetylation in Spontaneously Hypertensive Rats. (20th June 2014)

• Record Type: Journal Article
• Authors: Kim, Yong-Hoon; Hwang, Jung Hwan; Kim, Kyoung-Shim; Noh, Jung-Ran; Gang, Gil-Tae; Seo, Youngwon; Nam, Ki-Hoan; Kwak, Tae Hwan; Lee, Hee Gu; Lee, Chul-Ho
• Is Part Of: American journal of hypertension. Volume 28:Number 1(2015:Jan.)
• Page Start: 50
• Page End: 57
• Publication Date: 2014-06-20
• Subjects: blood pressure -- eNOS -- hypertension -- NQO1 -- SIRT1.; Hypertension -- Periodicals; 616.132005
• DOI: 10.1093/ajh/hpu116
• Languages: English
• ISSNs: 0895-7061

Abstract

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.