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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: Kim YH, Hwang JH, Kim KS, Noh JR, Gang GT, Seo Y, Nam KH, Kwak TH, Lee HG, Lee CH.
    Journal: Am J Hypertens; 2015 Jan; 28(1):50-7. PubMed ID: 24951727.
    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.
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