title: NAD(P)H:quinone oxidoreductase 1 activation reduces blood pressure through regulation of endothelial nitric oxide synthase acetylation in spontaneously hypertensive rats.
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
  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.
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea;
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea;
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea;
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea;
authors.forename: Jung-Ran
authors.initials: JR
authors.lastname: Noh
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea;
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea;
authors.forename: Youngwon
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea;
authors.forename: Ki-Hoan
authors.initials: KH
authors.lastname: Nam
authors.affiliation: KT&G Life Sciences Corporation/R&D Center, Suwon, South Korea;
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea.
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea; chullee@kribb.re.kr.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011918:Rats, Inbred SHR; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; C014638:beta-lapachone; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; C491732:Nqo1 protein, mouse; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: NQO1; SIRT1.; blood pressure; eNOS; hypertension