title: Activation of NAD(P)H:quinone oxidoreductase ameliorates spontaneous hypertension in an animal model via modulation of eNOS activity.
abstract: OBJECTIVE
  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). β-Lapachone (βL), 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 βL-induced activation of NQO1 modulates BP in an animal model of hypertension.
  
  
  RESULTS
  Spontaneously hypertensive rats (SHR), primary human aortic endothelial cells (HAEC), and endothelial cell lines were used to investigate the hypotensive effect of βL and its mode of action. βL 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 ω-nitro-l-arginine methyl ester. Aortic eNOS phosphorylation and eNOS protein expression were significantly increased in βL-treated SHR. In vitro studies revealed that βL 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, 111 Gwahangno, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Jung-Ran
authors.initials: JR
authors.lastname: Noh
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.forename: Do Hyung
authors.initials: DH
authors.lastname: Kim
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Son
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; 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 / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009285:Naphthoquinones / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011918:Rats, Inbred SHR; D013997:Time Factors; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D014665:Vasodilator Agents; D009243:NAD; C014638:beta-lapachone; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C507703:NQO1 protein, rat; C491732:Nqo1 protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D000109:Acetylcholine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester