title: NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats.
abstract: OBJECTIVE
  Angiotensin-converting enzyme (ACE) plays a key role in blood pressure (BP) homeostasis via regulation of angiotensin II. Active ACE ectodomain is enzymatically cleaved and released into body fluids, including plasma, and elevated plasma ACE levels are associated with increased BP. β-lapachone (βL) has been shown to increase cellular NAD(+)/NADH ratio via activation of NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, we evaluated whether NQO1 activation by βL modulates BP through regulation of ACE shedding in an animal model of hypertension.
  
  
  RESULTS
  Spontaneously hypertensive rats (SHR) and a human ACE-overexpressing rat lung microvascular endothelial cell line (RLMVEC-hACE) were used to investigate the mechanism by which βL exerts a hypotensive effect. In vitro studies revealed that βL significantly increased intracellular Ca(2+) ([Ca(2+)]i) levels and CaMKII Thr(286) phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca(2+)]i level changes through intracellular Ca(2+) chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca(2+)]i levels and CaMKII phosphorylation, but also βL-mediated decrease in ACE shedding. The effect of βL on ACE shedding was also blocked by inhibition of CaMKII. In SHR, βL reduced BP following increase of CaMKII Thr(286) phosphorylation in the lung and decrease of ACE activity and angiotensin II levels in plasma.
  
  
  CONCLUSIONS
  This is the first study demonstrating that ACE shedding is regulated by NQO1 activation, which is possibly correlated with relieving hypertension in SHR. These findings provide strong evidence suggesting that NQO1 might be a new target for ACE modulation and BP control.
authors.affiliation: Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, South Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Kyung-Shim
authors.initials: KS
authors.lastname: Kim
authors.forename: Jung-Ran
authors.initials: JR
authors.lastname: Noh
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Seung Pil
authors.initials: SP
authors.lastname: Jang
authors.forename: Sang-Ju
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Her
authors.forename: Kyeong-Hoon
authors.initials: KH
authors.lastname: Jeong
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.forename: Irina V
authors.initials: IV
authors.lastname: Balyasnikova
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D009285:Naphthoquinones / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D009285:Naphthoquinones; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007703:Peptidyl-Dipeptidase A; D002118:Calcium
keywords: Angiotensin-converting enzyme; Blood pressure; CaMKII; NQO1