title: Role of angiotensin-converting enzyme 2 in cardiac hypertrophy induced by nitric oxide synthase inhibition.
abstract: OBJECTIVE
  Angiotensin-converting enzyme 2 (ACE2) generates angiotensin-(1-7) [Ang-(1-7)], a peptide highlighted as exerting a pivotal role in cardiovascular remodeling. Moreover, the ACE2/Ang-(1-7)/Mas axis directly activates endothelial nitric oxide (NO) synthase and NO generation in the heart. However, the role of ACE2 in cardiovascular remodeling induced by persistent inhibition of NO under chronic activation of the renin-angiotensin system (RAS) remains poorly understood.
  
  
  RESULTS
  Chimeric hypertensive mice that exhibit activation of the human RAS were produced by mating human renin (hRN) and human angiotensinogen (hANG) transgenic mice. Persistent NO inhibition with NG-nitro-L-arginine methyl ester (L-NAME) was started at 8 weeks of age for 4 weeks. After administration of L-NAME, blood pressure (BP) markedly increased in the chimeric mice (hRN/hANG-Tg), whereas wild-type mice (C57BL/6J) showed little increase in BP. Cardiovascular remodeling with enhanced oxidative stress in hRN/hANG-Tg was markedly accelerated by NO inhibition compared with that in wild-type mice. Moreover, ACE2 mRNA expression and activity in cardiac tissue were markedly reduced in L-NAME-treated hRN/hANG-Tg. Co-administration of an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan, inhibited L-NAME-induced cardiovascular remodeling and improved the reduction in cardiac ACE2. The preventive effect of olmesartan on cardiac hypertrophy was blunted by co-administration of a selective Ang-(1-7) antagonist, [D-Ala7]-Ang-(1-7).
  
  
  CONCLUSIONS
  Our findings demonstrate that cardiovascular remodeling induced by persistent NO inhibition was enhanced in hRN/hANG-Tg. An ARB, olmesartan, blunted cardiac remodeling induced by NO inhibition with RAS activation partially through the ACE2/Ang-(1-7)/Mas axis in addition to directly through its classical ACE/Ang II/AT1 receptor axis-blocking action.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Inaba
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Megumi
authors.initials: M
authors.lastname: Furuno
authors.forename: Harumi
authors.initials: H
authors.lastname: Kanno
authors.forename: Izumi
authors.initials: I
authors.lastname: Senba
authors.forename: Hideki
authors.initials: H
authors.lastname: Okayama
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D019331:NG-Nitroarginine Methyl Ester