title: Angiotensin II-dependent chronic hypertension and cardiac hypertrophy are unaffected by gp91phox-containing NADPH oxidase.
abstract: The gp91phox-containing NADPH oxidase is the major source of reactive oxygen species (ROS) in the cardiovascular system and inactivation of gp91phox has been reported to blunt hypertension and cardiac hypertrophy seen in angiotensin (Ang) II-infused animals. In the current study, we sought to determine the role of gp91phox-derived ROS on cardiovascular outcomes of chronic exposure to Ang II. The gp91phox-deficient mice were crossed with transgenic mice expressing active human renin in the liver (TTRhRen). TTRhRen mice exhibit chronic Ang II-dependent hypertension and frank cardiac hypertrophy by age 10 to 12 weeks. Four genotypes of mice were generated: control, TTRhRen trangenics (TTRhRen), gp91phox-deficient (gp91-), and TTRhRen transgenic gp91phox-deficient (TTRhRen/gp91-). Eight to 10 mice/group were studied. ROS levels were significantly reduced (P<0.05) in the heart and aorta of TTRhRen/gp91- and gp91-mice compared with control counterparts, and this was associated with reduced cardiac, aortic, and renal NADPH oxidase activity (P<0.05). Systolic blood pressure (SBP), cardiac mass, and cardiac fibrosis were increased in TTRhRen versus controls. In contrast to its action on ROS generation, gp91phox inactivation had no effect on development of hypertension or cardiac hypertrophy in TTRhRen mice, although interstitial fibrosis was reduced. Cardiac and renal expression of gp91phox homologues, Nox1 and Nox4, was not different between groups. Thus, although eliminating gp91phox-associated ROS production may be important in cardiovascular consequences in acute insult models, it does not prevent the development of hypertension and cardiac hypertrophy in a model in which the endogenous renin-angiotensin system is chronically upregulated.
authors.affiliation: CIHR Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada. touyzr@ircm.qc.ca
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Chantel
authors.initials: C
authors.lastname: Mercure
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Danesh
authors.initials: D
authors.lastname: Javeshghani
authors.forename: Guoying
authors.initials: G
authors.lastname: Yao
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.forename: Alvaro
authors.initials: A
authors.lastname: Yogi
authors.forename: Nadheige
authors.initials: N
authors.lastname: Lochard
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Reudelhuber
mesh_terms: D000804:Angiotensin II / Q000097:blood*; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000209:etiology*; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000172:deficiency / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C002744:3-nitrotyrosine; D014443:Tyrosine; D003094:Collagen; D009247:NADH, NADPH Oxidoreductases; C056558:CYBB protein, human; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse; D012083:Renin