title: Effects of cardiac overexpression of the angiotensin II type 2 receptor on remodeling and dysfunction in mice post-myocardial infarction.
abstract: The activation of angiotensin II type 2 receptor (AT2R) has been considered cardioprotective. However, there are controversial findings regarding the role of overexpressing AT2R in the heart. Using transgenic mice with different levels of AT2R gene overexpression in the heart (1, 4, or 9 copies of the AT2R transgene: Tg1, Tg4, or Tg9), we studied the effect of AT2R overexpression on left ventricular remodeling and dysfunction post-myocardial infarction (MI). Tg1, Tg4, Tg9, and their wild-type littermates were divided into (1) sham MI, (2) MI plus vehicle, and (3) MI plus AT2R antagonist. Treatments were started 4 weeks after MI and continued for 8 weeks. AT2R protein and mRNA expression in the heart was significantly increased in transgenic mice, and the increase positively correlated with copies of the transgene. AT1R protein and mRNA expression remained unchanged in Tg1 and Tg4 but slightly increased in Tg9 mice. Systolic blood pressure and cardiac phenotypes did not differ among strains under basal conditions. MI caused myocardial hypertrophy, interstitial fibrosis, ventricular dilatation, and dysfunction associated with increased protein expression of Nox2 and transforming growth factor β1. These pathological responses were diminished in Tg1 and Tg4 mice. Moreover, the protective effects of AT2R were abolished by AT2R antagonist and also absent in Tg9 mice. We thus conclude that whether overexpression of AT2R is beneficial or detrimental to the heart is largely dependent on expression levels and possibly via regulations of Nox2 and transforming growth factor β1 signaling pathways.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, E&R 7081, 2799 W Grand Boulevard, Detroit, MI 48202-2689. xpyang1@hfhs.org.
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
authors.forename: Liping
authors.initials: L
authors.lastname: Zhu
authors.forename: Pamela
authors.initials: P
authors.lastname: Harding
authors.forename: Edward G
authors.initials: EG
authors.lastname: Shesely
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Dai
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: Edward
authors.initials: E
authors.lastname: Peterson
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight; D018628:Gene Dosage; D015870:Gene Expression; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009929:Organ Size; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics* / Q000502:physiology
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D008562:Membrane Glycoproteins; D044139:Receptor, Angiotensin, Type 2; D053773:Transforming Growth Factor beta1; D052250:Nitric Oxide Synthase Type III; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: mice, transgenic; myocardial infarction; receptor, angiotensin, type 1; receptor, angiotensin, type 2
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