title: Angiotensin-(1-7) prevents cardiomyocyte pathological remodeling through a nitric oxide/guanosine 3',5'-cyclic monophosphate-dependent pathway.
abstract: The renin-angiotensin (Ang) system plays a pivotal role in the pathogenesis of cardiovascular disease, with Ang II being the major effector of this system. Multiple lines of evidence have shown that Ang-(1-7) exerts cardioprotective effects in the heart by counterregulating Ang II actions. The questions that remain are how and where Ang-(1-7) exerts its effects. By using a combination of molecular biology, confocal microscopy, and a transgenic rat model with increased levels of circulating Ang-(1-7) (TGR[A1-7]3292), we evaluated the signaling pathways involved in Ang-(1-7) cardioprotection against Ang II-induced pathological remodeling in ventricular cardiomyocytes. Rats were infused with Ang II for 2 weeks. We found that ventricular myocytes from TGR(A1-7)3292 rats are protected from Ang II pathological remodeling characterized by Ca(2+) signaling dysfunction, hypertrophic fetal gene expression, glycogen synthase kinase 3beta inactivation, and nuclear factor of activated T-cells nuclear accumulation. Moreover, cardiomyocytes from TGR(A1-7)3292 rats infused with Ang II presented increased expression levels of neuronal NO synthase. To provide a signaling pathway involved in the beneficial effects of Ang-(1-7), we treated neonatal cardiomyocytes with Ang-(1-7) and Ang II for 36 hours. Treatment of cardiomyocytes with Ang-(1-7) prevented Ang II-induced hypertrophy by modulating calcineurin/nuclear factor of activated T-cell signaling cascade. Importantly, antihypertrophic effects of Ang-(1-7) on Ang II-treated cardiomyocytes were prevented by N(G)-nitro-l-arginine methyl ester and 1H-1,2,4oxadiazolo4,2-aquinoxalin-1-one, suggesting that these effects are mediated by NO/cGMP. Taken together, these data reveal a key role for NO/cGMP as a mediator of Ang-(1-7) beneficial effects in cardiac cells.
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte MG-CEP: 31270-901, Brazil.
authors.forename: Enéas R M
authors.initials: ER
authors.lastname: Gomes
authors.forename: Aline A
authors.initials: AA
authors.lastname: Lara
authors.forename: Pedro W M
authors.initials: PW
authors.lastname: Almeida
authors.forename: Diogo
authors.initials: D
authors.lastname: Guimarães
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Resende
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Campagnole-Santos
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
mesh_terms: D000803:Angiotensin I / Q000097:blood / Q000378:metabolism*; D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D015398:Signal Transduction
chemical_list: D050778:NFATC Transcription Factors; D010446:Peptide Fragments; D000804:Angiotensin II; D009569:Nitric Oxide; D000803:Angiotensin I; D006152:Cyclic GMP; C118790:angiotensin I (1-7); D002118:Calcium