Vias de sinalização ativadas pelo novo agonista do receptor MAS, CGEN-856S, em cardiomiócitos

• Ano de defesa: 2015
• Autor(a) principal: Eduardo Nocchi
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; ICB - INSTITUTO DE CIÊNCIAS BIOLOGICAS; Programa de Pós-Graduação em Ciências Biológicas - Fisiologia e Farmacologia; UFMG
• Palavras-chave em Português: Fisiologia; Farmacologia; Óxido nítrico; Angiotensinas
• Link de acesso: http://hdl.handle.net/1843/35644

Knowing the cardioprotective effects of angiotensin-(1-7)axis, new receptor agonists have been described. Shemesh et al. (2008) described two possible agonists of the receptor Mas: CGEN-856S and CGEN-857V. The cardioprotective effects of these peptides in vivo were confirmed by SAVERGNINI et al. (2010). The aim of this work was to investigate the effects of CGEN-856S and CGEN-857V peptides in the production and modulation of the nitric oxide pathway in cardiomyocytes and compare them with those promoted by Ang-(1-7). In this work we used a combination of molecular biology, confocal microscopy and a model of genetically modified mice with deletion of MAS receptor. The nitric oxide production was evaluated with a nitric oxide sensitive fluorescent probe. We also assessed the effect of acute treatment and the cardioprotective effects of chronic treatment with the peptides against Angiotensin II. Regardless of the concentration used, cardiomyocytes treated with CGEN-856S showed a significant increase in nitric oxide production, with no differences between the tested concentrations. On the contrary, treatment with CGEN-857V did not increase nitric oxide production. The same happened with cardiomyocytes from MAS knockout mice treated with CGEN-856S. Using western blot, we observed a significant increase in phosphorylation of AKT in the Serine 473 residue after acute treatment with CGEN-856S. We also tested the actions of CGEN-856S against Ang II induced hypertrophic effects. Neonatal cardiomyocytes treated with Ang II for 36 hours showed a significant increase in cell area, increased translocation of GRK5, and reduced the frequency of contractions. All these effects were prevented by concomitant treatment with CGEN-856S. When A779 (Mas receptor antagonist) or L-NAME (an inhibitor of nitric oxide synthases) was added to cells treated with Ang II and CGEN-856S, results similar to those found in cells incubated with Ang II alone were seen. CONCLUSIONS: In cardiac myocytes CGEN-856S peptide increases nitric oxide and is capable of preventing Ang II hypertrophic effects through the production of NO and via receptor Mas activation. These results indicate that CGEN-856S acts very similarly to Ang- (1-7) in cardiac myocytes.