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Hypertension. 2015 Aug;66(2):389-95. doi: 10.1161/HYPERTENSIONAHA.114.04893. Epub 2015 Jun 15.

Beneficial effects of angiotensin-(1-7) against deoxycorticosterone acetate-induced diastolic dysfunction occur independently of changes in blood pressure.

Author information

1
From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
2
From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. guatimosim@icb.ufmg.br.

Abstract

Mineralocorticoids have been implicated in the pathogenesis of diastolic heart failure. On the contrary, angiotensin (Ang)-(1-7) has emerged as a potential strategy for treatment of cardiac dysfunction induced by excessive mineralocorticoid receptor activation. A critical question about the cardioprotective effect of Ang-(1-7) in hypertensive models is its dependence on blood pressure (BP) reduction. Here, we addressed this question by investigating the mechanisms involved in Ang-(1-7) cardioprotection against mineralocorticoid receptor activation. Sprague-Dawley (SD) and transgenic (TG) rats that overexpress an Ang-(1-7) producing fusion protein (TG(A1-7)3292) were treated with deoxycorticosterone acetate (DOCA) for 6 weeks. After treatment, SD rats became hypertensive and developed ventricular hypertrophy. These parameters were attenuated in TG-DOCA. SD-DOCA rats developed diastolic dysfunction which was associated at the cellular level with reduced Ca(2+) transient. Oppositely, TG-DOCA myocytes presented enhanced Ca(2+) transient. Moreover, higher extracellular signal-regulated kinase phosphorylation, type 1 phosphatase, and protein kinase Cα levels were found in SD-DOCA cells. In vivo, pressor effects of DOCA can contribute to the diastolic dysfunction, raising the question of whether protection in TG was a consequence of reduced BP. To address this issue, BP in SD-DOCA was kept at TG-DOCA level by giving hydralazine or by reducing the DOCA amount given to rats (Low-DOCA). Under similar BP, diastolic dysfunction and molecular changes were still evident in DOCA-hydralazine and SD-low-DOCA, but not in TG-DOCA. In conclusion, Ang-(1-7) protective signaling against DOCA-induced diastolic dysfunction occurs independently of BP attenuation and is mediated by the activation of pathways involved in Ca(2+) handling, hypertrophy, and survival.

KEYWORDS:

angiotensins; hypertrophy; left ventricular; myocytes, cardiac

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