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(Hypertension. 2008;52:542.)
© 2008 American Heart Association, Inc.

Original Articles

Molecular Mechanisms Involved in the Angiotensin-(1-7)/Mas Signaling Pathway in Cardiomyocytes

Marco F. Dias-Peixoto; Robson A.S. Santos; Enéas R.M. Gomes; Márcia N.M. Alves; Pedro W.M. Almeida; Leonardo Greco; Mariana Rosa; Beatrix Fauler; Michael Bader; Natalia Alenina; Silvia Guatimosim

From the Department of Physiology and Biophysics (M.F.D.-P., R.A.S.S., E.R.M.G., M.N.M.A., P.W.M.A., L.G., M.R., B.F., S.G.), Federal University of Minas Gerais, Belo Horizonte, Brazil; and the Max-Delbrück Center for Molecular Medicine (M.B., N.A.), Berlin, Germany.

Correspondence to Silvia Guatimosim, Institute of Biological Sciences, Federal University of Minas Gerais, Av Antônio Carlos 6627, Belo Horizonte, MG-CEP 31270-901, Brazil. E-mail guatimosim{at}icb.ufmg.br

Recently there has been growing evidence suggesting that beneficial effects of angiotensin-(1-7) [Ang-(1-7)] in the heart are mediated by its receptor Mas. However, the signaling pathways involved in these effects in cardiomyocytes are unknown. Here, we investigated the involvement of the Ang-(1-7)/Mas axis in NO generation and Ca²⁺ handling in adult ventricular myocytes using a combination of molecular biology, intracellular Ca²⁺ imaging, and confocal microscopy. Acute Ang-(1-7) treatment (10 nmol/L) leads to NO production and activates endothelial NO synthase and Akt in cardiomyocytes. Ang-(1-7)–dependent NO raise was abolished by pretreatment with A-779 (1 µmol/L). To confirm that Ang-(1-7) action is mediated by Mas, we used cardiomyocytes isolated from Mas-deficient mice. In Mas-deficient cardiomyocytes, Ang-(1-7) failed to increase NO levels. Moreover, Mas-ablation was accompanied by significant alterations in the proteins involved in the regulation of endothelial NO synthase activity, indicating that endothelial NO synthase and its binding partners are important effectors of the Mas-mediated pathway in cardiomyocytes. We then investigated the role of the Ang-(1-7)/Mas axis on Ca²⁺ signaling. Cardiomyocytes treated with 10 nmol/L of Ang-(1-7) did not show changes in Ca²⁺-transient parameters such as peak Ca²⁺ transients and kinetics of decay. Nevertheless, cardiomyocytes from Mas-deficient mice presented reduced peak and slower [Ca²⁺]_i transients when compared with wild-type cardiomyocytes. Lower Ca²⁺ ATPase of the sarcoplasmic reticulum expression levels accompanied the reduced Ca²⁺ transient in Mas-deficient cardiomyocytes. Therefore, chronic Mas-deficiency leads to impaired Ca²⁺ handling in cardiomyocytes. Collectively, these observations reveal a key role for the Ang-(1-7)/Mas axis as a modulator of cardiomyocyte function.

Key Words: ventricular cardiomyocytes • NO • Ca²⁺ transient • Ang-(1-7), Mas

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