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

M. F. Dias-Peixoto, R. A.S. Santos, E. R.M. Gomes, M. N.M. Alves, P. W.M. Almeida, L. Greco, M. Rosa, B. Fauler, M. Bader, N. Alenina, S. Guatimosim
2008 Hypertension  
Recently there has been growing evidence suggesting that beneficial effects of angiotensin-(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 Ca 2ϩ handling in adult ventricular myocytes using a combination of molecular biology, intracellular Ca 2ϩ imaging, and confocal microscopy. Acute Ang-(1-7) treatment (10 nmol/L)
more » ... atment (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 mol/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 Ca 2ϩ signaling. Cardiomyocytes treated with 10 nmol/L of Ang-(1-7) did not show changes in Ca 2ϩ -transient parameters such as peak Ca 2ϩ transients and kinetics of decay. Nevertheless, cardiomyocytes from Mas-deficient mice presented reduced peak and slower [Ca 2ϩ ] i transients when compared with wild-type cardiomyocytes. Lower Ca 2ϩ ATPase of the sarcoplasmic reticulum expression levels accompanied the reduced Ca 2ϩ transient in Mas-deficient cardiomyocytes. Therefore, chronic Mas-deficiency leads to impaired Ca 2ϩ handling in cardiomyocytes. Collectively, these observations reveal a key role for the Ang-(1-7)/Mas axis as a modulator of cardiomyocyte function. (Hypertension. 2008;52:542-548.)
doi:10.1161/hypertensionaha.108.114280 pmid:18695148 fatcat:aiwcqbkrubgtxmk4xqgjga23be