Angiotensin-(1–7) attenuates angiotensin II-induced cardiac hypertrophy via a Sirt3-dependent mechanism

The objectives of the current study were to investigate the effect of Ang-(1-7) on the development of cardiac hypertrophy, and to identify the intracellular mechanism underlying this action of Ang-(1-7). Blood pressure and heart rate were recorded using radiotelemetry before and after chronic subcutaneous infusion of control (PBS), Ang II, Ang-(1-7), or Ang II+Ang-(1-7) for 4 weeks in normotensive rats. Chronic administration of Ang-(1-7) did not affect either basal blood pressure or the Ang II-induced elevation in blood pressure. However, Ang-(1-7) significantly attenuated Ang II-induced cardiac hypertrophy and perivascular fibrosis in these rats. These effects of Ang-(1-7) were confirmed in cultured cardiomyocytes, in which Ang-(1-7) significantly attenuated Ang II-induced increases in cell size. This protective effect of Ang-(1-7) was significantly attenuated by pretreatment with A779, a Mas receptor antagonist; Mito-TEMPO, mitochondria-targeting superoxide scavenger, as well as blockade of Sirt3, a deacetylation-acting protein, by viral vector-mediated overexpression of Sirt3-shRNA. Western blot analysis demonstrated that treatment with Ang-(1-7) dramatically increased Sirt3 expression. In addition, Ang (1-7) attenuated the Ang II-induced increase in mitochondrial ROS generation, an effect that was abolished by A779 or Sirt3-shRNA. Moreover, Ang-(1-7) increased FoxO3a deacetylation and SOD2 expression, and these effects were blocked by Sirt3-shRNA. In summary, the protective effects of Ang-(1-7) on Ang II-induced cardiac hypertrophy and increased ROS production are mediated by elevated SOD2 expression via stimulation of Sirt3-dependent deacetylation of FoxO3a in cardiomyocytes. Thus, activation of the Ang-(1-7)/Sirt3 signaling pathway could be a novel therapeutic strategy in the management of cardiac hypertrophy and associated complications.