Abstract
The objectives of the present 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 wk 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) or Mito-TEMPO (a mitochondria-targeting superoxide scavenger) as well as blockade of Sirt3 (a deacetylation-acting protein) by viral vector-mediated overexpression of sirtuin (Sirt)3 short hairpin (sh)RNA. 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 mitochondrial 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.NEW & NOTEWORTHY Chronic subcutaneous ANG-(1-7) has no effect on ANG II-induced elevations in blood pressure but significantly attenuates ANG II-induced cardiac hypertrophy and fibrosis by a mitochondrial ROS-dependent mechanism. This protective effect of ANG-(1-7) against the action of ANG II action is mediated by stimulation of sirtuin-3-mediated deacetylation of FoxO3a, which triggers SOD2 expression.