The Mas agonist CGEN-856S prevents Ang II induced cardiomyocyte hypertrophy via nitric oxide production.

With the previous knowledge of the cardioprotective effects of the Angiotensin-(1-7) axis, a agonist of Mas receptor has been described, the CGEN-856S. This peptide is more stable than Ang-(1-7), and has a low binding affinity to Angiotensin II receptors. Although the cardioprotective effects of CGEN-856S were previously shown in vivo, the mechanisms behind its effects are still unknown. Here, we employed a combination of molecular biology, confocal microscopy, and genetically modified mouse with Mas deletion to investigate the CGEN-856S protective signaling in cardiomyocytes. In isolated adult ventricular myocytes, CGEN-856S induced an increase in nitric oxide (NO) production which was absent in cells from Mas knockout mice. Using western blot, we observed a significant increase in phosphorylation of AKT after treatment with CGEN-856S. In addition, CGEN-856S prevented the Ang II induced hypertrophy and the nuclear translocation of GRK5 in a culture model of rat neonatal cardiomyocytes. Blockage of Mas receptor and inhibition of the NO synthase abolished the effects of CGEN-856S on Ang II treated cardiomyocytes. In conclusion, we show that CGEN-856S acting via receptor Mas induces NO raise to block Ang II induced cardiomyocyte hypertrophy. These results indicate that CGEN-856S acts very similarly to Ang-(1-7) in cardiac myocytes, highlighting its therapeutic potential for treating cardiovascular diseases.

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

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.