New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

Ferreira, Anderson J.; Murça, Tatiane M.; Fraga-Silva, Rodrigo A.; Castro, Carlos Henrique; Raizada, Mohan K.; Santos, Robson A. S.

Agonists. AVE 0991 was the first nonpeptide synthetic compound developed with the intention of stimulating the Mas receptor. This compound mimics the Ang-(1-7) effects in several organs such as vessels [140, 141] , kidney [101] , and heart [142, 143] . Similar to Ang-(1-7), AVE 0991 induced a vasodilation effect which was absent in aortic rings of Mas-deficient mice [140] . Moreover, its effects in aortic rings were blocked by the two Ang-(1-7) receptor antagonists, A-779 and D-Pro 7 -Ang-(1-7) [140] . AVE 0991 potentiated the acetylcholine-induced vasodilation in conscious normotensive rats, and this effect was abolished by A-779 and L-NAME [102] . Similarly, it was able to increase the hypotensive effect of Bk in normotensive rats, and A-779 also blocked this effect [107] . Ferreira et al. [142, 143] reported that AVE 0991 protects the heart against cardiac dysfunction and remodeling caused by isoproterenol treatment or by myocardial infarction in rats [142, 143] . In Mas-transfected cells, AVE 0991 induced NO release which was blunted by A-779 and not by AT 2 or AT 1 antagonists [101] . All these data support the concept that AVE 0991 is an Ang-(1-7) mimetic and that its actions are mediated by the interaction with Mas. Using a computational discovery platform for predicting novel naturally occurring peptides that may activate GPCR, two novel peptides, designated as CGEN-856 and CGEN-857, with amino acid sequence unrelated to angiotensin peptides, were found to display high specificity for Mas [23] . These peptides elicited Ca +2 influx in CHO cells overexpressing Mas without any activity in AT 1 or AT 2 receptors [144] . CGEN-856S, a derivative of the CGEN-856 peptide, induced beneficial cardiovascular effects similar to those caused by Ang-(1-7) [23] . This compound competes with Ang-(1-7) for the same bind site in Mas-transfected cells. Furthermore, similar to Ang-(1-7), CGEN-856S produced a vasodilation effect which was absence in Mas-deficient mice, indicating that this compound also acts via Mas [23] . This was confirmed by the inhibition of the CGEN-856S effects by the Mas antagonist A-779. Importantly, Savergnini et al. [23] showed that CGEN-856S promotes antiarrhythmogenic effects and produces a small dose-dependent decrease in arterial pressure of conscious SHR [23] .