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.

The vascular effects of Ang-(1-7) are endothelium dependent and involve the production of vasodilator products, such as prostanoids, NO, and endothelium-derived hyperpolarizing factor (EDHF) [16, 81, 100] . Pinheiro and coworkers [101] found that Ang-(1-7) promotes an increase in NO release in Mas-transfected chinese hamster ovary (CHO) cells [101] . Furthermore, short-term infusion of Ang-(1-7) improved the endothelial function by a mechanism involving NO release in rats [102] . Mas deletion resulted in endothelial dysfunction associated with an unbalance between NO and oxidative stress [83] . Also, Mas activation by Ang-(1-7) in human endothelial cells stimulated eNOS phosphorylation/activation via the Aktdependent pathway [81] . Other mechanisms appear to be involved in the Ang-(1-7) vascular actions. Roks et al. [103] have shown that Ang-(1-7) inhibits the vasoconstriction induced by Ang II in human internal mammary arteries, thereby suggesting that Ang-(1-7) can regulate the Ang II effects [103] . In fact, Ang-(1-7) negatively modulates the Ang II type 1 receptor-mediated activation of c-Src, and its downstream targets ERK1/2 and NAD(P)H oxidase [104] . The counterregulatory action of Ang-(1-7) on Ang II signaling has been also observed in cardiomyocytes [77] , vascular smooth muscle cells [105] , and fibroblasts [106] . Additionally, an interaction between Mas and bradykinin (Bk) type 2 (B 2 ) receptors may modulate some of the Ang-(1-7) effects in blood vessels [107] . Indeed, it has been demonstrated that Ang-(1-7) potentiates the vasodilator and hypotensive effects of Bk in several vascular beds [93, [108] [109] [110] .