FIGURE 11.

Intracellular signaling pathways induced by ANG-(1–7). ANG-(1–7) mediates, via AKT-dependent pathways, phosphorylation (Ser 1177) and activation of eNOS, stimulating nitric oxide (NO) production. ANG-(1–7)-mediated AKT activation is also involved in its metabolic actions, through GLUT phosphorylation and translocation to the membrane, enhancing glucose uptake. Although AKT is an important FOXO inactivator, ANG-(1–7) is able to dephosphorylate (Ser256) FOXO1, directly activating this transcription factor. ANG-(1–7) also counterregulates ANG II signaling, blunting phosphorylation of c-Src and the activation of NAD(P)H oxidase by ANG II, reducing reactive oxygen species (ROS) generation. This modulatory effect is mediated by phosphorylation of SHP-2, preventing ANG II-induced SHP-2 dephosphorylation and promoting interaction between SHP-2 and c-Src. Additionally, ANG-(1–7) inhibits MAPKs (ERK1/2, p38, JNK, and ERK5), central mediators in proliferation, fibrosis, and remodeling. Furthermore, ANG-(1–7) inhibits NF-κB, a key transcription factor in inflammation. The signaling pathways elicited by alamandine also involve NO release.