Figure 2.

Involvement of Ang-II, ACE2, and Ang-1–7 in atherogenic pathways. The Ang-II binding into AT1R can activate Nox5 through a calcium/calmodulin-dependent pathway. The activated Nox5 induces the formation of ROS and stimulates the RhoA/ROCK pathway, which in turn, activates MAPKs and induces the transactivation of several transcription factors such as NF-κB. The expression of several genes is regulated by NF-κB, for instance cytokines (TNF-α and IL-6), chemokines (MCP-1), adhesion molecules (P-selectin, ICAM-1 and VCAM-1), which are involved in Ang-II-induced migration of mononuclear leukocytes. In addition, Ang-II is cleaved by ACE2 and produces Ang-1–7, an important RAS counter-regulator. Ang-1–7 shows the potential to negatively regulate atherogenic pathways, inducing anti-inflammatory effect, weakening monocyte migration and decrease of vascular lipids accumulation. These actions attributed to Ang-1–7 are related to the reduction of oxidative stress and the synthesis of inflammatory cytokines due to inhibition of the Nox4 and NF-κB-mediated pathways. Furthermore, Ang-1–7 stimulates the PI3K/Akt pathway, leading to phosphorylation of eNOS and NO formation, which improves the endothelial function. Ang-1–7 is also capable of promoting endothelial activation of AT2R, which also stimulates the NO cascade. In VSMC, Ang-1–7 inhibits muscle cell migration and proliferation, in contrast to Ang-II which possess proliferative and hypertrophic effects.