Role of Renin-Angiotensin System Components in Atherosclerosis: Focus on Ang-II, ACE2, and Ang-1–7

Figures

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  Figure 1. Interactions between the renin-angiotensin system (RAS) and atherosclerosis. Angiotensin II (Ang-II) is formed from the angiotensin I (Ang-I) cleavage by angiotensin converting enzyme (ACE). Ang-II can bind to Ang-II type 1 (AT1R) or type 2 (AT2R) receptors. Ang-II undergoes the action of angiotensin converting enzyme type 2 (ACE2) to be converted into angiotensin 1–7 (Ang-1-7), which classically interacts with Mas receptor (MasR). Furthermore, Ang-1–7 can bind to AT2R or it can induce the β-arrestin pathway through its interaction with AT1R. Ang-1–7 also can be produced by neprylisin (NEP) from Ang-I. In summary, the ACE/Ang-II/AT1R pathway induces atherosclerosis while the ACE2/Ang-1–7/MasR and Ang-II and Ang-1–7/AT2R pathways inhibit the atherosclerotic events. In addition, some pharmacological tools have been shown to interfere in some components of RAS cascade and prevent the atherosclerosis, such as statins, ACE inhibitors (ACEi), angiotensin receptor blockers (ARB) and diminazene aceturate (DIZE). Gray arrows indicate classic pathways while gray dotted arrows indicate alternative pathways. Black lines indicate potential pharmacological approaches to stimulate/increase…

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  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…