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Review
. 2018 Jan 1;98(1):505-553.
doi: 10.1152/physrev.00023.2016.

The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7)

Robson Augusto Souza Santos  1 , Walkyria Oliveira Sampaio  1 , Andreia C Alzamora  1 , Daisy Motta-Santos  1 , Natalia Alenina  1 , Michael Bader  1 , Maria Jose Campagnole-Santos  1
Affiliations
Review

The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7)

Robson Augusto Souza Santos et al. Physiol Rev. .

Abstract

The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

FIGURE 1.
FIGURE 1.
ACE2/angiotensin-(1–7)/Mas axis discovery timeline.
FIGURE 2.
FIGURE 2.
The renin-angiotensin system cascade: updated view. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; APA, aminopeptidase A; APN, aminopeptidase N; PRCP, prolyl endopeptidase; PCP, prolylcarboxyendopeptidase; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; CP, carboxypeptidase; AP, aminopeptidase; Dcase, decarboxylase; THOP, thimet oligopeptidase.
FIGURE 3.
FIGURE 3.
Pharmacological and genetic tools for the study of the ACE2/angiotensin-(1–7)/Mas axis.
FIGURE 4.
FIGURE 4.
Localization of Mas in the central nervous system and main actions of angiotensin-(1–7) in the brain. See text for definitions.
FIGURE 5.
FIGURE 5.
Effects of ANG-(1–7) in the heart. The effects illustrated in the figure include the ones produced in coronary vessels, fibroblasts, and cardiomyocytes.
FIGURE 6.
FIGURE 6.
Main known effects of ANG-(1–7) in blood vessels.
FIGURE 7.
FIGURE 7.
Effects of ANG-(1–7) in the lung. Most of the known effects of ANG-(1–7) in the lungs are related to inflammation.
FIGURE 8.
FIGURE 8.
Protective effects of ANG-(1–7) on diabetes. ANG-(1–7) improves insulin signaling, increasing AKT phosphorylation, which is a key event for GLUT translocation to membrane and glucose uptake. This effect on AKT is also related to the increase in nitric oxide release and vasodilation. In addition to the anti-inflammatory and antioxidative properties, these effects lead to the reduction in microcapillary damage and in the vascular damage. Together, these actions result in clinical benefits, including reduction in cardiomyopathy and nephropathy, decrease in peripheral insulin resistance, protection against eye microcirculation damage, and retinopathy as well as acceleration in wound dermal repair.
FIGURE 9.
FIGURE 9.
Actions of ANG-(1–7) in the skeletal muscle system.
FIGURE 10.
FIGURE 10.
Effects of ANG-(1–7) in the liver.
FIGURE 11.
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.
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