Recent advances in the angiotensin‐converting enzyme 2–angiotensin(1–7)–Mas axis

Abstract

In the past few years, the classical concept of the renin-angiotensin system (RAS) has experienced substantial conceptual changes. The identification of: the renin/prorenin receptor; the angiotensin-converting enzyme homologue, ACE2, as an angiotensin peptide-processing enzyme and a virus receptor for severe acute respiratory syndrome, the Mas as a receptor for angiotensin (1-7) [Ang(1-7)], and the possibility of signaling through ACE have contributed to switch our understanding of the RAS from the classical limited-proteolysis linear cascade to a cascade with multiple mediators, multiple receptors and multifunctional enzymes. With regard to Ang(1-7), the identification of ACE2 and of Mas as a receptor implicated in its actions contributed to decisively establish this heptapeptide as a biologically active member of the RAS cascade. In this review, we will focus on the recent findings related to the ACE2-Ang(1-7)-Mas axis and, in particular, on its putative role as an ACE-Ang II-AT 1 receptor counter-regulatory axis within the RAS.

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

“…The current therapy to block the activity of the RAS includes ACE inhibitors, AT 1 receptors antagonists, and direct renin inhibitors. The accumulating evidence that stimulation of the ACE2/Ang-(1-7)/Mas axis produces cardioprotection and antihypertensive effects 8,19,35,39 raises the possibility of development of a next generation of RAS-related drugs aimed to increase the activity of this axis. 34,41 The results presented here, using CGEN-856S, in addition to reinforcing the concept that Mas stimulation produces beneficial cardiovascular effects, illustrates the potential of this novel therapeutic strategy for treating cardiovascular diseases.…”

“…10 Effects described for Ang-(1-7) acting through Mas include vasodilation, antiarrhythmogenesis, antifibrogenesis, antitrombogenesis, facilitation of erectile function, and improvement of glicidic and lipidic metabolism. 1,8,10,11 The growing evidence supporting the beneficial effects of the Mas/Ang-(1-7) pathway prompted us to search for novel peptide ligands for Mas. This was achieved using a computational biology discovery platform, which we developed recently, that uses machine learning algorithms designed to predict novel G protein-coupled receptor (GPCR) peptide ligands cleaved from secreted proteins (extracted from the Swiss-Prot protein database) by convertase proteolysis, as described previously.…”

New therapeutic pathways in the RAS

“…Stimulation of the AT2-receptor or Mas has been shown in multiple experimental models to ameliorate the course not only of cardiovascular, but also of renal, immunological and neurological diseases. 4,5 Thus, AT2-receptors and Mas are nowadays regarded as future drug targets, and respective agonists are in various phases of drug development.…”

Role of the ACE2/angiotensin1–7/Mas axis in the cardiovascular system

“…Previous reports indicate that Ang1-7 induces vasodilatation, anti-inflammatory responses and anti-cell growth effects. 3 These results suggest that Ang1-7 functions as an inhibitor or modulator of the angiotensin II receptor (AT 1 receptor)-mediated responses caused by classical Ang II. Ang1-7 seems to function mainly as a local mediator, but it may also function as a circulating hormone.…”