Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system Robson A S Santos 1 , Anderson J Ferreira 2 , Thiago Verano-Braga 1,3 and Michael Bader 4 Departments of 1 Physiology and Biophysics and 2 Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil 3 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark 4 Max-Delbru ¨ ck Center for Molecular Medicine (MDC), Robert-Ro ¨ ssle-Street 10, 13125 Berlin, Germany Correspondence should be addressed to M Bader Email mbader@mdc-berlin.de Abstract Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin– angiotensin system (RAS). Ang-(1–7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1–7). Thus, the axis formed by ACE2/Ang-(1–7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/ proliferative arm of the RAS consisting of ACE, Ang II, and AT 1 receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1–7) and Mas with AT 1 and AT 2 receptors. Key Words " Angiotensin II " ACE2 " Mas " Cardiovascular functions " Metabolism Journal of Endocrinology (2013) 216, R1–R17 Introduction Santos et al. (1988) described the formation of the heptapeptide angiotensin (Ang)-(1–7) from Ang I by an Ang-converting enzyme (ACE)-independent pathway. In the same year, Schiavone et al. (1988) published the first report of a biological action of this heptapeptide in vitro, release of vasopressin from hypothalamus–neurohypo- physeal explants. One year later, Chappell et al. (1989) discovered the peptide in the rat brain and Campagnole- Santos et al. (1989) described the first in vivo action of Ang-(1–7) using microinjection in the nucleus tractus solitarii (nTS) of anesthetized rats. These seminal studies and many others that followed led to the recognition of Ang-(1–7) as a biologically active peptide of the renin– angiotensin system (RAS; Carey & Siragy 2003, Santos et al. 2005, Ferrario 2006, Bader 2010). The identification of the ACE homolog, ACE2, as a key Ang-(1–7)-forming enzyme unravels the existence of a distinct enzymatic pathway for the production of this peptide (Donoghue et al. 2000, Tipnis et al. 2000). This monocarboxypeptidase can remove the amino acid leucine from the C-terminus of Ang I to form the biologically active peptide Ang-(1–9) (Donoghue et al. Journal of Endocrinology Review R A S SANTOS and others ACE2/Ang-(1–7)/Mas axis 216 :2 R1–R17 http://joe.endocrinology-journals.org Ñ 2013 Society for Endocrinology DOI: 10.1530/JOE-12-0341 Printed in Great Britain Published by Bioscientifica Ltd.