G-Protein–Coupled Receptor Mas Is a Physiological Antagonist of the Angiotensin II Type 1 Receptor

Abstract

Background-We previously identified the G-protein-coupled receptor Mas, encoded by the Mas proto-oncogene, as an endogenous receptor for the heptapeptide angiotensin-(1-7); however, the receptor is also suggested to be involved in actions of angiotensin II. We therefore tested whether this could be mediated indirectly through an interaction with the angiotensin II type 1 receptor, AT 1 . Methods and Results-In transfected mammalian cells, Mas was not activated by angiotensin II; however, AT 1 receptor-mediated, angiotensin II-induced production of inositol phosphates and mobilization of intracellular Ca 2ϩ was diminished by 50% after coexpression of Mas, despite a concomitant increase in angiotensin II binding capacity. Mas and the AT 1 receptor formed a constitutive hetero-oligomeric complex that was unaffected by the presence of agonists or antagonists of the 2 receptors. In vivo, Mas acts as an antagonist of the AT 1 receptor; mice lacking the Mas gene show enhanced angiotensin II-mediated vasoconstriction in mesenteric microvessels.Conclusions-These results demonstrate that Mas can hetero-oligomerize with the AT 1 receptor and by so doing inhibit the actions of angiotensin II. This is a novel demonstration that a G-protein-coupled receptor acts as a physiological antagonist of a previously characterized receptor. Consequently, the AT 1 -Mas complex could be of great importance as a target for pharmacological intervention in cardiovascular diseases.

Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

“…Thus, as demonstrated previously in Mas knockout mice, this receptor seems to be essential for vascular biological actions of Ang- (1-7). 18,25,26 Although we cannot exclude an interaction of Mas with Ang II type 1 or type 2 receptors, 27,28 we have obtained enough evidence in this study to suggest a primary role for Mas, at least, in Ang-(1-7)-induced NO release.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…Binding studies showed that Ang-(1-7) binds a receptor, which was completely blocked with the addition of D-Ala 7 -Ang-(1-7) (Tallant et al 1997), suggesting involvment of the mas receptor. Therefore, it is known that Ang-(1-7) binds the mas receptor and is a least partially responsible for the physiological effects reported for Ang-(1-7), but given the current data on interactions of the different angiotensin receptors (Castro et al 2005;Kostenis et al 2005), we do not even come close to understanding the roles of the angiotensin receptor types as they pertain to their physiological actions and/or interactions. The role of this newly reported Ang-(1-7) receptor remains to be elucidated, and its functional significance may bring scientists to a better understanding of how the system functions not only within itself, but also with other endogenous physiological systems.…”

Role of the receptor Mas in macrophage-mediated inflammation in vivo

“…A particular example is the heptapeptide Ang-(1-7), which is derived from Ang I and Ang II by several metalloproteinases and endopeptidases including ACE2 and neprilysin. Ang-(1-7) has been shown to activate its own seventransmembrane G protein-coupled receptor called Mas (9,10). Mas is expressed on various tissues of the central nervous (CNS) and cardiovascular system (11).…”