AT2 receptors: functional relevance in cardiovascular disease

Abstract

The renin angiotensin system (RAS) is intricately involved in normal cardiovascular homeostasis. Excessive stimulation by the octapeptide angiotensin II contributes to a range of cardiovascular pathologies and diseases via angiotensin type 1 receptor (AT1R) activation. On the other hand, tElsevier Inc.he angiotensin type 2 receptor (AT2R) is thought to counter-regulate AT1R function. In this review, we describe the enhanced expression and function of AT2R in various cardiovascular disease settings. In addition, we illustrate that the RAS consists of a family of angiotensin peptides that exert cardiovascular effects that are often distinct from those of Ang II. During cardiovascular disease, there is likely to be an increased functional importance of AT2R, stimulated by Ang II, or even shorter angiotensin peptide fragments, to limit AT1R-mediated overactivity and cardiovascular pathologies.

Fig. 1

Summary of the RAS incorporating the Ang peptide family and physiological effects mediated via ATR subtypes. Under the classical RAS schema, Ang II is produced, via renin and ACE, to act with equal affinity on two ATR subtypes, AT₁R and AT₂R (large arrows). However, it is now appreciated that a number of breakdown products of Ang II, namely Ang (1–7), Ang III and Ang IV, exert their own unique effects that are distinct (and often opposite) to those of Ang II. Such effects are often mediated via newly recognized receptors such as MasR for Ang (1–7) and AT₄R (also known as IRAP) for Ang IV, or additionally via AT₂R stimulation. ACE2 is also a new pathway for the formation of Ang (1–7). Newly identified Ang receptor binding proteins associated with different ATR subtypes may also modify ATR activation. Thus, over-stimulation of AT₁R (and (P)RR) by Ang II, which can contribute to a plethora of cardiovascular disease processes, may be counter-regulated by a number of non-AT₁R mechanisms. Most notably, AT₂R stimulation usually causes opposing effects to AT₁R, as indicated. It is also likely that the MasR exerts a similar counter-regulatory role, whereas the evidence is more preliminary and speculative for AT₄R/IRAP. In terms of mediators, Ang II itself stimulates AT₂R whereas the shorter Ang peptides stimulate their cognate receptors and possibly also AT₂R.

Fig. 2

The in vitro and in vivo vasodilator effects of AT₂R stimulation are often difficult to detect because of the overriding effects of AT₁R-mediated vasoconstriction. This state can be dramatically changed by performing AT₂R stimulation against a background of low-dose AT₁R antagonist (sartan), even using sartan doses that are sub-threshold for BP-lowering (A). Under these circumstances, AT₂R-mediated vasodilatation can be unmasked and subsequently abolished by concomitant AT₂R blockade using PD123319 (B).