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, overstimulation of AT1R (and PRR) 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.
