A place in our hearts for the lowly angiotensin 1-7 peptide?

It is absolutely astounding that over a hundred years after the discovery of renin, important new discoveries continue to be made concerning the importance of the renin–angiotensin system (RAS) in biology and disease. In addition to its accepted role as a modulator of blood pressure and fluid volume, it is now clear that the RAS contributes to renal development (reviewed in Reference 1), and mounting evidence suggests that it modulates memory and cardiac and respiratory function. Most of the recent discoveries revolve around peptide products of the RAS that were previously thought to be simply breakdown products but that are increasingly taking center stage in physiology and pathophysiology. The RAS is classically described as a circulating enzymatic pathway of which the sole product of importance is the vasoactive peptide angiotensin II (Ang II; Figure 1). Inhibition of the RAS is now the major pharmacological target in North America for prevention of hypertension and a host of other cardiovascular complications. Although Ang II plays a key role in the biology of the RAS, it is certainly not the only biologically active peptide produced by this system, particularly within tissues (Figure 1). For example, Ang II can be converted to smaller peptide products with biological activity by the action of aminopeptidase A, which removes a single amino acid from the amino terminus of Ang II to produce angiotensin III (Ang III or Ang 2-8). Additional action of aminopeptidases can generate the hexapeptide angiotensin IV (Ang IV or Ang 3-8). Although Ang III can bind to and signal through the Ang II type 1 (AT1) and Ang II type 2 (AT2) receptors, Ang IV is a poor ligand for these receptors and has been reported to bind to a unique receptor that leads to increased renal cortical blood flow and appears to potentiate memory. Surprisingly, the Ang IV “receptor” may actually be the insulinregulated aminopeptidase (reviewed in Reference 2). In addition to being a substrate for Ang II production, Ang I can also be converted by neutral endopeptidase to the heptapetide angiotensin 1-7 (Ang 1-7). Alternatively, Ang 1-7 can be produced directly from Ang II by the recently discovered carboxypeptidase angiotensin-converting enzyme (ACE) 2.3 The Ang 1-7 produced has been reported to have vasodilatory effects (recently reviewed in Reference 4) and may act through the G-coupled protein receptor mas.5 ACE2 can also remove a single amino acid from the carboxy terminus of Ang I to produce angiotensin 1-9 (Ang 1-9), which has no known function to date. The most surprising new discoveries in the renin–angiotensin field in the last 2 years have involved either Ang 1-7 or ACE2.