Devil and angel in the renin–angiotensin system: ACE–angiotensin II–AT(1) receptor axis vs. ACE2–angiotensin-(1–7)–Mas receptor axis

Recent studies have established a new regulatory axis in the renin–angiotensin system (RAS). In this axis, angiotensin (Ang)-(1–7) is finally produced from Ang I or Ang II by the catalytic activity of angiotensin-converting enzyme 2 (ACE2). Ang-(1–7) shows actions different from those of AT(1) receptor stimulation, such as vasodilatation, natriuresis, anti-proliferation and an increase in the bradykinin–NO (nitric oxide) system. As the catalytic efficiency of ACE2 is approximately 400-fold higher with Ang II as a substrate than with Ang I, this axis is possibly acting as a counter-regulatory system against the ACE/Ang II/AT(1) receptor axis. The signaling pathway of the ACE2–Ang-(1–7) axis has not yet been totally and clearly understood. However, a recent report suggests that the Mas oncogene acts as a receptor for Ang-(1–7). Intracellular signaling through Mas is not clear yet. Several factors such as Akt phosphorylation, protein kinase C activation and mitogen-activated protein (MAP) kinase inhibition seem to be involved in this signaling pathway. Further investigations are needed to clarify the regulation and mechanism of action of ACE2 and Ang-(1–7). However, this second axis through ACE2 and Ang-(1–7) in RAS can be an important target for the therapy of cardiovascular and metabolic disorders.