Emerging Evidence for a Functional Angiotensin-Converting Enzyme 2-Angiotensin-(1-7)-Mas Receptor Axis

Abstract

From the initial description of renin activity over a century ago, the ongoing study of the renin-angiotensin (Ang)-aldosterone system (RAAS) continues to yield unexpected findings that redefine the functional nature of this system, as well as our concepts on the mechanisms of cardiovascular regulation. The functional arc of the RAAS can no longer be viewed solely in terms of increasing blood pressure and inducing vasoconstriction, although these still remain the dominant aspects of at least the angiotensin II receptor subtype 1 (AT1R) pathway. There is clearly compelling evidence that other components of the RAAS may buffer actions, because the Ang II-AT2 receptor pathway uses the identical ligand coupled to a different receptor subtype to evoke, in many cases, actions that oppose AT1 activation1 (for a more extensive review). Moreover, parallel pathways within the RAAS result in novel products distinct from Ang II that require additional “Ang”-converting enzymes (ACEs) and unique receptors for these products. Indeed, the recent discoveries of ACE2, the Ang-(1-7) [AT(1-7)] receptor, and Ang-(1-12)2 as a potentially new precursor add significant impetus to revise the RAAS as multiple systems that may amplify or oppose one another (see the Figure). In this brief review, the current evidence for the physiological relevance of these new components of the RAAS is assessed. Figure. Cascade of the processing of angiotensin peptides and their interaction with AT1 and AT(1-7) receptor systems. ACE cleaves Ang I, releasing the dipeptide His-Leu to form Ang II, and ACE2 subsequently hydrolyzes Ang II to Ang-(1-7). ACE also metabolizes Ang-(1-7) to Ang-(1-5) and the dipeptide His-Pro. Ang-(1-12) may be cleaved from angiotensinogen (Aogen) and potentially processed (\---|>) directly to Ang II or Ang-(1-7). Ang-(1-7) may attenuate the inflammatory and fibrotic actions of the Ang II-AT1 receptor pathway …