Rethinking the Renin-Angiotensin System and Its Role in Cardiovascular Regulation

Abstract

Angiotensin-converting enzyme (ACE) plays a pivotal role in the renin-angiotensin system (RAS) and ACE-inhibitors are widely used in several clinical conditions, including hypertension and heart failure. Recently, a homologue of ACE, ACE₂ has been discovered. Both ACE and ACE₂ are emerging as key enzymes of the RAS, where ACE₂ may play a role as negative regulator of ACE. Moreover, ACE₂ appears to be an important enzyme outside the classical RAS, as it hydrolyzes apelins, dynorphin A 1-13, des-Arg-bradykinin and other peptide substrates. The precise interplay between tissue ACE, ACE₂, and their substrates and by-products are presently still unclear. ACE-inhibitors reduce angiotensin II formation and bradykinin degradation, but do not inhibit ACE₂ activity. Moreover, ACE-inhibitors differ in their affinity for tissue ACE, and it has been suggested that tissue ACE affinity might be responsible for some of the beneficial properties of these drugs. ACE-inhibitors also increase nitric oxide availability, and activate several kinases that may regulate protein synthesis by interacting with the nucleus of the cells (outside-in signaling). The outside-in signaling may also be activated by bradykinin itself. Although, the precise significance of the outside-in signaling is still unclear, this new role of ACE-inhibitors may represent a discriminant factor versus angiotensin II receptors antagonists. This mini review will summarize some new aspects concerning the recently discovered biological functions of RAS and in particular of ACE, ACE₂ and ACE-inhibitors in cardiovascular system.