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. 2005;19(1):77–87. doi: 10.1007/s10557-005-6900-8

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

Pasquale Pagliaro 1,2,✉, Claudia Penna 1
PMCID: PMC7087601  PMID: 15883759

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.

Key Words: angiotensin-converting enzyme (ACE), ACE-associated kinases, ACE-inhibitors, Bradykinin, renin-angiotensin system

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