Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart

Abstract

Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin- converting enzyme (ACE), converts angiotensin (Ang) I to Ang(1-9) and Ang II to Ang(1-7), but does not directly process Ang I to Ang II. Cardiac function is compromised in ACE2 null mice; however, the importance of ACE2 in the processing of angiotensin peptides within the murine heart is not known. We determined the metabolism of angiotensins in wild-type (WT), ACE (ACE-/-) and ACE2 null mice (ACE2-/-). Angiotensin II was converted almost exclusively to Ang(1-7) in the cardiac membranes of WT and ACE-/- strains, although generation of Ang(1-7) was greater in the ACE-/- mice (27.4 ± 4.1 versus 17.5 ± 3.2 nmol-1 mg h-1 for WT). The ACE2 inhibitor MLN4760 significantly attenuated Ang II metabolism and the subsequent formation of Ang(1-7) in both strains. In the ACE2-/- hearts, Ang II metabolism and the generation of Ang(1-7) were significantly attenuated; however, the ACE2 inhibitor reduced the residual Ang(1-7)-forming activity in this strain. Angiotensin I was primarily converted to Ang(1-9) (WT, 28.9 ± 3.1 nmol-1 mg h-1; ACE-/-, 49.8 ± 5.3 nmol-1 mg h-1; and ACE2-/-, 35.9 ± 5.4 nmol-1 mg h-1) and to smaller quantities of Ang(1-7) and Ang II. Although the ACE2 inhibitor had no effect on Ang(1-9) formation, the carboxypeptidase A inhibitor benzylsuccinate essentially abolished the formation of Ang(1-9) and increased the levels of Ang I in cardiac membranes. In conclusion, our studies in the murine heart suggest that ACE2 is the primary pathway for the metabolism of Ang II and the subsequent formation of Ang(1-7), a peptide that, in contrast to Ang II, exhibits both antifibrotic and antiproliferative actions. © 2008 The Authors.