Received November 20, 2007
Revised January 11, 2008
Accepted after revision March 13, 2008
DISTINCT ROLES FOR ANGIOTENSIN CONVERTING ENZYME 2 AND CARBOXYPEPTIDASE A IN THE PROCESSING OF ANGIOTENSINS IN THE MURINE HEART
Paul J. Garabelli 1,
J. Gregory Modrall 2,
Josef M Penninger 3,
Carlos M. Ferrario 1,
Mark C. Chappell 1*
1 Wake Forrest University School of Medicine
2 University of Texas Southwestern Medical Center,
3 Institute for Molecular Biotechnology of the Austrian Academy of Sciences
* To whom correspondence should be addressed. E-mail: mchappel{at}wfubmc.edu.
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Abstract |
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Angiotensin converting enzyme 2 (ACE2), a homolog of ACE, converts angiotensin I (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 wildtype (WT), ACE (ACE-/-) and ACE2 (ACE2-/-) null mice. Ang II was converted almost exclusively to Ang-(1-7) in the cardiac membranes WT and ACE-/- strains, although Ang-(1-7) generation was greater in the ACE-/- mice [27.4 ± 4.1. vs. 17.5 ± 3.2 nmol/mg/hr 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. Ang I was primarily converted to Ang-(1-9) [WT: 28.9 ± 3.1; ACE-/-: 49.8 ± 5.3 nmol/mg/hr] and 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 anti-fibrotic and anti-proliferative actions.
Key Words:
Angiotensin, Cardiovascular, Heart
