TY - JOUR
T1 - Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart
AU - Garabelli, Paul J.
AU - Modrall, J. Gregory
AU - Penninger, Josef M.
AU - Ferrario, Carlos M.
AU - Chappell, Mark C.
PY - 2008/5
Y1 - 2008/5
N2 - 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.
AB - 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.
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U2 - 10.1113/expphysiol.2007.040246
DO - 10.1113/expphysiol.2007.040246
M3 - Article
C2 - 18356559
AN - SCOPUS:42649112051
SN - 0958-0670
VL - 93
SP - 613
EP - 621
JO - Experimental Physiology
JF - Experimental Physiology
IS - 5
ER -