Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart.
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.
Garabelli
Paul J
PJ
The Hypertension and Vascular Disease Center, Winston-Salem, NC, USA.
Modrall
J Gregory
JG
Penninger
Josef M
JM
Ferrario
Carlos M
CM
Chappell
Mark C
MC
D000803:Angiotensin I / Q000096:biosynthesis / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D005355:Fibrosis / Q000517:prevention & control; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D013386:Succinates / Q000494:pharmacology
C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D007093:Imidazoles; D010446:Peptide Fragments; D011480:Protease Inhibitors; D013386:Succinates; C030196:benzylsuccinate; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D043422:Carboxypeptidases A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine; C118790:angiotensin I (1-7)