A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9

ACE2, the first known human homologue of angiotensin-converting enzyme (ACE ), was identified from 5' sequencing of a human heart failure ventricle cDN A library. ACE2 has an apparent signal peptide, a single metalloprotease ac tive site, and a transmembrane domain. The metalloprotease catalytic domain s of ACE2 and ACE are 42%, identical, and comparison of the genomic structu res indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 pr otein predominantly in the endothelium of coronary and intrarenal vessels a nd in renal tubular epithelium. Active ACE2 enzyme is secreted from transfe cted cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-arg br adykinin and neurotensin but not bradykinin or 15 other vasoactive and horm onal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin- angiotensin system of the heart and kidney. The full text of this article i s available at http://www.circresaha.org.