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Abstract
ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was
identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2
has an apparent signal peptide, a single metalloprotease active site, and a transmembrane
domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and
comparison of the genomic structures 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 protein
predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular
epithelium. Active ACE2 enzyme is secreted from transfected 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
bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal
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 is available at http://www. circresaha.org.