A Novel Angiotensin-Converting Enzyme–Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9

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.

Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — A population study

“…For example, a new gene in the ACE family, the ACE2 gene, has been identified and shown to map to defined quantitative trait loci on the X chromosome [3,4]. Although there is significant homology in their respective protein sequences, ACE and ACE2 appear to have opposing roles.…”

“…There may also be genetic differences between men and women with CHF. In particular, a new gene in the angiotensin converting enzyme (ACE) family, the ACE2 gene, has been identified and shown to map to defined quantitative trait loci on the X chromosome [3,4]. However, little is known about whether there are differences in the optimal treatment of CHF between men and women.…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…128 In the kidney, ACE2 has a distribution similar to ACE, with major localization in renal tubules. [128][129][130] It has been suggested that both mRNA and protein expression of ACE2 are reduced in kidney biopsy specimens from type 2 diabetic patients with nephropathy compared with normal controls or patients with other renal disease. 131 In another study, ACE2 levels in kidney biopsy of diabetic patients were reduced only at the protein level, not at the mRNA level, and only in the tubulointerstitial region, not in the glomeruli, compared with non-diabetic controls.…”

Angiotensin‐converting enzyme inhibitors and survival in women and men with heart failure

“…The presence of a significant interaction term (HR 0.89, CI 0.83-0.95) in our study suggests that ACE inhibitors may act differently in women and men with CHF. Recently, a new gene in the ACE family, the ACE2 gene, has been identified and shown to map to defined quantitative trait loci on the X chromosome [25,26]. ACE and ACE2 appear to have opposing roles.…”