title: Physiological relevance of hydrolysis of atrial natriuretic peptide by endothelin-converting enzyme-1.
abstract: Endothelin-converting enzyme-1 (ECE-1) is a membrane-bound metalloprotease that cleaves  biologically inactive big endothelin-1 (ET-1) into active ET-1. ET-1 is involved in the cardiovascular  homeostasis and the development of cardiovascular diseases including pulmonary arterial hypertension  and heart failure. Atrial natriuretic peptide (ANP) is an endogenous hormone that is released from the  heart in response to myocardial stretch and overload. ANP was shown to be hydrolyzed by neutral  endopeptidase 24.11 (NEP) which shares important structural features with ECE-1. Previous in vitro  studies using recombinant soluble ECE-1 suggested that ECE-1 cleaved several biologically active  peptides including ANP in addition to big ET-1. However, physiological relevance of ANP-degrading  activity by ECE-1 has stayed unclear. Here, we aimed to investigate whether endogenous ECE-1 is  able to hydrolyze ANP using live-cell based assay and ECE-1-deficient mice. Chinese hamster  ovary (CHO) cells, which lack detectable levels of ECE activity, degraded ANP in the medium efficiently  when transfected with ECE-1 cDNA. ANP peptide contents in the E14-15 embryos were significantly higher  in ECE-1+/- mice compared with ECE-1+/+ mice. These observations strongly suggest that ECE-1 is involved  in the physiological degradation of ANP in vivo. Thus, pharmacological inhibition of ECE-1 may provide  a novel strategy to treat various cardiovascular diseases by suppressing and potentiating the ET and  ANP pathway, respectively.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University  Graduate School of Medicine, Kobe, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Noriaki
authors.initials: N
authors.lastname: Emoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignon-Zellweger
authors.forename: Keiko
authors.initials: K
authors.lastname: Yagi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirata
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D006868:Hydrolysis; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D015260:Neprilysin / Q000378:metabolism
chemical_list: D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes