title: The Metalloprotease Neprilysin Degrades and Inactivates Apelin Peptides.
abstract: The apelinergic system is a mammalian peptide hormone network with key physiological roles. Apelin isoforms and analogues are believed to be promising therapeutics for cardiovascular disease. Despite extensive studies on apelin-13 degradation patterns, only one protease, angiotensin-converting enzyme 2 (ACE2), had been implicated in its physiological regulation. Through use of a peptide-based fluorescent probe, we identified the metalloprotease neprilysin (NEP, a target for Entresto used in treatment of heart failure) as an enzyme that cleaves apelin isoforms. In vitro NEP proteolysis generated fragments that lacked the ability to bind to the apelin receptor, thereby making NEP the first protease to fully inactivate apelin. The involvement of NEP in the apelinergic system contributes to the understanding of its role in cardiovascular physiology.
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.
authors.forename: Shaun M K
authors.initials: SM
authors.lastname: McKinnie
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.
authors.forename: Conrad
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.
authors.forename: Kelvin M H
authors.initials: KM
authors.lastname: Tran
authors.affiliation: Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.
authors.forename: Fabricio
authors.initials: F
authors.lastname: Mosquera
authors.affiliation: Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada. john.vederas@ualberta.ca.
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
mesh_terms: D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D015260:Neprilysin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005456:Fluorescent Dyes; D036341:Intercellular Signaling Peptides and Proteins; C495199:apelin-13 peptide; D015260:Neprilysin
keywords: bioorganic chemistry; cardiovascular system; fluorescent probes; peptides; proteases