title: Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions.
abstract: ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA's structure-activity relationships and report the identification of analogue 3 (ELA(19-32)), a fragment of ELA that binds to APJ, activates the Gαi1 and β-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Murza
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sainsily
authors.affiliation: Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Coquerel
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Côté
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Marx
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Élie
authors.initials: É
authors.lastname: Besserer-Offroy
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Longpré
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Lainé
authors.affiliation: Laboratory of Human Embryology & Genetics, Institute of Medical Biology, A*STAR , 8A Biomedical Grove, 138648 Singapore.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: IPS Thérapeutique Inc. , Sherbrooke, J1G 5J6 Québec, Canada.
authors.forename: Dany
authors.initials: D
authors.lastname: Salvail
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Dumaine
authors.affiliation: Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lesur
authors.affiliation: Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Mannix
authors.initials: M
authors.lastname: Auger-Messier
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.|Institut de Pharmacologie de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Marsault
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000075244:Apelin Receptors; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology*; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D036361:Peptide Hormones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000601133:APELA protein, human; C104575:APLNR protein, human; D000075244:Apelin Receptors; D002317:Cardiovascular Agents; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide