title: Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expression in Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Elabela/toddler (ELA) is a critical cardiac developmental peptide that acts through the G-protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern, and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is downregulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model.
  
  
  METHODS
  In silicodocking analysis, competition binding experiments, and downstream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using real-time quantitative polymerase chain reaction, dual-labeling immunofluorescent staining, and immunoassays. Acute cardiac effects of ELA-32 and [Pyr1]apelin-13 were assessed by MRI and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline- and Sugen/hypoxia-exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the monocrotaline rat model.
  
  
  RESULTS
  ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated byin silicomodeling. ELA activated G-protein- and β-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, and cardiac output and elicited vasodilatation in rat in vivo. ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in monocrotaline-exposed rats.
  
  
  CONCLUSIONS
  These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, and is downregulated in human disease and rodent PAH models, and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in humans.
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Peiran
authors.initials: P
authors.lastname: Yang
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Cai
authors.initials: C
authors.lastname: Read
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Rhoda E
authors.initials: RE
authors.lastname: Kuc
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Guido
authors.initials: G
authors.lastname: Buonincontri
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Rubben
authors.initials: R
authors.lastname: Torella
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Paul D
authors.initials: PD
authors.lastname: Upton
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Alexi
authors.initials: A
authors.lastname: Crosby
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawiak
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: T Adrian
authors.initials: TA
authors.lastname: Carpenter
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Robert C
authors.initials: RC
authors.lastname: Glen
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.).
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
authors.affiliation: From Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK (P.Y., C.R., R.E.K., J.J.M., A.P.D.); Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, University of Cambridge, UK (G.B., S.J.S., T.A.C.); Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge, UK (M.S.); Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, UK (R.T., R.C.G.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK (P.D.U., A.C., N.W.M.); and Biomolecular Medicine, Department of Surgery and Cancer, Imperial College, London, UK (R.C.G.). apd10@medschl.cam.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000073861:Apelin; D001665:Binding Sites; D002404:Catheterization; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D056004:Molecular Dynamics Simulation; D036361:Peptide Hormones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000601133:APELA protein, human; C115436:APLN protein, human; D000073861:Apelin; D036341:Intercellular Signaling Peptides and Proteins; D036361:Peptide Hormones; C495199:apelin-13 peptide
keywords: Elabela/Toddler; apelin; cardiopulmonary; pulmonary hypertension; receptors, G-protein-coupled