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dc.contributor.authorYang, Pen
dc.contributor.authorRead, Cen
dc.contributor.authorKuc, REen
dc.contributor.authorBuonincontri, Gen
dc.contributor.authorSouthwood, Men
dc.contributor.authorTorella, Ren
dc.contributor.authorUpton, Paulen
dc.contributor.authorCrosby, Aen
dc.contributor.authorSawiak, Stephenen
dc.contributor.authorCarpenter, Adrianen
dc.contributor.authorGlen, Roberten
dc.contributor.authorMorrell, Nicholasen
dc.contributor.authorMaguire, Janeten
dc.contributor.authorDavenport, Anthonyen
dc.date.accessioned2017-03-10T12:00:36Z
dc.date.available2017-03-10T12:00:36Z
dc.identifier.issn0009-7322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/263005
dc.description.abstractBACKGROUND: -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 down-regulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. METHODS: -In silico docking analysis, competition binding experiments and down-stream 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 RT-qPCR, dual-labelling immunofluorescent staining and immunoassays. Acute cardiac effects of ELA-32 and [Pyr(1)]apelin-13 were assessed by magnet resonance imaging and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline (MCT) 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 MCT rat model. RESULTS: -ELA competed for binding of apelin in human heart with overlap for the two peptides indicated by in silico modeling. 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, 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 MCT exposed rats. CONCLUSIONS: -These results show ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, is down-regulated 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 man.
dc.description.sponsorshipSupported by the Wellcome Trust 107715/Z/15/Z and Programme in Metabolic and Cardiovascular Disease 096822/Z/11/Z, Medical Research Council MC_PC_14116, British Heart Foundation PS/02/001, PG/05/127/19872, FS/14/59/31282 and in part by the National Institute for Health Research Cambridge Biomedical Research Centre and the Pulmonary Hypertension Association UK.
dc.languageengen
dc.language.isoenen
dc.publisherWolters Kluwer
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectAPELAen
dc.subjectElabelaen
dc.subjectGPCRen
dc.subjectMonocrotalineen
dc.subjectToddleren
dc.subjectapelinen
dc.subjectpeptideen
dc.subjectpulmonary hypertensionen
dc.subjectreceptoren
dc.titleElabela/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 Hypertensionen
dc.typeArticle
prism.publicationNameCirculationen
dc.identifier.doi10.17863/CAM.8307
dcterms.dateAccepted2017-01-17en
rioxxterms.versionofrecord10.1161/CIRCULATIONAHA.116.023218en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-01-17en
dc.contributor.orcidUpton, Paul [0000-0003-2716-4921]
dc.contributor.orcidSawiak, Stephen [0000-0003-4210-9816]
dc.contributor.orcidCarpenter, Adrian [0000-0002-2939-8222]
dc.contributor.orcidGlen, Robert [0000-0003-1759-2914]
dc.contributor.orcidMorrell, Nicholas [0000-0001-5700-9792]
dc.contributor.orcidMaguire, Janet [0000-0002-9254-7040]
dc.contributor.orcidDavenport, Anthony [0000-0002-2096-3117]
dc.identifier.eissn1524-4539
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (096822/Z/11/Z)
pubs.funder-project-idWELLCOME TRUST (107715/Z/15/Z)
pubs.funder-project-idMRC (MC_PC_14116 v2)
pubs.funder-project-idWellcome Trust (096822/Z/11/A)
pubs.funder-project-idBritish Heart Foundation (FS/14/59/31282)
pubs.funder-project-idBritish Heart Foundation (PG/13/91/30579)
pubs.funder-project-idBritish Heart Foundation (RG/13/4/30107)
cam.issuedOnline2017-01-30en
rioxxterms.freetoread.startdate2018-01-30


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International