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dc.contributor.authorBrame, Aimee Len
dc.contributor.authorMaguire, Janeten
dc.contributor.authorYang, Peiranen
dc.contributor.authorDyson, Alexen
dc.contributor.authorTorella, Rubbenen
dc.contributor.authorCheriyan, Josephen
dc.contributor.authorSinger, Mervynen
dc.contributor.authorGlen, Roberten
dc.contributor.authorWilkinson, Ianen
dc.contributor.authorDavenport, Anthonyen
dc.date.accessioned2015-04-29T09:23:51Z
dc.date.available2015-04-29T09:23:51Z
dc.date.issued2015-02-23en
dc.identifier.citationHypertension 2015; 65: 834-840, DOI: 10.1161/HYPERTENSIONAHA.114.05099en
dc.identifier.issn0194-911X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247471
dc.description.abstract[Pyr1]apelin-13 is an endogenous vasodilator and inotrope but is downregulated in pulmonary hypertension and heart failure, making the apelin receptor an attractive therapeutic target. Agonists acting at the same G-protein–coupled receptor can be engineered to stabilize different conformational states and function as biased ligands, selectively stimulating either G-protein or β-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In β-arrestin and internalization assays (G-protein– independent), MM07 was 2 orders of magnitude less potent than [Pyr1]apelin-13. In a G-protein–dependent saphenous vein contraction assay, both peptides had comparable potency (pD2:[Pyr1]apelin-13 9.93±0.24; MM07 9.54±0.42) and maximum responses with a resulting bias for MM07 of ≈350- to 1300-fold for the G-protein pathway. In rats, systemic infusions of MM07 (10-100nmol) caused a dose-dependent increase in cardiac output that was significantly greater than the response to [Pyr1]apelin-13. Similarly, in human volunteers, MM07 produced a significant dose-dependent increase in forearm blood flow with a maximum dilatation double that is seen with [Pyr1]apelin-13. Additionally, repeated doses of MM07 produced reproducible increases in forearm blood flow. These responses are consistent with a more efficacious action of the biased agonist. In human hand vein, both peptides reversed an established norepinephrine constrictor response and significantly increased venous flow. Our results suggest that MM07 acting as a biased agonist at the apelin receptor can preferentially stimulate the G-protein pathway, which could translate to improved efficacy in the clinic by selectively stimulating vasodilatation and inotropic actions but avoiding activating detrimental β-arrestin–dependent pathways.
dc.description.sponsorshipWe acknowledge the Wellcome Trust Programmes in Translational Medicines and Therapeutics (085686) and in Metabolic and Cardiovascular Disease (096822/Z/11/Z), the British Heart Foundation PG/09/050/27734, the Medical Research Council, the Pulmonary Hypertension Association, and the National Institute for Health Research Cambridge Biomedical Research Centre.
dc.languageEnglishen
dc.language.isoenen
dc.publisherAmerican Heart Association
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.subjectβ-arrestin G-protein coupled receptorsen
dc.subjectpulmonary arterial hypertensionen
dc.subject[Pyr1]apelin-13en
dc.titleDesign, Characterization, and First-In-Human Study of the Vascular Actions of a Novel Biased Apelin Receptor Agonisten
dc.typeArticle
dc.description.versionThis is the final published version. It first appeared at http://hyper.ahajournals.org/content/65/4/834.long.en
prism.endingPage840
prism.publicationDate2015en
prism.publicationNameHypertensionen
prism.startingPage834
prism.volume65en
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderBHF
dc.rioxxterms.funderMRC
dc.rioxxterms.funderNIHR
dc.rioxxterms.projectid085686
dc.rioxxterms.projectid096822/Z/11/Z
dc.rioxxterms.projectidPG/09/050/27734
rioxxterms.versionofrecord10.1161/HYPERTENSIONAHA.114.05099en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-02-23en
dc.contributor.orcidMaguire, Janet [0000-0002-9254-7040]
dc.contributor.orcidCheriyan, Joseph [0000-0001-6921-1592]
dc.contributor.orcidGlen, Robert [0000-0003-1759-2914]
dc.contributor.orcidWilkinson, Ian [0000-0001-6598-9399]
dc.contributor.orcidDavenport, Anthony [0000-0002-2096-3117]
dc.identifier.eissn1524-4563
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (096822/Z/11/Z)
pubs.funder-project-idBritish Heart Foundation (PG/09/050/27734)
pubs.funder-project-idWellcome Trust (097114/Z/11/Z)
pubs.funder-project-idMRC (MC_PC_12012)
pubs.funder-project-idMRC (MC_PC_13059)
pubs.funder-project-idWellcome Trust (096822/Z/11/A)
pubs.funder-project-idWellcome Trust (085686/Z/08/J)
pubs.funder-project-idBritish Heart Foundation (FS/12/8/29377)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales