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dc.contributor.authorRead, Cai
dc.contributor.authorNyimanu, Duuamene
dc.contributor.authorYang, Peiran
dc.contributor.authorKuc, Rhoda E.
dc.contributor.authorWilliams, Thomas L.
dc.contributor.authorFitzpatrick, Christopher M.
dc.contributor.authorFoster, Richard
dc.contributor.authorGlen, Robert C.
dc.contributor.authorMaguire, Janet J.
dc.contributor.authorDavenport, Anthony P.
dc.date.accessioned2021-02-04T05:12:34Z
dc.date.available2021-02-04T05:12:34Z
dc.date.issued2021-01-21
dc.date.submitted2020-07-29
dc.identifier.other588669
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/317120
dc.description.abstractSignaling through the apelin receptor is beneficial for a number of diseases including pulmonary arterial hypertension. The endogenous small peptides, apelin and elabela/toddler, are downregulated in pulmonary arterial hypertension but are not suitable for exogenous administration owing to a lack of bioavailability, proteolytic instability and susceptibility to renal clearance. CMF-019, a small molecule apelin agonist that displays strong bias towards G protein signaling over β-arrestin (∼400 fold), may be more suitable. This study demonstrates that in addition to being a positive inotrope, CMF-019 caused dose-dependent vasodilatation in vivo (50 nmol 4.16 ± 1.18 mmHg, **p < 0.01; 500 nmol 6.62 ± 1.85 mmHg, **p < 0.01), without receptor desensitization. Furthermore, CMF-019 rescues human pulmonary artery endothelial cells from apoptosis induced by tumor necrosis factor α and cycloheximide (5.66 ± 0.97%, **p < 0.01) by approximately 50% of that observable with rhVEGF (11.59 ± 1.85%, **p < 0.01), suggesting it has disease-modifying potential in vitro. CMF-019 displays remarkable bias at the apelin receptor for a small molecule and importantly recapitulates all aspects of the cardiovascular responses to the endogenous ligand, [Pyr1]apelin-13, in vivo. Additionally, it is able to protect human pulmonary artery endothelial cells from apoptosis, suggesting that the beneficial effects observed with apelin agonists extend beyond hemodynamic alleviation and address disease etiology itself. These findings support CMF-019 as a G protein biased small molecule apelin agonist in vitro and in vivo that could form the basis for the design of novel therapeutic agents in chronic diseases, such as, pulmonary arterial hypertension.
dc.languageen
dc.publisherFrontiers Media S.A.
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectPharmacology
dc.subjectapelin
dc.subjectbias
dc.subjectcardiovascular
dc.subjectin vivo
dc.subjectapoptosis
dc.subjectpulmonary artery endothelial cell
dc.subjectG protein coupled receptor
dc.titleThe G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo
dc.typeArticle
dc.date.updated2021-02-04T05:12:34Z
prism.publicationNameFrontiers in Pharmacology
prism.volume11
dc.identifier.doi10.17863/CAM.64229
dcterms.dateAccepted2020-12-02
rioxxterms.versionofrecord10.3389/fphar.2020.588669
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.identifier.eissn1663-9812


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