期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 7, 页码 2962-2972出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01549
关键词
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资金
- Universite de Sherbrooke
- Natural Sciences and Engineering Research Council of Canada
- Canada Foundation for Innovation
- Merck Sharpe Dohme
- FRQS-funded Reseau Quebecois de Recherche sur le Medicament (RQRM)
- The Institut de Pharmacologie de Sherbrooke (IPS)
- MITACS
- Heart and Stroke Foundation of Canada (HFSC) New Investigator award
- Canada Research Chair in Neurophysiopharmacology of Chronic Pain
- FRQNT
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 G alpha(i1) and beta-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.
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