Abstract
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 Gαi1 and β-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Apelin Receptors
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Blood Pressure / drug effects
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Cardiovascular Agents / chemistry
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Cardiovascular Agents / pharmacology*
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Electrocardiography
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Heart / drug effects
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Heart Ventricles / drug effects
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Heart Ventricles / physiopathology
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Humans
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Intercellular Signaling Peptides and Proteins / pharmacology
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Male
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Molecular Sequence Data
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Organ Culture Techniques
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology*
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Peptide Hormones / chemistry*
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Peptide Hormones / metabolism
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Peptide Hormones / pharmacology
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Rats, Sprague-Dawley
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Receptors, G-Protein-Coupled / metabolism
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Structure-Activity Relationship*
Substances
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APELA protein, human
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APLNR protein, human
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Apelin Receptors
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Cardiovascular Agents
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Intercellular Signaling Peptides and Proteins
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Peptide Fragments
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Peptide Hormones
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Receptors, G-Protein-Coupled
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apelin-13 peptide