title: Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart.
abstract: The G protein-coupled apelin receptor regulates important processes of the cardiovascular homeostasis, including cardiac development, cardiac contractility, and vascular tone. Most recently, a novel endogenous peptide ligand for the apelin receptor was identified in zebrafish, and it was named apela/elabela/toddler. The peptide was originally considered as an exclusively embryonic regulator, and so far its function in the adult organism remains elusive. We show here that apela is predominantly expressed in the non-cardiomyocyte fraction in the adult rodent heart. We also provide evidence that apela binds to apelin receptors in the heart. Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level. The inotropic effect, as revealed by Western blot analysis, is accompanied by a significant increase in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Pharmacological inhibition of ERK1/2 activation markedly attenuates the apela-induced inotropy. Analysis of samples from infarcted mouse hearts showed that expression of both apela and apelin receptor is induced in failing mouse hearts and correlate with left ventricular ejection fraction. Hence, we conclude that apela is present in the adult heart, is upregulated in post-infarction cardiac remodeling, and increases cardiac contractility in an ERK1/2-dependent manner.
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.|Heart Institute, Medical School, University of Pécs, Pécs, 7624, Hungary.
authors.forename: Ábel
authors.initials: Á
authors.lastname: Perjés
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Kilpiö
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ulvila
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Magga
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Alakoski
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szabó
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Vainio
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Halmetoja
authors.affiliation: Department of Physiology, Research Unit of Biomedicine, University of Oulu, 90014, Oulu, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Vuolteenaho
authors.affiliation: Department of Anatomy and Cell Biology, Unit of Cancer Research and Translational Medicine, University of Oulu, 90014, Oulu, Finland.|Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors.forename: Ulla
authors.initials: U
authors.lastname: Petäjä-Repo
authors.affiliation: Heart Institute, Medical School, University of Pécs, Pécs, 7624, Hungary.|Szentágothai Research Centre, Medical School, University of Pécs, Pécs, 7624, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Szokodi
authors.affiliation: Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland. risto.kerkela@oulu.fi.|Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland. risto.kerkela@oulu.fi.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
mesh_terms: D000375:Aging; D000818:Animals; D000075244:Apelin Receptors; D015153:Blotting, Western; D004195:Disease Models, Animal; D006321:Heart; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; C491284:Aplnr protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled
keywords: Apela; Cardiovascular; Cell signaling; Contractility; Extracellular signal-regulated kinase (ERK); G protein-coupled receptor (GPCR); Heart failure; Myocardial infarction; Peptides