Apelin Increases Cardiac Contractility via Protein Kinase Cε- and Extracellular Signal-Regulated Kinase-Dependent Mechanisms

Apelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain...

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Vydáno v:	PloS one Ročník 9; číslo 4; s. e93473
Hlavní autoři:	Perjés, Ábel, Skoumal, Réka, Tenhunen, Olli, Kónyi, Attila, Simon, Mihály, Horváth, Iván G., Kerkelä, Risto, Ruskoaho, Heikki, Szokodi, István
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 02.04.2014 Public Library of Science (PLoS)
Témata:	Activation Animals Apelin Biology and life sciences Calcium Cardiomyocytes Cytosol Extracellular signal-regulated kinase Heart Heart attacks Heart diseases Heart failure Heart Ventricles - metabolism Heart Ventricles - physiopathology Inhibition Intercellular Signaling Peptides and Proteins - metabolism Kinases Light Male MAP Kinase Signaling System - physiology Medical schools Medicine and Health Sciences Muscle contraction Muscle Contraction - physiology Myocardial Contraction - physiology Myosin Myosin-light-chain kinase Myosin-Light-Chain Kinase - metabolism Peptides Pharmacology Phosphorylation Phosphorylation - physiology Protein kinase C Protein Kinase C-alpha - metabolism Protein Kinase C-epsilon - metabolism Proteins Rats Rats, Sprague-Dawley Research and Analysis Methods Rodents Signal Transduction - physiology Signaling Stimulators Toxicology Translocation Ventricle Hungary Finland
ISSN:	1932-6203, 1932-6203
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Shrnutí:	Apelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin. In isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKCε, but not PKCα, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity. Apelin increases cardiac contractility through parallel and independent activation of PKCε and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKCε and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: AP RS HR IS. Performed the experiments: AP RS AK. Analyzed the data: AP RS AK MS. Contributed reagents/materials/analysis tools: IGH OT RK HR. Wrote the paper: AP IS. Revised manuscript for important intellectual content: RS OT AK MS IGH RK HR.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0093473