Apelin increases cardiac contractility via protein kinase Cε- and extracellular signal-regulated kinase-dependent mechanisms.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland; Heart Institute, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary.
Ábel
Á
Perjés
Heart Institute, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary.
Réka
R
Skoumal
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
Olli
O
Tenhunen
Heart Institute, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary.
Attila
A
Kónyi
Heart Institute, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary.
Mihály
M
Simon
Heart Institute, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary.
Iván G
IG
Horváth
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu, Finland.
Risto
R
Kerkelä
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland; Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Heikki
H
Ruskoaho
Heart Institute, Medical School, University of Pécs, Pécs, Hungary; Szentágothai Research Center, University of Pécs, Pécs, Hungary.
István
I
Szokodi
D000818:Animals; D000073861:Apelin; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
D000073861:Apelin; C498579:Apln protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D009219:Myosin-Light-Chain Kinase