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

PLoS One. 2014 Apr 2;9(4):e93473. doi: 10.1371/journal.pone.0093473. eCollection 2014.


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.

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apelin
  • Heart Ventricles / metabolism
  • Heart Ventricles / physiopathology
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Male
  • Muscle Contraction / physiology*
  • Myocardial Contraction / physiology*
  • Myosin-Light-Chain Kinase / metabolism
  • Phosphorylation / physiology
  • Protein Kinase C-alpha / metabolism
  • Protein Kinase C-epsilon / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology


  • Apelin
  • Apln protein, rat
  • Intercellular Signaling Peptides and Proteins
  • Protein Kinase C-alpha
  • Protein Kinase C-epsilon
  • Myosin-Light-Chain Kinase

Grant support

This work was supported by the Academy of Finland Center of Excellence, the Sigrid Juselius Foundation, the Finnish Foundation for Cardiovascular Research, the Biocenter Finland (to Á.P.), and the Foundation for the Development of Interventional Cardiology (Hungary). In addition, the study was supported by the Social Renewal Operational Programme of New Hungary Development Plan (TÁMOP-4.2.4.A/2-11-1-2012-0001, Zoltán Magyary Postdoctoral Fellowship in the frames of the “National Excellence Program” to R.S.; and TÁMOP 4.2.2./B-10/1-2010-0029 Supporting Scientific Training of Talented Youth at the University of Pécs to M.S., subsidized by the European Union and co-financed by the European Social Fund). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.