Basic Research in Cardiology

, 108:309

Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury

Authors

  • Nan Wang
    • Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical SciencesGhent University
  • Elke De Vuyst
    • Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical SciencesGhent University
  • Raf Ponsaerts
    • Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus GasthuisbergKatholieke Universiteit Leuven
  • Kerstin Boengler
    • Physiologisches InstitutJustus-Liebig Universität Giessen
  • Nicolás Palacios-Prado
    • Dominick P. Purpura Department of NeuroscienceAlbert Einstein College of Medicine
  • Joris Wauman
    • Faculty of Medicine and Health Sciences, Cytokine Receptor Laboratory, VIB Department of Medical Protein ResearchGhent University
  • Charles P. Lai
    • Neuroscience Program, Departments of Neurology and Radiology, Massachusetts General HospitalHarvard Medical School
  • Marijke De Bock
    • Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical SciencesGhent University
  • Elke Decrock
    • Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical SciencesGhent University
  • Mélissa Bol
    • Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical SciencesGhent University
  • Mathieu Vinken
    • Faculty of Medicine and Pharmacy, Department of ToxicologyVrije Universiteit Brussel
  • Vera Rogiers
    • Faculty of Medicine and Pharmacy, Department of ToxicologyVrije Universiteit Brussel
  • Jan Tavernier
    • Faculty of Medicine and Health Sciences, Cytokine Receptor Laboratory, VIB Department of Medical Protein ResearchGhent University
  • W. Howard Evans
    • Department of Medical Biochemistry and ImmunologyCardiff University School of Medicine
  • Christian C. Naus
    • Faculty of Medicine, Department of Cellular and Physiological Sciences, Life Sciences InstituteUniversity of British Columbia
  • Feliksas F. Bukauskas
    • Dominick P. Purpura Department of NeuroscienceAlbert Einstein College of Medicine
  • Karin R. Sipido
    • Division of Experimental Cardiology, Department of Cardiovascular DiseasesKatholieke Universiteit Leuven
  • Gerd Heusch
    • Institute for PathophysiologyUniversitätsklinikum Essen
  • Rainer Schulz
    • Physiologisches InstitutJustus-Liebig Universität Giessen
  • Geert Bultynck
    • Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus GasthuisbergKatholieke Universiteit Leuven
    • Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical SciencesGhent University
Original Contribution

DOI: 10.1007/s00395-012-0309-x

Cite this article as:
Wang, N., De Vuyst, E., Ponsaerts, R. et al. Basic Res Cardiol (2013) 108: 309. doi:10.1007/s00395-012-0309-x

Abstract

Connexin-43 (Cx43), a predominant cardiac connexin, forms gap junctions (GJs) that facilitate electrical cell–cell coupling and unapposed/nonjunctional hemichannels that provide a pathway for the exchange of ions and metabolites between cytoplasm and extracellular milieu. Uncontrolled opening of hemichannels in the plasma membrane may be deleterious for the myocardium and blocking hemichannels may confer cardioprotection by preventing ionic imbalance, cell swelling and loss of critical metabolites. Currently, all known hemichannel inhibitors also block GJ channels, thereby disturbing electrical cell–cell communication. Here we aimed to characterize a nonapeptide, called Gap19, derived from the cytoplasmic loop (CL) of Cx43 as a hemichannel blocker and examined its effect on hemichannel currents in cardiomyocytes and its influence in cardiac outcome after ischemia/reperfusion. We report that Gap 19 inhibits Cx43 hemichannels without blocking GJ channels or Cx40/pannexin-1 hemichannels. Hemichannel inhibition is due to the binding of Gap19 to the C-terminus (CT) thereby preventing intramolecular CT–CL interactions. The peptide inhibited Cx43 hemichannel unitary currents in both HeLa cells exogenously expressing Cx43 and acutely isolated pig ventricular cardiomyocytes. Treatment with Gap19 prevented metabolic inhibition-enhanced hemichannel openings, protected cardiomyocytes against volume overload and cell death following ischemia/reperfusion in vitro and modestly decreased the infarct size after myocardial ischemia/reperfusion in mice in vivo. We conclude that preventing Cx43 hemichannel opening with Gap19 confers limited protective effects against myocardial ischemia/reperfusion injury.

Keywords

ConnexinHemichannelGap junctionSingle channelMyocardial injury

Supplementary material

395_2012_309_MOESM1_ESM.pdf (1.4 mb)
Supplementary material 1 (PDF 1472 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2012