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

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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.

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Acknowledgments

Special thanks to K. Leurs, K. Vermeulen and K. Welkenhuyzen for superb technical support. We express our gratitude to Dr. B. Himpens for support, to Dr. P. Zimmermann for the use of the Biacore 2000, to Dr. P. Sorgen for providing the pGEX6p2-Cx43CT plasmid, to Dr. G. Antoons for support with experiments on pig myocytes, and to Dr. D. Laird and Dr. S. Penuela for providing the anti-Panx1 antibody. We are very grateful to A. Gadicherla and Dr. B. Nilius for critically reading and commenting the manuscript. Research supported by the Fund for Scientific Research Flanders, Belgium (FWO, grant nos. G.0354.07, G.0140.08, 3G.0134.09 and G.0298.11 N to L.L. and G.0545.08 to G.B.), the Interuniversity Attraction Poles Program (Belgian Science Policy, project P6/31 and P7/10 to K.R.S and L.L., and P7 to J.T. and G.B.), the Concerted Actions program at KULeuven (grant no. GOA/09/012 to G.B.), the German Research Foundation (Schu 843/7-2 to R.S.), the BFH grant (grant no. PG/01/1298 to W.H.E), the Heart & Stroke Foundation of BC & Yukon and the Canadian Institutes of Health Research to C.C.N. and NIH grants (HL084464 and NS072238 to F.F.B.).

Conflict of interest

None.

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Authors and Affiliations

  1. Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical Sciences, Ghent University, De Pintelaan 185 (Block B-Rm 310), B-9000, Ghent, Belgium

    Nan Wang, Elke De Vuyst, Marijke De Bock, Elke Decrock, Mélissa Bol & Luc Leybaert

  2. Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus Gasthuisberg, Katholieke Universiteit Leuven, O/N-1 bus 802, KU Leuven, Leuven, Belgium

    Raf Ponsaerts & Geert Bultynck

  3. Physiologisches Institut, Justus-Liebig Universität Giessen, Giessen, Germany

    Kerstin Boengler & Rainer Schulz

  4. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA

    Nicolás Palacios-Prado & Feliksas F. Bukauskas

  5. Faculty of Medicine and Health Sciences, Cytokine Receptor Laboratory, VIB Department of Medical Protein Research, Ghent University, Ghent, Belgium

    Joris Wauman & Jan Tavernier

  6. Neuroscience Program, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Charles P. Lai

  7. Faculty of Medicine and Pharmacy, Department of Toxicology, Vrije Universiteit Brussel, Brussels, Belgium

    Mathieu Vinken & Vera Rogiers

  8. Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, UK

    W. Howard Evans

  9. Faculty of Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada

    Christian C. Naus

  10. Division of Experimental Cardiology, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Leuven, Belgium

    Karin R. Sipido

  11. Institute for Pathophysiology, Universitätsklinikum Essen, Essen, Germany

    Gerd Heusch

Authors
  1. Nan Wang
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  2. Elke De Vuyst
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  3. Raf Ponsaerts
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  4. Kerstin Boengler
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  5. Nicolás Palacios-Prado
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  6. Joris Wauman
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  7. Charles P. Lai
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  8. Marijke De Bock
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  9. Elke Decrock
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  10. Mélissa Bol
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  11. Mathieu Vinken
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  12. Vera Rogiers
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  13. Jan Tavernier
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  14. W. Howard Evans
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  15. Christian C. Naus
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  16. Feliksas F. Bukauskas
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  17. Karin R. Sipido
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  18. Gerd Heusch
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  19. Rainer Schulz
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  20. Geert Bultynck
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  21. Luc Leybaert
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Corresponding author

Correspondence to Luc Leybaert.

Additional information

N. Wang, E. De Vuyst, R. Ponsaerts contributed equally. G. Bultynck, L. Leybaert share senior authorship.

T. Miura, Sapporo, Japan served as guest editor for the manuscript and was responsible for all editorial decisions, including the selection of reviewers. The policy applies to all manuscripts with authors from the editor’s institution.

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Wang, N., De Vuyst, E., Ponsaerts, R. et al. Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res Cardiol 108, 309 (2013). https://doi.org/10.1007/s00395-012-0309-x

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  • DOI: https://doi.org/10.1007/s00395-012-0309-x

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