Basic Research in Cardiology

, 108:309 | Cite as

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

  • Nan Wang
  • Elke De Vuyst
  • Raf Ponsaerts
  • Kerstin Boengler
  • Nicolás Palacios-Prado
  • Joris Wauman
  • Charles P. Lai
  • Marijke De Bock
  • Elke Decrock
  • Mélissa Bol
  • Mathieu Vinken
  • Vera Rogiers
  • Jan Tavernier
  • W. Howard Evans
  • Christian C. Naus
  • Feliksas F. Bukauskas
  • Karin R. Sipido
  • Gerd Heusch
  • Rainer Schulz
  • Geert Bultynck
  • Luc Leybaert
Original Contribution

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

Connexin Hemichannel Gap junction Single channel Myocardial injury 

Notes

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.

Supplementary material

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

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© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Nan Wang
    • 1
  • Elke De Vuyst
    • 1
  • Raf Ponsaerts
    • 2
  • Kerstin Boengler
    • 3
  • Nicolás Palacios-Prado
    • 4
  • Joris Wauman
    • 5
  • Charles P. Lai
    • 6
  • Marijke De Bock
    • 1
  • Elke Decrock
    • 1
  • Mélissa Bol
    • 1
  • Mathieu Vinken
    • 7
  • Vera Rogiers
    • 7
  • Jan Tavernier
    • 5
  • W. Howard Evans
    • 8
  • Christian C. Naus
    • 9
  • Feliksas F. Bukauskas
    • 4
  • Karin R. Sipido
    • 10
  • Gerd Heusch
    • 11
  • Rainer Schulz
    • 3
  • Geert Bultynck
    • 2
  • Luc Leybaert
    • 1
  1. 1.Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical SciencesGhent UniversityGhentBelgium
  2. 2.Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus GasthuisbergKatholieke Universiteit LeuvenLeuvenBelgium
  3. 3.Physiologisches InstitutJustus-Liebig Universität GiessenGiessenGermany
  4. 4.Dominick P. Purpura Department of NeuroscienceAlbert Einstein College of MedicineBronxUSA
  5. 5.Faculty of Medicine and Health Sciences, Cytokine Receptor Laboratory, VIB Department of Medical Protein ResearchGhent UniversityGhentBelgium
  6. 6.Neuroscience Program, Departments of Neurology and Radiology, Massachusetts General HospitalHarvard Medical SchoolCharlestownUSA
  7. 7.Faculty of Medicine and Pharmacy, Department of ToxicologyVrije Universiteit BrusselBrusselsBelgium
  8. 8.Department of Medical Biochemistry and ImmunologyCardiff University School of MedicineCardiffUK
  9. 9.Faculty of Medicine, Department of Cellular and Physiological Sciences, Life Sciences InstituteUniversity of British ColumbiaVancouverCanada
  10. 10.Division of Experimental Cardiology, Department of Cardiovascular DiseasesKatholieke Universiteit LeuvenLeuvenBelgium
  11. 11.Institute for PathophysiologyUniversitätsklinikum EssenEssenGermany

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