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01-01-2013 | Original Contribution

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

Authors: 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

Published in: Basic Research in Cardiology | Issue 1/2013

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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Title: Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury
Authors: 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
Publication date: 01-01-2013
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 1/2013
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-012-0309-x

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

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