Document Detail


Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury.
MedLine Citation:
PMID:  23184389     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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.
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
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Publication Detail:
Type:  Journal Article     Date:  2012-11-08
Journal Detail:
Title:  Basic research in cardiology     Volume:  108     ISSN:  1435-1803     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-11-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  309     Citation Subset:  IM    
Affiliation:
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.
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