title: Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury.
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.
authors.affiliation: Faculty of Medicine and Health Sciences, Physiology group, Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Elke
authors.initials: E
authors.lastname: De Vuyst
authors.forename: Raf
authors.initials: R
authors.lastname: Ponsaerts
authors.forename: Kerstin
authors.initials: K
authors.lastname: Boengler
authors.forename: Nicolás
authors.initials: N
authors.lastname: Palacios-Prado
authors.forename: Joris
authors.initials: J
authors.lastname: Wauman
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lai
authors.forename: Marijke
authors.initials: M
authors.lastname: De Bock
authors.forename: Elke
authors.initials: E
authors.lastname: Decrock
authors.forename: Mélissa
authors.initials: M
authors.lastname: Bol
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
authors.forename: Vera
authors.initials: V
authors.lastname: Rogiers
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.forename: W Howard
authors.initials: WH
authors.lastname: Evans
authors.forename: Christian C
authors.initials: CC
authors.lastname: Naus
authors.forename: Feliksas F
authors.initials: FF
authors.lastname: Bukauskas
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Luc
authors.initials: L
authors.lastname: Leybaert
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018031:Connexin 43 / Q000037:antagonists & inhibitors*; D017629:Gap Junctions / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010446:Peptide Fragments / Q000494:pharmacology*; D013552:Swine
chemical_list: D018031:Connexin 43; D007473:Ion Channels; D010446:Peptide Fragments; D000255:Adenosine Triphosphate