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 & 1 others Luc Leybaert

Research output: Contribution to journalArticle

121 Citations (Scopus)

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.

Original languageEnglish (US)
Article number309
JournalBasic Research in Cardiology
Volume108
Issue number1
DOIs
StatePublished - 2013

Fingerprint

Myocardial Reperfusion Injury
Connexin 43
Reperfusion Injury
Myocardial Ischemia
Gap Junctions
Cardiac Myocytes
Reperfusion
Ischemia
Myocardial Reperfusion
Connexins
Ion Exchange
HeLa Cells
Cell Communication
Myocardium
Cytoplasm
Cell Death
Swine
Cell Membrane
Peptides

Keywords

  • Connexin
  • Gap junction
  • Hemichannel
  • Myocardial injury
  • Single channel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Wang, N., De Vuyst, E., Ponsaerts, R., Boengler, K., Palacios-Prado, N., Wauman, J., ... Leybaert, L. (2013). Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Research in Cardiology, 108(1), [309]. https://doi.org/10.1007/s00395-012-0309-x

Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. / Wang, Nan; De Vuyst, Elke; Ponsaerts, Raf; Boengler, Kerstin; Palacios-Prado, Nicolás; Wauman, Joris; Lai, Charles P.; De Bock, Marijke; Decrock, Elke; Bol, Mélissa; Vinken, Mathieu; Rogiers, Vera; Tavernier, Jan; Evans, W. Howard; Naus, Christian C.; Bukauskas, Feliksas F.; Sipido, Karin R.; Heusch, Gerd; Schulz, Rainer; Bultynck, Geert; Leybaert, Luc.

In: Basic Research in Cardiology, Vol. 108, No. 1, 309, 2013.

Research output: Contribution to journalArticle

Wang, N, De Vuyst, E, Ponsaerts, R, Boengler, K, Palacios-Prado, N, Wauman, J, Lai, CP, De Bock, M, Decrock, E, Bol, M, Vinken, M, Rogiers, V, Tavernier, J, Evans, WH, Naus, CC, Bukauskas, FF, Sipido, KR, Heusch, G, Schulz, R, Bultynck, G & Leybaert, L 2013, 'Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury', Basic Research in Cardiology, vol. 108, no. 1, 309. https://doi.org/10.1007/s00395-012-0309-x
Wang, Nan ; De Vuyst, Elke ; Ponsaerts, Raf ; Boengler, Kerstin ; Palacios-Prado, Nicolás ; Wauman, Joris ; Lai, Charles P. ; De Bock, Marijke ; Decrock, Elke ; Bol, Mélissa ; Vinken, Mathieu ; Rogiers, Vera ; Tavernier, Jan ; Evans, W. Howard ; Naus, Christian C. ; Bukauskas, Feliksas F. ; Sipido, Karin R. ; Heusch, Gerd ; Schulz, Rainer ; Bultynck, Geert ; Leybaert, Luc. / Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. In: Basic Research in Cardiology. 2013 ; Vol. 108, No. 1.
@article{af854e4f104a455c94ccfe4d143e7eac,
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.",
keywords = "Connexin, Gap junction, Hemichannel, Myocardial injury, Single channel",
author = "Nan Wang and {De Vuyst}, Elke and Raf Ponsaerts and Kerstin Boengler and Nicol{\'a}s Palacios-Prado and Joris Wauman and Lai, {Charles P.} and {De Bock}, Marijke and Elke Decrock and M{\'e}lissa Bol and Mathieu Vinken and Vera Rogiers and Jan Tavernier and Evans, {W. Howard} and Naus, {Christian C.} and Bukauskas, {Feliksas F.} and Sipido, {Karin R.} and Gerd Heusch and Rainer Schulz and Geert Bultynck and Luc Leybaert",
year = "2013",
doi = "10.1007/s00395-012-0309-x",
language = "English (US)",
volume = "108",
journal = "Basic Research in Cardiology",
issn = "0300-8428",
publisher = "D. Steinkopff-Verlag",
number = "1",

}

TY - JOUR

T1 - Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury

AU - Wang, Nan

AU - De Vuyst, Elke

AU - Ponsaerts, Raf

AU - Boengler, Kerstin

AU - Palacios-Prado, Nicolás

AU - Wauman, Joris

AU - Lai, Charles P.

AU - De Bock, Marijke

AU - Decrock, Elke

AU - Bol, Mélissa

AU - Vinken, Mathieu

AU - Rogiers, Vera

AU - Tavernier, Jan

AU - Evans, W. Howard

AU - Naus, Christian C.

AU - Bukauskas, Feliksas F.

AU - Sipido, Karin R.

AU - Heusch, Gerd

AU - Schulz, Rainer

AU - Bultynck, Geert

AU - Leybaert, Luc

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Connexin

KW - Gap junction

KW - Hemichannel

KW - Myocardial injury

KW - Single channel

UR - http://www.scopus.com/inward/record.url?scp=84869863191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84869863191&partnerID=8YFLogxK

U2 - 10.1007/s00395-012-0309-x

DO - 10.1007/s00395-012-0309-x

M3 - Article

VL - 108

JO - Basic Research in Cardiology

JF - Basic Research in Cardiology

SN - 0300-8428

IS - 1

M1 - 309

ER -