TLR2-Dependent Reversible Oxidation of Connexin 43 at Cys260 Modifies Electrical Coupling After Experimental Myocardial Ischemia/Reperfusion

  • Florian Jürgen RaimannEmail author
  • Stefan Dröse
  • Erik Bonke
  • Lea Schneider
  • Elisabeth Tybl
  • Ilka Wittig
  • Juliana Heidler
  • Heinrich Heide
  • Ivana Josipovic
  • Matthias Leisegang
  • Ralf Peter Brandes
  • Jochen Roeper
  • Kai Zacharowski
  • Jan Mersmann
Original Article


We have shown previously that during myocardial ischemia/reperfusion (MI/R), toll-like receptor 2 (TLR2) signaling regulates connexin 43 (Cx43) subcellular localization and function and dampens arrhythmia formation. We aimed to identify sites capable of TLR2-dependent redox modification within Cx43. Post-ischemic TLR2−/− or wild-type (WT) mouse hearts were analyzed by OxICAT. Cx43 was mutated to exclude redox modification and transfected into HL-1 cardiomyocytes (CM) that were challenged with a TLR2 agonist. We identified Cys260 of Cx43 to be susceptible to reversible oxidation MI/R; TLR2−/− leads to reduced H2O2 production in post-ischemic isolated mitochondria and subsequently reduced oxidation of Cx43 at Cys260. Cx43 was dephosphorylated in WT, while phosphorylation was preserved in TLR2−/−. Mutation of Cx43 (C260A) and lentiviral transfection in HL-1 CM accelerated pacemaker activity and reduced activity after TLR2 ligand stimulation. We here provide evidence for TLR2-dependent reversible oxidation of Cx43 at Cys260, which led to decreased Cx43 phosphorylation and affected CM pacemaker frequency and intercellular communication.


Myocardial ischemia Reperfusion Toll-like receptor 2 Connexin 43 Redox regulation 





Rate-corrected SNRT


Connexin 43




Ischemia and reperfusion


Mouse heart mitochondria


Myocardial ischemia/reperfusion


Reverse electron transfer


Reactive oxygen species


Sinus node recovery time


Toll-like receptor 2


Vesicular stomatitis virus


Wild type



HL-1 mouse atrial cardiomyocytes were a kind gift from William C Claycomb.

Source of Funding

This work was supported by a grant of the Deutsche Forschungsgemeinschaft (SFB815 A17 to J.M. and K.Z.; SFB815 A02 to S.D.; SFB815 A01 to R.B.; SFB815 A13 to J.R.; and SFB815 Z01 to I.W.). SFB stands for SonderForschungsBereich.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Florian Jürgen Raimann
    • 1
    Email author
  • Stefan Dröse
    • 1
  • Erik Bonke
    • 1
  • Lea Schneider
    • 2
  • Elisabeth Tybl
    • 1
  • Ilka Wittig
    • 2
  • Juliana Heidler
    • 2
  • Heinrich Heide
    • 2
    • 3
  • Ivana Josipovic
    • 4
  • Matthias Leisegang
    • 4
  • Ralf Peter Brandes
    • 4
  • Jochen Roeper
    • 5
  • Kai Zacharowski
    • 1
  • Jan Mersmann
    • 1
  1. 1.Department of Anaesthesiology, Intensive Care Medicine, and Pain TherapyUniversity Hospital FrankfurtFrankfurtGermany
  2. 2.Functional Proteomics, SFB 815 Core UnitGoethe UniversityFrankfurtGermany
  3. 3.Thermo Fisher Scientific GmbHDreieichGermany
  4. 4.Institute for Cardiovascular PhysiologyGoethe UniversityFrankfurtGermany
  5. 5.Institute of NeurophysiologyGoethe UniversityFrankfurtGermany

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