Basic Research in Cardiology

, 114:40 | Cite as

Connexin 43 dephosphorylation contributes to arrhythmias and cardiomyocyte apoptosis in ischemia/reperfusion hearts

  • Jingyi Xue
  • Xinxin Yan
  • Yutong Yang
  • Min Chen
  • Lulin Wu
  • Zhongshan Gou
  • Zhipeng Sun
  • Shaletanati Talabieke
  • Yuanyuan Zheng
  • Dali LuoEmail author
Original Contribution


Connexin 43 (Cx43)-associated gap junctions form electrical and mechanical conduits between adjacent ventricular cardiomyocytes, ensuring coordinate electrical excitation and synchronic contraction for each heartbeat. Cx43 dephosphorylation is a characteristic of ischemia, arrhythmia, and a failing and aging myocardium, but the exact phosphosite(s) triggering myocardial apoptosis and electrical disturbance and its underlying mechanisms are unclear. We previously found that Cx43-serine 282 phosphorylation (pS282) can regulate cardiomyocyte survival and electrical stability. Here, we investigated the hypothesis that S282 dephosphorylation occurs in and contributes to ischemia/reperfusion (I/R)-induced cardiac injury. We found enhanced Cx43-pS262 and Cx43-pS368 but decreased Cx43-pS282 in rat hearts subjected to I/R (30 min/2 h). I/R rats had ventricular arrhythmias and myocardial apoptosis with activation of the p38 mitogen-activated protein kinase (p38)/factor-associated suicide (Fas)/Fas-associating protein with a novel death domain (FADD) pathway. Similarly, S282 dephosphorylation, abnormal Ca2+ transients, cell apoptosis and p38/Fas/FADD activation also occurred in neonatal rat ventricular myocytes exposed to anoxia/reoxygenation (12/6 h). To confirm the causative role of S282 dephosphorylation in cardiac injury, rat hearts were intramyocardially injected with a virus carrying the S282 mutant substituted with alanine (S282A), thus causing arrhythmias and reducing cardiac output and myocardial apoptosis with p38/Fas/FADD pathway activation. Moreover, Cx43-S282A+/− mice displayed arrhythmias and impaired cardiac output with global myocardial apoptosis. Our findings revealed that Cx43 dephosphorylation at S282 triggers arrhythmias and, at least partly, contributes to cardiomyocyte death upon I/R by activating the p38/Fas/FADD pathway, providing a novel molecular mechanism and potential target for protecting against cardiac I/R injury.


Connexin 43 Phosphorylation Ischemia/reperfusion Apoptosis Arrhythmia 



This work was supported by the National Natural Science Foundation of China (81370339, 81570206) and the Scientific Research Key Program of Beijing Municipal Commission of Education (KZ201710025023).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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Supplementary material 5 (DOCX 26 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jingyi Xue
    • 1
  • Xinxin Yan
    • 1
    • 2
  • Yutong Yang
    • 1
  • Min Chen
    • 1
  • Lulin Wu
    • 1
  • Zhongshan Gou
    • 1
    • 2
  • Zhipeng Sun
    • 1
  • Shaletanati Talabieke
    • 1
  • Yuanyuan Zheng
    • 1
  • Dali Luo
    • 1
    Email author
  1. 1.Department of Pharmacology, Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, School of Basic Medical SciencesCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhouPeople’s Republic of China

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