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

• Published in: Basic research in cardiology Vol. 114; no. 5; pp. 40 - 16
• Main Authors: Xue, Jingyi, Yan, Xinxin, Yang, Yutong, Chen, Min, Wu, Lulin, Gou, Zhongshan, Sun, Zhipeng, Talabieke, Shaletanati, Zheng, Yuanyuan, Luo, Dali
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2019; Springer Nature B.V
• Subjects: Activation; Aging; Alanine; Animals; Anoxia; Apoptosis; Apoptosis - physiology; Arrhythmia; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Calcium; Calcium ions; Cardiac arrhythmia; Cardiac muscle; Cardiac output; Cardiology; Cardiomyocytes; Connexin 43; Connexin 43 - metabolism; Contraction; Dephosphorylation; Electrical junctions; Electrical raceways; FADD protein; Gap junctions; Heart; Injuries; Ischemia; Kinases; Male; MAP kinase; Medicine & Public Health; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - physiopathology; Myocardium; Myocytes; Myocytes, Cardiac - pathology; Neonates; Original Contribution; Phosphorylation; Protein kinase; Proteins; Rats; Rats, Sprague-Dawley; Reperfusion; Serine; Serine - metabolism; Suicide; Ventricle; Viruses; Phosphorylation; Connexin 43; Arrhythmia; Ischemia/reperfusion; Apoptosis
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-019-0748-8

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 Ca 2+ 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.