Connexin 43 dephosphorylation contributes to arrhythmias and cardiomyocyte apoptosis in ischemia/reperfusion hearts
Connexin 43 dephosphorylation contributes to arrhythmias and cardiomyocyte apoptosis in ischemia/reperfusion hearts
复制标题
连接蛋白 43 去磷酸化导致缺血/再灌注心脏中的心律失常和心肌细胞凋亡
DOI：
10.1007/s00395-019-0748-8
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发表时间：
2019-09-01
影响因子：
9.5
通讯作者：
Luo, Dali
中科院分区：
文献类型：
--
作者：
Xue, Jingyi;Yan, Xinxin;Luo, Dali
连接蛋白 43 (Cx43) 相关间隙连接在相邻心室心肌细胞之间形成电气和机械导管，确保每次心跳的协调电激发和同步收缩。 Cx43 去磷酸化是缺血、心律失常以及心肌衰竭和老化的一个特征，但触发心肌细胞凋亡和电紊乱的确切磷酸位点及其潜在机制尚不清楚。我们之前发现Cx43-丝氨酸282磷酸化（pS282）可以调节心肌细胞的存活和电稳定性。在这里，我们研究了这样的假设：S282 去磷酸化发生在缺血/再灌注 (I/R) 诱导的心脏损伤中并导致其发生。我们发现 I/R（30 分钟/2 小时）大鼠心脏中的 Cx43-pS262 和 Cx43-pS368 增强，但 Cx43-pS282 降低。I/R 大鼠因 p38 丝裂原激活蛋白激酶 (p38)/自杀因子相关蛋白 (Fas)/具有新型死亡结构域的 Fas 相关蛋白的激活而出现室性心律失常和心肌细胞凋亡（FADD）途径。同样，暴露于缺氧/复氧（12/6 小时）的新生大鼠心室肌细胞中也发生了 S282 去磷酸化、异常 Ca2+ 瞬态、细胞凋亡和 p38/Fas/FADD 激活。为了证实S282去磷酸化在心脏损伤中的致病作用，向大鼠心脏心肌内注射携带丙氨酸取代的S282突变体（S282A）的病毒，从而通过激活p38/Fas/FADD途径引起心律失常、心输出量减少和心肌细胞凋亡。此外，Cx43-S282A+/-小鼠表现出心律失常和心输出量受损以及整体心肌细胞凋亡。我们的研究结果表明，S282 处的 Cx43 去磷酸化会引发心律失常，并且至少在一定程度上通过激活 p38/Fas/FADD 途径导致 I/R 时心肌细胞死亡，这为预防心脏 I/R 损伤提供了一种新的分子机制和潜在靶点。
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 toI/R(30 min/2 h).I/Rrats 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 uponI/Rby activating the p38/Fas/FADD pathway, providing a novel molecular mechanism and potential target for protecting against cardiacI/Rinjury.