Connexin 43 dephosphorylation at serine 282 induces spontaneous arrhythmia and increases susceptibility to ischemia/reperfusion injury.
Connexin 43 dephosphorylation at serine 282 induces spontaneous arrhythmia and increases susceptibility to ischemia/reperfusion injury.
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DOI：
10.1016/j.heliyon.2023.e15879
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发表时间：
2023-05
期刊：
影响因子：
4
通讯作者：
Luo, Dali
中科院分区：
文献类型：
--
作者：
Wu, Lulin;Jiang, Tianhui;Fu, Zhiping;Wang, Luqi;You, Hongjie;Xue, Jingyi;Luo, Dali
连接蛋白43（Cx43）是心脏中主要的间隙连接蛋白，在生理和病理状态下通过特异性的磷酸化（去磷酸化）过程改变其结构和功能。以前我们发现Cx43 S282磷酸化缺陷可通过激活p38丝裂原活化蛋白激酶（mitogen-activated protein kinase，p38 MAPK）/因子相关自杀（factor-associated suicide，Fas）/Fas相关蛋白（factor-associated protein，Fas-associated protein）和一种新的死亡结构域（death domain，FADD）通路损害心肌细胞间通讯，促进心肌细胞凋亡，这一通路参与了缺血/再灌注（ischemia/reperfusion，I/R）心肌损伤。此外，Cx43 S282突变体被丙氨酸杂合小鼠（S282 A +/-）表现出不同程度的室性心律失常，只有部分发生心肌细胞凋亡。本研究旨在探讨Cx43 pS282在不同心脏病理表型中的作用。我们通过心电图、超声心动图、组织学染色和免疫共沉淀，然后通过Western blot检测了S282 A +/−小鼠（2、10和30周龄）的心脏功能、结构和相关蛋白表达。在S282 A +/-小鼠中应用腹腔内注射异丙肾上腺素和I/R手术作为外部刺激。2，3，5-氯化三苯基四氮唑染色用于心肌梗死评价。成年S282 A +/−小鼠（10周龄和30周龄）仍表现出自发性心律失常。与新生儿阶段（约2周龄）不同，在成人S282 A +/−心脏中未观察到与凋亡相关的表现和p38 MAPK-Fas-FADD凋亡途径的激活。S282 A +/−新生小鼠心肌细胞凋亡表现出超过60%的Cx43 S282去磷酸化比WT小鼠，而不到40%的S282去磷酸化在成年S282 A +/−小鼠。此外，尽管S282 A +/−小鼠显示出正常的心脏功能，但它们对异丙肾上腺素诱导的心电图交替非常敏感，并且在I/R发作时容易发生心脏损伤和死亡。这些结果进一步证实了Cx43 S282去磷酸化在基础条件下调节心肌细胞存活和心脏电稳态中作为易感因子，并在I/R设置中促进心肌损伤。Cx43 S282磷酸化能够诱导自发性心律失常、心肌细胞凋亡和死亡，其程度取决于S282去磷酸化的程度。
Connexin 43 (Cx43), the predominant gap junction protein in hearts, is modified by specific (de)phosphorylation events under physiological and pathological states to affect myocardium function and structure. Previously we found that deficiency in Cx43 S282 phosphorylation could impair intercellular communication and contribute to cardiomyocyte apoptosis by activating p38 mitogen-activated protein kinase (p38 MAPK)/factor-associated suicide (Fas)/Fas-associating protein with a novel death domain (FADD) pathway, which is involved in myocardium injury in ischemia/reperfusion (I/R) heart. In addition, mutant at Cx43 S282 substituted with alanine heterozygous mice (S282A+/−) exhibited different degrees of ventricular arrhythmias and only some underwent myocardium apoptosis. In this study, we aimed to investigate the role of Cx43 pS282 in different cardiac pathological phenotypes. We examined cardiac function, structure, and relevant protein expression in S282A+/− mice (aged 2, 10 and 30 weeks) by electrocardiograph, echocardiography, histological staining, and co-immunoprecipitation followed by Western blot. Intraperitoneal isoprenaline injection and I/R surgery were applied in S282A+/− mice as external stimulus. 2,3,5-triphenyltetrazolium chloride staining was used for myocardium infarction evaluation. Adult S282A+/− mice (aged 10 and 30 weeks) still exhibited spontaneous arrhythmia. Unlike neonatal stage (aged around 2 weeks), no apoptosis-related manifestations and the activation of p38 MAPK-Fas-FADD apoptotic pathway were observed in adult S282A+/− hearts. S282A+/− neonatal mice with cardiomyocytes apoptosis exhibited more than 60% dephosphorylation at Cx43 S282 than WT mice, while less than 40% S282 dephosphorylation were found in adult S282A+/− mice. In addition, although S282A+/− mice displayed normal cardiac function, they were highly susceptible to isoproterenol-induced ECG alternans and prone to cardiac injury and deaths upon I/R attack. These results reinforce that Cx43 S282 dephosphorylation acts as a susceptibility factor in regulating cardiomyocyte survival and cardiac electrical homeostasis in basal conditions and contributes to myocardium injury in the setting of I/R. Cx43 S282 phosphorylation was competent to induce spontaneous arrhythmias, cardiomyocyte apoptosis and deaths based on the degree of S282 dephosphorylation.
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影响因子：
9
作者：
Rinaldi F;Hartfield EM;Crompton LA;Badger JL;Glover CP;Kelly CM;Rosser AE;Uney JB;Caldwell MA
通讯作者：
Caldwell MA
S279/282 上的 Cx43 磷酸化和细胞间通讯受 IP3/IP3 受体信号传导调节。
DOI：
10.1186/s12964-014-0058-6
发表时间：
2014-09-28
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Kang M;Lin N;Li C;Meng Q;Zheng Y;Yan X;Deng J;Ou Y;Zhang C;He J;Luo D
通讯作者：
Luo D
影响因子：
3.4
作者：
Leithe, Edward;Mesnil, Marc;Aasen, Trond
通讯作者：
Aasen, Trond
DOI：
10.1159/000092569
发表时间：
2006-01-01
期刊：
CARDIOVASCULAR GAP JUNCTIONS
影响因子：
--
作者：
Boyett, M. R.;Inada, S.;Dobrzynski, H.
通讯作者：
Dobrzynski, H.
影响因子：
8.2
作者：
Fu, Zhi-ping;Wu, Lu-lin;Luo, Da-li
通讯作者：
Luo, Da-li