Protein Kinase C-Mediated Hyperphosphorylation and Lateralization of Connexin 43 Are Involved in Autoimmune Myocarditis-Induced Prolongation of QRS Complex.
Protein Kinase C-Mediated Hyperphosphorylation and Lateralization of Connexin 43 Are Involved in Autoimmune Myocarditis-Induced Prolongation of QRS Complex.
复制标题
DOI：
10.3389/fphys.2022.815301
复制
发表时间：
2022
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
心肌炎是一种严重的和潜在的威胁生命的疾病，它会导致心功能障碍和心源性猝死。越来越多的证据表明，心肌炎也是冠状病毒肺炎的恶性并发症，与心力衰竭和心源性猝死有关。与心肌炎引起的恶性心律失常相关的QRS波群延长显著增加患者心源性猝死的风险。然而，其分子机制目前还不完全清楚。在这项研究中，我们确定蛋白激酶C（PKC）作为一个新的调节QRS波群。在正常大鼠离体心脏，PKC激动剂，佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA），诱导QRS波群的延长。在机制上，PKC引起的连接蛋白43（Cx43）的过度磷酸化和偏侧化诱导Cx43间隙连接通道的解聚和内化以及QRS时限的延长。相反，PKC抑制剂Ro-32-0432在实验性自身免疫性心肌炎（EAM）大鼠中在最严重的炎症期后给药，仍然显著挽救了Cx43缝隙连接的稳定性，并减轻了QRS波群的延长。Ro-32-0432可降低EAM大鼠心肌Cx43的磷酸化水平，阻断Cx43的转位，但对心室离子通道及其他调节蛋白的mRNA表达水平无影响，提示抑制PKC可能对EAM大鼠心室动作电位产生的离子通道无保护作用。这些结果表明，PKC的药理学抑制通过抑制Cx43的过度磷酸化，偏侧化和Cx43的间隙连接通道的解聚，从而改善EAM大鼠的QRS波群的延长，这为心肌炎诱导的心律失常提供了一种潜在的治疗策略。
Myocarditis is a serious and potentially life-threatening disease, which leads to cardiac dysfunction and sudden cardiac death. An increasing number of evidence suggests that myocarditis is also a malignant complication of coronavirus pneumonia, associated with heart failure and sudden cardiac death. Prolonged QRS complexes that are related to malignant arrhythmias caused by myocarditis significantly increase the risk of sudden cardiac death in patients. However, the molecular mechanisms are not fully known at present. In this study, we identify protein kinase C (PKC) as a new regulator of the QRS complex. In isolated hearts of normal rats, the PKC agonist, phorbol-12-myristate-13-acetate (PMA), induced prolongation of the QRS complex. Mechanistically, hyperphosphorylation and lateralization of connexin 43 (Cx43) by PKC induced depolymerization and internalization of Cx43 gap junction channels and prolongation of the QRS duration. Conversely, administration of the PKC inhibitor, Ro-32-0432, in experimental autoimmune myocarditis (EAM) rats after the most severe inflammation period still significantly rescued the stability of the Cx43 gap junction and alleviated prolongation of the QRS complex. Ro-32-0432 reduced phosphorylation and blocked translocation of Cx43 in EAM rat heart but did not regulate the mRNA expression level of ventricular ion channels and the other regulatory proteins, which indicates that the inhibition of PKC might have no protective effect on ion channels that generate ventricular action potential in EAM rats. These results suggest that the pharmacological inhibition of PKC ameliorates the prolongation of the QRS complex via suppression of Cx43 hyperphosphorylation, lateralization, and depolymerization of Cx43 gap junction channels in EAM rats, which provides a potential therapeutic strategy for myocarditis-induced arrhythmias.
登录
查看更多内容
CX43对于右心功能的重要性。
影响因子：
5.6
作者：
Boengler K;Rohrbach S;Weissmann N;Schulz R
通讯作者：
Schulz R
影响因子：
4.4
作者：
Chang, He;Hanawa, Haruo;Aizawa, Yoshifusa
通讯作者：
Aizawa, Yoshifusa
影响因子：
15.9
作者：
De Smet, Maarten A. J.;Lissoni, Alessio;Leybaert, Luc
通讯作者：
Leybaert, Luc
影响因子：
20.1
作者：
KODAMA, M;HANAWA, H;SHIBATA, A
通讯作者：
SHIBATA, A
DOI：
10.1155/2017/2071952
发表时间：
2017
期刊：
Evidence-based complementary and alternative medicine : eCAM
影响因子：
--
作者：
Min Q;Bai Y;Zhang Y;Yu W;Zhang M;Liu D;Diao T;Lv W
通讯作者：
Lv W