CaMKII信号通路调控室早性心肌病猝死相关室性心律失常的机制

Frequent premature ventricular contractions (PVC) can cause PVC-induced cardiomyopathy (PVC-ICM) and increase the risk of sudden cardiac death (SCD). Malignant ventricular arrhythmia (VA) is a pivotal trigger of SCD. There is evident that VA vulnerability was markedly increased in PVC-ICM animal, but the underlying mechanisms are poorly understood. In the preliminary study, we developed a PVC-ICM animal model and observed increased expression of calmodulin dependent protein kinase II (CaMKII) and phosphorylated CaMKII in PVC-ICM hearts, indicating high burden PVC stimulation led to CaMKII activation. Previous studies demonstrated that CaMKII overexpression and/or overactivation can lead to abnormal Ca2+ homeostasis and cardiac electrical remodeling, and hence to promote VA. The aims of this project are as follows:① we will evaluate the effects of CaMKII pathway specific inhibitors on cellular Ca2+ homeostasis, cardiac electrical properties and VA vulnerability of PVC-ICM hearts by in vitro and cellular electrophysiological and molecular-biologic studies; ② We will assessed the time course of CaMKII activation, Ca2+ homeostasis and electrical properties alternations in high burden PVC stimulated-ventricular cardiomyocytes by cellular electrophysiological and molecular-biologic studies. The results of the present study might elucidate the mechanisms of CaMKII pathway underlies PVC-ICM related-VA and provide new insights into the prevention of SCD caused by PVC-ICM.

频发室性早搏（PVC）可导致PVC性心肌病（PVC-ICM），并增加心源性猝死（SCD）风险。恶性室性心律失常（VA）是SCD的重要诱因。PVC-ICM后VA易感性显著增加，但其具体机制尚未阐明。在PVC-ICM动物模型中，我们观察到心室钙/钙调素依赖性蛋白激酶II（CaMKII）表达增加且活性增强。既往研究表明CaMKII过表达和/或过度激活可诱发心肌Ca2+紊乱和电重构，进而促进VA发生。本项目拟进一步研究：①运用细胞、离体电生理和分子生物学技术评价CaMKII信号通路抑制剂对PVC-ICM后心室Ca2+稳态、电生理特性及VA易感性的影响；②运用细胞电生理和分子生物学技术探讨高负荷PVC刺激下心室细胞不同时间点CaMKII活性变化及其对细胞Ca2+稳态和电生理特性的影响。通过本研究，阐明CaMKII信号通路在PVC-ICM后VA发生中的作用及其机制，为PVC-ICM后SCD防治提供新思路。

频发室性期前收缩（PVC）可导致PVC心肌病（PVC-ICM），从而增加心源性猝死（SCD）风险。本研究在成功建立PVC-ICM 在体模型及心室细胞高负荷 PVC 刺激离体模型基础上，做了以下进一步研究：1）评价心室钙/钙调素依赖性蛋白激酶II（CaMKII）信号通路抑制剂对PVC-ICM后心室Ca2+稳态、电生理特性及VA易感性的影响， 我们发现PVC-ICM后心室细胞钙瞬变幅度显著减小，而舒张期Ca2+水平、心室有效不应期、动作电位时程（APD）、早后除极易感性、晚后除极易感性、APD电交替、VA易感性却显著增加，而这些改变可被CaMKII特异性抑制剂AIP及RyR2受体稳定剂丹曲林所抑制；2）探讨高负荷PVC刺激下心室细胞不同时间点CaMKII活性变化及其对细胞Ca2+稳态和电生理特性的影响，我们发现24小时高负荷PVC刺激心室细胞钙交替易感性、舒张期细胞内钙水平、舒张期钙衰减时间、磷酸化CaMKII表达均显著增加，而瞬时外向钾电流(Ito)及内向整流钾电流（IK1）电流密度、细胞收缩力、钙瞬变最大幅度、内质网钙泵表达均显著减小，而这些改变可被CaMKII特异性抑制剂AIP所抑制。通过本研究，阐明了CaMKII信号通路在PVC-ICM后VA发生中的作用及其机制，为PVC-ICM后SCD防治提供了新思路。