Loss of Camk2n1 aggravates cardiac remodeling and malignant ventricular arrhythmia after myocardial infarction in mice via NLRP3 inflammasome activation
Loss of Camk2n1 aggravates cardiac remodeling and malignant ventricular arrhythmia after myocardial infarction in mice via NLRP3 inflammasome activation
复制标题
Camk2n1 缺失通过 NLRP3 炎性体激活加剧小鼠心肌梗死后的心脏重塑和恶性室性心律失常
DOI：
10.1016/j.freeradbiomed.2021.03.014
复制
发表时间：
2021-03-26
影响因子：
7.4
通讯作者：
Li, Yi-Gang
中科院分区：
文献类型：
--
作者：
Wei, Zhixing;Fei, Yudong;Li, Yi-Gang
目的：炎症反应和随后的心室重构与心肌梗死（MI）后室性心律失常的发生密切相关。然而，作为钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 的重要内源性抑制剂，CaMKII 抑制剂 1 (Camk2n1) 对 MI 后心律失常底物生成过程的影响仍不清楚。在本研究中，我们研究了 Camk2n1 在心肌梗死后室性心律失常中的作用及其潜在机制。方法与结果：Camk2n1主要在心肌细胞中表达，并抑制梗死边界区CaMKII8的磷酸化。与野生型（WT）同窝小鼠相比，Camk2n1基因敲除小鼠（Camk2n1-/-）表现出心功能障碍加剧、纤维化面积更大、室性早搏（PVC）发生率更高、MI后更容易出现室性心动过速（VT）或心室颤动（VF）。 RNA测序（RNA-seq）的结果表明，NLRP3炎症小体的过度激活导致炎症反应加剧，从而导致遭受MI的Camk2n1-/-小鼠出现不良的心脏重塑。更重要的是，体内和体外实验均证实 Camk2n1-/- 小鼠中 NLRP3 炎性体激活是通过 CaMKII8-p38/JNK 通路加剧的。结论：总的来说，我们的结果强调了 Camk2n1 通过 CaMKII8-p38/JNK-NLRP3 炎症小体通路减少心肌细胞炎症激活，在减轻心室重构和 MI 后恶性室性心律失常方面的重要性，靶向 Camk2n1 可能作为 MI 后的一种新型治疗策略。
Aims: Inflammation response and subsequent ventricular remodeling are critically involved in the development of ventricular arrhythmia post myocardial infarction (MI). However, as the vital endogenous inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), the effects of CaMKII inhibitor 1 (Camk2n1) on the process of arrhythmia substrate generation following MI remains unclear. In this study, we investigated the role of Camk2n1 in ventricular arrhythmia post-MI and the underlying mechanisms. Methods and results: Camk2n1 was mainly expressed in cardiomyocytes and inhibited the phosphorylation of CaMKII8 in the infarcted border zone. Compared to wild type (WT) littermates mice, Camk2n1 knockout mice (Camk2n1-/- ) manifested exacerbated cardiac dysfunction, larger fibrosis area, higher incidence of premature ventricular contractions (PVCs) and higher vulnerability to ventricular tachycardia (VT) or ventricular fibrillation (VF) after MI. The results of RNA sequencing (RNA-seq) identified that excessive activation of NLRP3 inflammasome was responsible for aggravated inflammation response which led to adverse cardiac remodeling in Camk2n1-/- mice subjected to MI. More importantly, both in vivo and in vitro experiments verified that aggravated NLRP3 inflammasome activation occurred via CaMKII8-p38/JNK pathway in Camk2n1-/- mice. Conclusions: Collectively, our results highlight the importance of Camk2n1 in alleviating ventricular remodeling and malignant ventricular arrhythmia post-MI by reducing cardiomyocytes inflammation activation via CaMKII8-p38/JNK-NLRP3 inflammasome pathway, targeting Camk2n1 might serve as a novel therapeutic strategy after MI.