Mo Guixi, Liu Xin, Zhong Yiyue, Mo Jian, Li Zhiyi, Li Daheng, Zhang Liangqing, Liu Yijun
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical university, Zhanjiang, Guangdong, P.R. China.
Cell Death Discov. 2021 Feb 10;7(1):31. doi: 10.1038/s41420-021-00404-4.
Intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial enzymes, infarct area, Ca level, NLRP3/Caspase-1, and pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block Ca channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced Ca overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca level caused H/R-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits Ca overload, thus alleviating pyroptosis and MI/R injury.
细胞内离子通道肌醇1,4,5 - 三磷酸受体（IP3R1）可从内质网释放钙离子。IP3R1功能紊乱与多种神经退行性疾病相关。本研究探讨了IP3R1在心肌缺血/再灌注（MI/R）中的作用机制。在建立MI/R模型后，沉默MI/R大鼠心肌中的IP3R1表达，以探究其在心肌酶浓度、梗死面积、钙离子水平、NLRP3/Caspase - 1以及细胞焦亡标志物和炎症因子方面的作用。分离并培养成年大鼠心肌细胞，建立缺氧/再灌注（H/R）细胞模型。在H/R诱导的细胞中下调IP3R1表达或过表达ERP44。向H/R诱导的细胞中添加硝苯地平D6以阻断钙通道，或添加尼日利亚菌素以激活NLRP3。IP3R1在MI/R大鼠心肌中高表达，沉默IP3R1可减轻MI/R损伤，减少MI/R大鼠及H/R诱导细胞中的钙超载、炎症和细胞焦亡。ERP44与IP3R1的结合可抑制钙超载，减轻心肌细胞炎症和细胞焦亡。细胞内钙离子水平升高通过NLRP3/Caspase - 1途径导致H/R诱导的心肌细胞焦亡。激活NLRP3途径可逆转IP3R1抑制/ERP44过表达/硝苯地平D6对H/R诱导细胞的保护作用。总体而言，ERP44与IP3R1结合可抑制钙超载，从而减轻细胞焦亡和MI/R损伤。
