IP3R1 regulates Ca(2+) transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury.
IP3R1 regulates Ca(2+) transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury.
复制标题
DOI：
10.1038/s41420-021-00404-4
复制
发表时间：
2021-02-10
影响因子：
7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Mo G;Liu X;Zhong Y;Mo J;Li Z;Li D;Zhang L;Liu Y
细胞内离子通道肌醇1，4，5-三磷酸受体（IP 3R 1）从内质网释放Ca ~（2+）。IP 3R 1的紊乱与多种神经退行性疾病有关。本研究探讨了IP 3R 1在心肌缺血/再灌注（MI/R）中的作用机制。在MI/R模型建立后，沉默心肌IP 3R 1表达，观察IP 3R 1对心肌酶浓度、梗死面积、Ca 2+水平、NLRP 3/Caspase-1、心肌细胞凋亡标志物和炎症因子的影响。分离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，IP 3R 1表达下调或ERP 44过表达。在H/R诱导的细胞中加入硝苯地平D 6阻断Ca ~（2+）通道，或加入黄曲霉素激活NLRP 3。IP 3R 1在MI/R大鼠心肌组织中高表达，沉默IP 3R 1可减轻MI/R损伤，减少MI/R大鼠心肌细胞Ca 2+超载、炎症反应和细胞凋亡，减少H/R诱导的细胞凋亡。ERP 44与IP 3R 1的结合抑制了Ca 2+超载，减轻了心肌细胞炎症和焦亡。细胞内Ca ~（2+）水平的升高通过NLRP 3/Caspase-1途径引起H/R诱导的心肌细胞凋亡。NLRP 3通路的激活逆转了IP 3R 1抑制/ERP 44过表达/硝苯地平D 6对H/R诱导的细胞的保护作用。总之，ERP 44与IP 3R 1的结合抑制了Ca 2+超载，从而减轻了焦亡和MI/R损伤。
Intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca2+ 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, Ca2+ 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 Ca2+ 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 Ca2+ overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca2+ overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca2+ 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 Ca2+ overload, thus alleviating pyroptosis and MI/R injury.
登录
查看更多内容
影响因子：
8.7
作者：
Man SM;Karki R;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
3.7
作者：
Hu, Fudong;Zhang, Shengye;Chen, Kui
通讯作者：
Chen, Kui
影响因子：
--
作者：
Ma, Hui-Jie;Li, Qian;Zhang, Yi
通讯作者：
Zhang, Yi
影响因子：
6.1
作者：
An, Pengpeng;Xie, Jing;Tang, Ming
通讯作者：
Tang, Ming
影响因子：
16.6
作者：
通讯作者：
--