Deficiency of tenascin-C attenuated cardiac injury by inactivating TLR4/NLRP3/caspase-1 pathway after myocardial infarction.
Deficiency of tenascin-C attenuated cardiac injury by inactivating TLR4/NLRP3/caspase-1 pathway after myocardial infarction.
复制标题
心肌梗塞后，腱蛋白-C 缺乏可通过灭活 TLR4/NLRP3/caspase-1 通路来减轻心脏损伤。
DOI：
10.1016/j.cellsig.2021.110084
复制
发表时间：
2021-07
影响因子：
4.8
通讯作者：
Huang Rongchong
中科院分区：
文献类型：
--
作者：
Xu Mingyue;Ye Zhishuai;Zhao Xin;Guo Hongzhou;Gong Xuhe;Huang Rongchong
炎症和焦亡在心肌梗死（MI）后心功能障碍中起着有害作用。NLRP3/caspase-1在焦亡和炎症中是一个公认的轴。在本研究中，我们通过NLRP3检测TN-C对焦亡的影响尚不清楚。我们构建了18只tn - c敲除小鼠和38只WT雄性小鼠模型，分为WT sham （n= 16）、WT MI （n= 22）、TNKO sham （n= 6）、TNKO MI （n= 12）。采用Elisa、免疫染色、TTC、qPCR、CCK8、流式细胞术、western blot、超声心动图、TUNEL染色等技术。通过GEPIA数据库，我们发现心脏组织TN-C与NLRP3呈正相关（r= 0.52,p< 0.05）。结果表明，TN-C在心肌梗死后第5天升高并达到峰值，TN-C缺乏可减轻心功能障碍（LVEF、FS、LVIDd和LVIDs）和心肌细胞死亡。心肌梗死和h2o2刺激时，细胞内与心肌焦亡相关的细胞因子caspase-1、cleaved caspase-1、NLRP3、IL-18、IL-1β水平均上调，但敲除TN-C可抑制心肌焦亡，减轻心肌焦亡，并进一步降低IL-6、TNF-α、MCP-1的表达。TN-C敲低抑制TLR4表达，通过使TLR4/NF-kB通路失活，减少下游因子的释放，同时保护心肌细胞。TLR4抑制剂TAK-242显著降低心肌梗死后NLRP3的表达水平。我们首次证明了心肌梗死诱导的TN-C上调与caspase-1依赖性心肌细胞焦亡之间存在直接联系，这一过程至少部分由TLR4/NF-kB/NLRP3和IL-18、IL-1β信号通路介导。这些发现为TN-C在心肌梗死后心肌细胞焦亡和炎症中的作用提供了新的见解。
Inflammation and pyroptosis play a deleterious role in cardiac dysfunction after myocardial infarction (MI). NLRP3/caspase-1 is a well-established axis in pyroptosis and inflammation. In this study, we examined the effects of TN-C on pyroptosis through NLRP3 is unclear. We constructed 18 TN-C-knockout and 38 WT male mice model and divided into WT sham (n= 16), WT MI (n= 22), TNKO sham (n= 6), TNKO MI (n= 12). Elisa, immunostaining, TTC, qPCR, CCK8, flow cytometry, and western blot, echocardiographic, TUNEL staining technologies were applied. Here, we found a positive correlation between TN-C and NLRP3 in heart tissue via the GEPIA database (r= 0.52,p< 0.05). The findings indicate that TN-C was elevated and peaked on the fifth day after MI. TN-C deficiency alleviated cardiac dysfunction (LVEF, FS, LVIDd, and LVIDs) and cardiomyocyte death. Though the intracellular levels of pyroptosis-related cytokine caspase-1, cleaved caspase-1, NLRP3, IL-18, IL-1β were upregulated both in MI and H2O2stimulation, knockout of TN-C resisted such injury and alleviated cardiac pyroptosis, which further decreased IL-6, TNF-α, MCP-1 expression. TN-C knockdown inhibited TLR4 expression, reduces the release of downstream factors by inactivating the TLR4/NF-kB pathway, while protects the cardiomyocytes. And TLR4 inhibitor TAK-242 significantly reduced NLRP3 expression levels after MI. We demonstrated for the first time a direct link between MI-induced TN-C upregulation and caspase-1-dependent cardiomyocyte pyroptosis, a process mediated, at least in part, by TLR4/NF-kB/NLRP3 and IL-18, IL-1β signaling pathways. These findings provide new insights into the role of TN-C in post-MI cardiomyocytes' pyroptosis and inflammation.