Deficiency of tenascin-C attenuated cardiac injury by inactivating TLR4/ NLRP3/caspase-1 pathway after myocardial infarction

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-1 beta were upregulated both in MI and H2O2 stimulation, knockout of TN-C resisted such injury and alleviated cardiac pyroptosis, which further decreased IL-6, TNF-alpha, 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-1 beta signaling pathways. These findings provide new insights into the role of TN-C in post-MI cardiomyocytes' pyroptosis and inflammation.

Automated summary

The study found that elevated TN-C after heart disease can lead to increased pyroptosis, but the deficiency of TN-C can alleviate cardiac dysfunction and cardiomyocyte death.