International immunopharmacology · 2025
UPF1 alleviates myocardial ischemia/reperfusion injury via suppressing NLRP3-mediated cardiomyocyte pyroptosis by inhibiting KLF6/TXNIP axis.
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Yan Wei, Liu Momu, Qiu Mali
Аннотация
BACKGROUND: Kruppel-like factor 6 (KLF6) is considered to be a regulator for myocardial ischemia/reperfusion (I/R) injury. Therefore, its role and mechanism deserve further investigation.
METHODS: Myocardial I/R injury mice models and hypoxia/reoxygenation (H/R)-treated HL-1 cell models were established. TTC, HE and Masson staining were used to assess myocardial infarction, injury, and fibrosis, respectively. IL-1β and IL-18 levels in serum samples and cell supernatants were tested using ELISA. The expressions of NLRP3, Cleaved caspase-1, IL-1β, IL-18, KLF6, up-frameshift protein 1 (UPF1), and thioredoxin-interacting protein (TXNIP) were tested by western blot or qRT-PCR. Cell viability and pyroptosis were measured using CCK8 assay and flow cytometry. Besides, NLRP3 and Caspase-1 signals were checked using immunofluorescence staining. The interaction between KLF6 and UPF1 or TXNIP was examined.
RESULTS: After constructing the mice models of myocardial I/R injury, we detected the activated inflammasome and upregulated KLF6. KLF6 knockdown repressed NLRP3-mediated pyroptosis in H/R-induced HL-1 cells. Besides, UPF1 interacted with KLF6 to promote its mRNA degradation. Overexpressed UPF1 repressed H/R-induced cell pyroptosis and inflammation by downregulating KLF6. Also, KLF6 bound to TXNIP promoter region to activate its transcription, and TXNIP overexpression abolished the inhibitory effect of KLF6 silencing on cell pyroptosis and inflammation. Meanwhile, UPF1 overexpression alleviated mice myocardial I/R injury by regulating KLF6/TXNIP/NLRP3 axis.
CONCLUSION: UPF1-mediated KLF6 mRNA degradation ameliorated myocardial I/R injury via repressing cardiomyocyte pyroptosis by inhibiting TXNIP/NLRP3 axis.
METHODS: Myocardial I/R injury mice models and hypoxia/reoxygenation (H/R)-treated HL-1 cell models were established. TTC, HE and Masson staining were used to assess myocardial infarction, injury, and fibrosis, respectively. IL-1β and IL-18 levels in serum samples and cell supernatants were tested using ELISA. The expressions of NLRP3, Cleaved caspase-1, IL-1β, IL-18, KLF6, up-frameshift protein 1 (UPF1), and thioredoxin-interacting protein (TXNIP) were tested by western blot or qRT-PCR. Cell viability and pyroptosis were measured using CCK8 assay and flow cytometry. Besides, NLRP3 and Caspase-1 signals were checked using immunofluorescence staining. The interaction between KLF6 and UPF1 or TXNIP was examined.
RESULTS: After constructing the mice models of myocardial I/R injury, we detected the activated inflammasome and upregulated KLF6. KLF6 knockdown repressed NLRP3-mediated pyroptosis in H/R-induced HL-1 cells. Besides, UPF1 interacted with KLF6 to promote its mRNA degradation. Overexpressed UPF1 repressed H/R-induced cell pyroptosis and inflammation by downregulating KLF6. Also, KLF6 bound to TXNIP promoter region to activate its transcription, and TXNIP overexpression abolished the inhibitory effect of KLF6 silencing on cell pyroptosis and inflammation. Meanwhile, UPF1 overexpression alleviated mice myocardial I/R injury by regulating KLF6/TXNIP/NLRP3 axis.
CONCLUSION: UPF1-mediated KLF6 mRNA degradation ameliorated myocardial I/R injury via repressing cardiomyocyte pyroptosis by inhibiting TXNIP/NLRP3 axis.