Abstract

BACKGROUND AND PURPOSE Fucosyltransferase 8 (FUT8)-mediated core fucosylation (CF) has been confirmed to regulate multiple disease progression. However, its role in myocardial ischaemia/reperfusion (I/R) injury are unclear. EXPERIMENTAL APPROACH The mouse model of myocardial I/R injury was constructed, injecting 2-fluorofucose (2FF) to explore the effect of CF inhibitor on myocardial injury. Infarct size was analysed by TTC staining. Myocardial injury was assessed by H&E staining, Masson staining, myocardial enzyme level detection and cardiac function evaluation. CF level was assessed by lectin blotting and immunofluorescence. The levels of macrophage markers, JAK2/STAT3-related markers, FUT8 and Krüppel-like factor 6 (KLF6) were examined by western blot or qRT-PCR. RAW264.7 cells were induced with hypoxia/reoxygenation (H/R). Flow cytometry measured macrophage surface markers. The effect of FUT8 on CF level of KLF6 was assessed by immunoprecipitation assay. KEY RESULTS CF level was up-regulated in myocardial I/R injury mice, and its inhibitor 2FF alleviated myocardial I/R injury by repressing macrophage M1 polarization. Furthermore, FUT8 increased expression in myocardial I/R injury patients and mice, and its down-regulation suppressed macrophage M1 polarization in H/R-induced RAW264.7 cells. FUT8 enhanced the CF level of KLF6 to activate the JAK2/STAT3 pathway, and FUT8 knockdown reversed the promoting effect of KLF6 overexpression on macrophage M1 polarization. Moreover, FUT8 knockout alleviated myocardial I/R injury by inactivating the KLF6/JAK2/STAT3 pathway and inhibiting macrophage M1 polarization. CONCLUSION AND IMPLICATIONS FUT8-mediated CF of KLF6 promoted macrophage M1 polarization to aggravate myocardial I/R injury by activating JAK2/STAT3 pathway, providing a novel treatment of myocardial I/R injury.