Exosomal miR-27a-5p inhibits indoxyl sulfate-induced cardiac dysfunction by targeting the USF2/FUT8 axis.

Uremic cardiomyopathy (UCM) is the leading cause of hemodialysis patient mortality. Indoxyl sulfate (IS), a key uremic toxin, activates multiple signaling pathways, causing cardiac hypertrophy and apoptosis. We previously demonstrated that core fucosylation (CF), a post-translational modification, is crucial in activating these pathways. Additionally exosome-mediated cardiac microvascular endothelial cell (CMEC)-cardiomyocyte (CM) crosstalk is important for UCM progression. However, the characteristics and roles of CF modification in IS-induced CMEC-derived exosomes (IS-Exos) that cause CM injury remain unexplored. Our studies have revealed that hemodialysis patients had significantly higher serum IS and α1,6-fucosyltransferase (FUT8), which were positively correlated with the severity of cardiac injury. Using a microfluidic chip model of IS-induced cardiac injury, we visualized exosome transfer from CMECs to CMs, which caused mitochondrial impairment, hypertrophy and apoptosis in CMs, with elevated CF levels playing critical roles. To investigate this further, we performed FUT8 knockout in IS-mice treated with IS-Exos and transfected FUT8 siRNA into CMs exposed to IS-Exos. We found that the inhibition of FUT8 leads to a reduction in ARG2 expression, which consequently diminishes reactive oxygen species (ROS) and ameliorates cardiac hypertrophy and apoptosis. Mechanistically, miR-27a-5p was markedly downregulated in IS-Exos. CD44 on IS-Exos interacts with EGFR in CMs, enhancing cardiac injury. Supplementation with miR-27a-5p in vivo and in vitro specifically targets USF2, leading to a downregulation of FUT8 expression. This cascade leads to a diminished expression of ARG2, alleviation of ROS, and the reversal of cardiac hypertrophy and apoptosis. Our findings offer new insights, suggesting that targeting CF modification may represent a promising therapeutic strategy for alleviating UCM in the future.