Extracellular vesicles (EVs) curb important biological functions. We previously disclosed that ischemia‐reperfusion (IR) induces increased release of EVs (IR‐EVs) in the heart. However, the role of IR‐EVs in IR pathological process remains poorly understood. Here we found that adoptive transfer of IR‐EVs aggravated IR induced heart injury, and EV inhibition by GW4869 reduced the IR injury. Our in vivo and in vitro investigations substantiated that IR‐EVs facilitated M1‐like polarization of macrophages with increased expression of proinflammatory cytokines. Further, we disclosed the miRNA profile in cardiac EVs and confirmed the enrichment of miRNAs, such as miR‐155‐5p in IR‐EVs compared to EVs from the sham heart (S‐EVs). In particular, IR‐EVs transferred miR‐155‐5p to macrophages and enhanced the inflammatory response through activating JAK2/STAT1 pathway. Interestingly, IR‐EVs not only boosted the local inflammation in the heart, but even triggered systemic inflammation in distant organs. Taken together, we newly identify an IR‐EVs–miR‐155‐5p – M1 polarization axis in the heart post IR. The EVs derived from IR‐injured heart contribute to both local and systemic inflammation. Importantly, EV inhibition by GW4869 is supposed to be a promising therapeutic strategy for IR injury.
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