Exosomes secreted by HUVECs attenuate hypoxia/reoxygenation-induced apoptosis in neural cells by suppressing miR-21-3p.

Background: Remote ischemic postconditioning (RIPostC) is an effective strategy for preventing key organs from becoming impaired due to an ischemia/reperfusion injury. In the current study, we investigated how remote exosome transfer of microRNAs (miRs) may contribute to the treatment effect of RIPostC on the central nerve system (CNS).

Methods: Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia/reoxygenation (H/R) and their miR expression profiles were investigated using the microarray method. The pathways associated with dysregulated miRs were analyzed by gene ontology (GO) annotation of the target genes and a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The role played by the most significantly down-regulated miR (miR-21-3p) in the protective effect of HUVEC-derived exosomes on H/R-treated neural cells was further investigated. The pathway mediating the effect of miR-21-3p was then explored by focusing on activity of autophagy-related 12 (ATG12) protein.

Results: The miR expression profile of HUVECs significantly changed after H/R administration, with 104 miRs becoming upregulated and 249 miRs becoming downregulated. Based on the GO and KEGG analyses, the target genes of 8 selected miRs were involved in multiple biological pathways, including the hippo signaling pathway and longevity regulating pathway. Further studies showed that inhibition of miR-21-3p by HUVEC-derived exosomes or a specific inhibitor could the block apoptotic process in H/R-treated neural cells. Molecular level studies showed that the effect of miR-21-3p inhibition depended on the restored function of ATG12, which resulted in the activation of autophagy and suppression of apoptosis.

Conclusion: Taken together, these results suggest that H/R caused significant changes of miR expression in exosomes derived from H/R-treated HUVECs, and the exosomes protect neurons against H/R-induced injuries by suppressing miR-21-3p.