Endothelial cells secrete small extracellular vesicles to promote neuron endoplasmic reticulum stress injury via miR-146a-5p/Eif4g2 axis in ischemic stroke.

Abstract

INTRODUCTION: Ischemic stroke (IS) ranks among the top global causes of mortality and disability, with existing treatments proving inadequate because of its complex pathological process. Cell communication mediated by extracellular vesicle (EV)-containing miRNAs between vascular endothelial cells and neurons is essential for IS formation. OBJECTIVES: This research sought to explore the effects and molecular mechanisms of endothelial cell EV-derived miR-146a-5p on neuron injury in IS. METHODS: We investigated the role of miR-146a-5p in IS using a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model and oxygen-glucose deprivation/reperfusion (OGD/R) endothelial cells. We characterized miR-146a-5p expression in small EVs (sEVs) derived from MCAO/R rat brains and OGD/R endothelial cells, and the miR-146a-5p target to Eif4g2 expression. Neuronal injury was assessed by apoptosis induction and proliferation inhibition. RESULTS: The expression level of miR-146a-5p in sEVs was significantly elevated in the brains of MCAO/R rats and in OGD/R endothelial cells, correlating with increased neuron injury via apoptosis induction and proliferation inhibition. Transfer of miR-146a-5p to neurons through sEVs targeted and inhibited Eif4g2, triggering endoplasmic reticulum stress-mediated neuron injury. Increasing and decreasing miR-146a-5p expression levels significantly promoted and ameliorated neuron injury, respectively. Additionally, we identified the neuroprotective agent of 3-n-butyl phthalide (NBP) as a potential miR-146a-5p targeted inhibitor using molecular docking analysis and validated. CONCLUSION: Our research clarifies the role of miR-146a-5p-containing sEVs in inducing neuron injury by targeting Eif4g2-mediated ER stress in IS. Additionally, we demonstrated a new mechanism for NBP treating IS. These results clarify the molecular mechanisms of IS pathogenesis and provide perspectives on new therapeutic approaches.