Extracellular Vesicles Derived from Human Umbilical Cord MesenchymalStromal Cells Protect Cardiac Cells Against Hypoxia/Reoxygenation Injury byInhibiting Endoplasmic Reticulum Stress via Activation of the PI3K/AktPathway

摘要

Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of manydiseases, including myocardial ischemia/reperfusion injury. We hypothesized thathuman umbilical cord mesenchymal stromal cells derived extracellular vesicles(HuMSC-EVs) could protect cardiac cells against hyperactive ER stress induced byhypoxia/reoxygenation (H/R) injury. The H/R model was generated using the H9c2cultured cardiac cell line. HuMSC-EVs were extracted using a commerciallyavailable exosome isolation reagent. Levels of apoptosis-related signalingmolecules and the degree of ER stress were assessed by western blot. The role ofthe PI3K/Akt pathway was investigated using signaling inhibitors. Lactatedehydrogenase leakage and 3-(4,5-Dimethylthiazol-2-yl)-2,5-DiphenyltetrazoliumBromide (MTT) analysis were used for evaluating the therapeutic effects ofHuMSC-EVs in vitro. The results showed that ER stress and therate of apoptosis were increased in the context of H/R injury. Treatment withHuMSC-EVs inhibited ER stress and increased survival in H9c2 cells exposed toH/R. Mechanistically, the PI3K/Akt pathway was activated by treatment withHuMSC-EVs after H/R. Inhibition of the PI3K/Akt pathway by a specific inhibitor,LY294002, partially reduced the protective effect of HuMSC-EVs. Our findingssuggest that HuMSC-EVs could alleviate ER stress–induced apoptosis during H/Rvia activation of the PI3K/Akt pathway.