Exosomes derived from MSC pre‐treated with oridonin alleviates myocardial IR injury by suppressing apoptosis via regulating autophagy activation

Abstract This study aimed to investigate the molecular mechanisms underlying the role of bone marrow mesenchymal stem cells (BMMSCs)‐derived exosomes in ischaemia/reperfusion (IR)‐induced damage, and the role of oridonin in the treatment of IR. Exosomes were isolated from BMMSCs. Western blot analysis was done to examine the expression of proteins including CD63, CD8, apoptotic‐linked gene product 2 interacting protein X (AliX), Beclin‐1, ATG13, B‐cell lymphoma‐2 (Bcl‐2), apoptotic peptidase activating factor 1 (Apaf1) and Bcl2‐associated X (Bax) in different treatment groups. Accordingly, the expression of CD63, CD81 and AliX was higher in BMMSCs‐EXOs and IR + BMMSCs‐EXOs + ORI groups compared with that in the BMMSCs group. And BMMSCs‐derived exosomes inhibited the progression of IR‐induced myocardial damage, while this protective effect was boosted by the pre‐treatment with oridonin. Moreover, Beclin‐1, ATG13 and Bcl‐2 were significantly down‐regulated while Apaf1 and Bax were significantly up‐regulated in IR rats. And the presence of BMMSCs‐derived exosomes partly alleviated IR‐induced dysregulation of these proteins, while the oridonin pre‐treatment boosted the effect of these BMMSCs‐derived exosomes. The inhibited proliferation and promoted apoptosis of H9c2 cells induced by hypoxia/reperfusion (HR) were mitigated by the administration of BMMSCs‐derived exosomes. Meanwhile, HR also induced down‐regulation of Beclin‐1, ATG13 and Bcl‐2 expression and up‐regulation of Apaf1 and Bax, which were mitigated by the administration of BMMSCs‐derived exosomes. And oridonin pre‐treatment boosted the effect of BMMSCs‐derived exosomes. In conclusion, our results validated that BMMSCs‐derived exosomes suppressed the IR‐induced damages by participating in the autophagy process, while the pre‐treatment with oridonin could boost the protective effect of BMMSCs‐derived exosomes.