Tanshinone IIA enhances the therapeutic efficacy of mesenchymal stem cells derived exosomes in myocardial ischemia/reperfusion injury via up-regulating miR-223-5p

Myocardial ischemia-reperfusion injury (MI/RI) is a serious obstacle for patients with coronary heart disease (CHD) to benefit from post-ischemic reflow. The low immunogenicity and low carcinogenicity of mesenchymal stem cells (MSCs)-derived exosomes (exo) offer advantage in treating myocardial injuries. Tanshinone IIA (TSA) is an effective drug for MI/RI treatment. However, the underlying mechanism and targets remain obscure. In this study, we systematically investigated the therapeutic effect and its mechanism of TSA-pretreated MSC-derived exosomes (TSA-MSCexo) in ameliorating MI/RI in rats. Expectedly, the MI/RI was significantly relieved by TSA-MSCexo compared with MSCexo. Moreover, the overexpression of CCR2 in rats' heart was used to determine CCR2 had a regulatory effect on monocyte infiltration and angiogenesis after MI/RI. MiRNA microarray analysis of MSCexo and TSA-MSCexo revealed miR-223-5p an effective candidate mediator for TSA-MSCexo to exert its car-dioprotective function and CCR2 as the downstream target. In summary, our findings indicated that miR-223-5p packaged in TSA-MSCexo inhibited CCR2 activation to reduce monocyte infiltration and enhanced angiogenesis to alleviate MI/RI. Thus, the development of cell free therapies for exosomes derived from the combination TSA and MSC provides an effective strategy for the clinical therapies of ischemic cardiomyopathy.

Automated summary

This study investigated the therapeutic effect and mechanism of TSA-pretreated MSC-derived exosomes (TSA-MSCexo) in ameliorating myocardial ischemia-reperfusion injury in rats. The results showed that TSA-MSCexo significantly relieved myocardial injury compared to MSCexo. MiRNA microarray analysis identified miR-223-5p as a potential mediator for TSA-MSCexo's cardio-protective function by inhibiting CCR2 activation and reducing monocyte infiltration, while enhancing angiogenesis.