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 cardioprotective 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.