RESUMEN
Exosomes of different origins have been found to be protective against ischemic-induced myocardial injury. This study examined the protective effects of circulating exosomes in the mice model of acute myocardial infarction (AMI) and explored the underlying molecular mechanisms. The effects of exosomes on myocardial injury were assessed in the AMI mice model. The in vivo studies showed that circulating exosomes reduced the infarcted size, improved the morphology of heart tissues and also reduced apoptosis of the heart tissues. In addition, the model mice showed an increase in the CD34 + /VEGFR2 + cell population and CD31, CXCR4 and CXCL12 expression after exosomes treatment. MiR-190a-3p was significantly down-regulated in the exosomes derived from the culture medium of hypoxia-treated human cardiomyocytes (HCMs). Further analysis revealed that miR-190a-3p could physically interact with CXCR4/CXCL12 by targeting the respective 3'UTRs. These exosomes could up-regulated CXCR4 and CXCL12 expression in the EPCs; in addition, miR-190a-3p mimics repressed CXCR4/CXCL12 expression in EPCs, while its inhibitor had opposite effects. The in vitro functional assays showed that miR-190a-3p overexpression suppressed the cell viability, proliferation, migration, adhesion and tube formation of EPCs; while miR-190a-3p inhibitor had the opposite effects; exosomes derived from the culture medium of hypoxia-treated HCMs exhibited similar actions of miR-190a-3p inhibitor. Moreover, miR-190a-3p was down-regulated in exosomes from serum in the AMI group when compared to that from sham group. Treatment with exosomes from serum in the AMI group promoted cell proliferation, migration, adhesion and tube formation of EPCs when compared to that in the sham group. More importantly, IT1t attenuated the enhanced effects of miR-190a-3p inhibition on EPC proliferation, migration, adhesion and tube formation. In conclusion, circulating exosomes exerted protective effects on myocardial injury in the AMI mice model, and down-regulation of miR-190a-3p in the circulating exosomes may exert protective effects against myocardial injury. Hypoxia induced the downregulation of miR-190a-3p in the culture medium of HCMs, and the mechanistic investigations indicated that exosomes of hypoxia-conditioned HCM culture medium promoted the cell viability, proliferation, migration, adhesion and tube formation of EPCs via regulating miR-190a-3p/CXCR4/CXCL12 pathway.