Exosomes derived from miR-146a-modified adipose-derived stem cells attenuate acute myocardial infarction-induced myocardial damage via downregulation of early growth response factor 1.

Abstract

Multiple studies demonstrated that early growth response factor 1 (EGR1) induces myocardial damage after acute myocardial infarction (AMI). Recent evidence indicates that microRNAs (miRNA) play an important role in exosome-mediated cardioprotection after AMI. Bioinformatics analysis has shown that miR-146a can regulate the expression of EGR1, so the aim of this study was to determine if miR-146a plays a role in exosome-mediated cardioprotection by regulation of EGR1 after AMI. Exosomes were isolated from wild- or miR-146a-modified adipose-derived stem cells (ADSCs), and the therapeutic effect of exosomes was assessed in an AMI model in rats and hypoxic-induced H9c2 model cells. The results showed that miR-146a containing exosomes had more effect than the exosome treatment group on the suppression of AMI-induced apoptosis, inflammatory response, and fibrosis in an AMI rat model. Both in vivo and in vitro experiments found that miR-146a interacted with the 3'-untranslated region of EGR1 and suppressed posttranscriptional EGR1 expression, which was confirmed by the luciferase reporter assay. We also found that suppressed EGR1 expression reversed AMI or hypoxia-induced TLR4/NFκB signal activation, which played an important role in the promotion of myocardial cell apoptosis, inflammatory response, and fibrosis. Taken together, these findings suggested that exosomes derived from miR-146a-modified ADSCs attenuated AMI-induced myocardial damage via downregulation of EGR1.