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. K E Y W O R D Sacute myocardial infarction (AMI), adipose-derived stem cells (ADSCs), early growth response factor 1 (EGR1), exosomes, miR-146a

Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent

“…MSCs overexpressing miR-133 produced exosomes that decreased inflammation and myocardial fibrosis in an acute MI rat model [141]. Furthermore, MSCs that overexpressed miR-93-5p and miR-146 produced exosomes that attenuated MI-induced myocardial damage by suppressing expression of inflammatory cytokines and hypoxia-induced autophagy in vitro [140], and by decreasing expression of early growth response factor 1 in vivo [142]. Exosomes derived from miR-126-overexpressing MSCs also reduced hypoxia-induced expression of inflammation factors and promoted microvascular generation and myocardial cell migration in vitro; these exosomes also decreased cardiac fibrosis and the level of inflammatory cytokines in vivo [143].…”

New insights into the immunomodulatory role of exosomes in cardiovascular disease

“…A large number of studies have shown that exosomes carry proteins, lipids, RNA and microRNAs, participating in intercellular communication (Zhang et al, 2019), promoting angiogenesis (Ju et al, 2018), conferring anti-apoptotic effects (Pan et al, 2019a), reducing infarct size (Li et al, 2019b), and improving cardiac function (Zhu et al, 2018). Their roles in antigen presentation, inflammatory response, and immune regulation (Chan et al, 2019) have aroused significant research interest.…”

“…In order to enhance their cardiaoprotective effect, exosomes can be pretreated by hypoxia preconditioning (Luo et al, 2019), gene programming (Wang et al, 2018), or drug intervention (Huang et al, 2019). Pan et al (2019a) showed that exosomes derived from miR-146a-modified adipose-derived stem cells ADSC-Exos inhibit the release of interleukin-6 (IL-6), interleukin-1β (IL-1β ) and tumor necrosis factor-α (TNF-α), as well as reducing the local inflammatory response, improving the local microenvironment, and attenuating acute myocardial infarction-induced myocardial damage via the down-regulation of early growth response factor 1 (EGR1). In the same study, Pan et al also demonstrated that suppression of EGR1 expression reversed AMI or hypoxia-induced TLR4/NFκB signal activation, which prevented cardiomyocyte apoptosis, alleviated cardiac fibrosis, reduced myocardial infarct size, and improved cardiac function.…”

Calcium Ionophore-Induced Extracellular Vesicles Mediate Cytoprotection against Simulated Ischemia/Reperfusion Injury in Cardiomyocyte-Derived Cell Lines by Inducing Heme Oxygenase 1

“…This protection was prevented by the inhibition of HSP70 and by blocking TLR4 in cardiomyocytes, indicating that EVs deliver endogenous protective signals to the heart via a pathway involving TLR4 and cardioprotective HSPs [ 32 ]. Very recently, it has also been documented that exosomes derived from miR-146a-modified adipose-derived stem cells decreased the infarct size and reversed myocardial infarction-induced TLR4/NF-κB activation in rats [ 33 ]. Since EVs have been shown to be involved in RIC [ 16 ], it seems that TLR signaling might mediate EV-induced cardioprotection.…”