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

The mitochondria are highly dynamic organelles, carefully maintaining network homeostasis by regulating mitochondrial fusion and fission. Mitochondrial dynamics are involved in the regulation of a variety of pathophysiological processes, including cell proliferation. Oxidative stress serves an important role in the remodeling of arterial vascular tissue in diabetic patients by affecting the proliferation of vascular smooth muscle cells (VSMCs). Salidroside is the primary active component of Rhodiola rosea and has been demonstrated to be an antioxidant with cardio- and vascular-protective effects, in addition to improving glucose metabolism. Therefore, the present study aimed to examine the impact of Salidroside on VSMC proliferation, reactive oxygen species (ROS) generation and mitochondrial dynamics under high glucose conditions and the potential mechanisms involved. The current study used Salidroside and a mitochondrial division inhibitor, specifically of Drp1 (Mdivi-1) to treat VSMCs under high glucose conditions for 24 h and assessed VSMCs proliferation, the state of mitochondrial fission and fusion and the expression level of proteins related to mitochondrial dynamics including dynamin-related protein (Drp1) and mitofusin 2 (Mfn2), ROS level and nicotinamide adenine dinucleotide phosphate oxidase activity. The results of the present study indicate that Salidroside and Mdivi-1 inhibit VSMC proliferation, Drp1 expression and oxidative stress and upregulate Mfn2 expression (all P<0.05). The inhibitive effect on VSMC proliferation may be partly reversed by exogenous ROS. In addition, the inhibitive effect on VSMCs proliferation and oxidative stress may also be in part reversed by Mfn2-siRNA. Collectively, these data suggest that Salidroside inhibits VSMCs proliferation induced by high-glucose and may perform its therapeutic effect via maintaining mitochondrial dynamic homeostasis and regulating oxidative stress level, with Mfn2 as a therapeutic target.

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