Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-133a Restrains Myocardial Fibrosis and Epithelial-Mesenchymal Transition in Viral Myocarditis Rats Through Suppressing MAML1.

Myocarditis is a disease characterized by localized or diffuse inflammation of the myocardium without efficient treatment. This study explored the regulatory mechanism of microRNA-133 (miR-133) secreted from bone marrow mesenchymal stem cell-derived exosome (BMSC-Exo) on myocardial fibrosis and epithelial-mesenchymal transition (EMT) in viral myocarditis (VMC) rats through regulating mastermind-like 1 (MAML1). BMSCs in rats were isolated and cultured to identify their immune phenotype and osteogenic and adipogenic ability, and BMSC-Exo were extracted and identified. Exosomes were obtained through ultracentrifugation, which were identified by transmission electron microscope and western blot analysis. The rats were injected with Coxsackie B3 virus for preparation of VMC model, and cardiomyocytes were isolated, cultured and grouped in the same way as animal experiments (NC, Ad-miR-133a, Adas-miR-133a). In vivo and in vitro experiments were conducted to figure out the roles of exosomal miR-133a and MAML1 in inflammation, apoptosis, EMT, fibrosis, and cell viability. The targeting relationship between miR-133a and MAML1 was verified by dual luciferase reporter gene assay. BMSC-Exo raised miR-133a expression in VMC rats and effectively improved the VMC rat cardiac function and myocardial fibrosis, increased cardiomyocyte viability and inhibited the EMT process. Elevated miR-133a in exosomes strengthened the improvements. Silenced miR-133a effectively reversed the effects of BMSC-Exo on VMC rats. miR-133a targeted MAML1. Inhibition of MAML1 improved cardiac function and myocardial fibrosis in VMC rats and could reverse the effect of miR-133a-silenced exosomes on VMC rats. Our study suggests that elevated exosomal miR-133a suppresses myocardial fibrosis and EMT in rats with VMC via down-regulating MAML1, thereby inhibiting the progression of myocarditis.