Mesenchymal stem cells-derived exosomes prevent sepsis-induced myocardial injury by a CircRTN4/miR-497-5p/MG53 pathway

Abstract

Sepsis is a life-threatening organ function dysfunction featured by stimulated oxidative stress and inflammatory responses, in which about 40%–60% of sepsis patients are accompanied with cardiac dysfunction. Mesenchymal stem cells (MSCs)-derived exosomes exert critical roles in the treatment of multiple diseases through transferring non-coding RNAs. Circular RNA (circRNA) is a novel form of functional RNAs that involves in the progression of multiple cardiac pathological condition. Nevertheless, the function of MSCs-derived exosomal circRTN4 in sepsis-induced myocardial injury is still obscure. Significantly, FISH assay demonstrated the location of circRTN4 in cytoplasm of cardiomyocytes. The expression of circRTN4 was reduced in the cardiac tissues from caecal ligation and puncture (CLP) rats and LPS-treated cardiomyocytes. CircRTN4 could be delivered to cardiomyocytes cells via MSCs-derived exosomes. The cardiac injury and apoptosis were induced in the CLP rats and the treatment of MSCs-derived exosomal circRTN4 relieved the phenotypes. MSCs-derived exosomal circRTN4 notably suppressed the upregulated ROS level in the CLP rats. The activity of SOD and GSH was repressed in CLP rats, in which MSCs-derived exosomal circRTN4 rescued the activity in the rats. The upregulated IL-1β, IL-6, and TNF-α levels in CLP rats were reduced by the treatment of MSCs-derived exosomal circRTN4. MSCs-derived exosomal circRTN4 improved cell survival and suppressed apoptosis of LPS-treated cardiomyocytes. CircRTN4 direct interact with miR-497-5p to upregulate MG53 expression in cardiomyocytes. MSCs-derived exosomal circRTN4 relieves LPS-stimulated cardiomyocyte damage via targeting miR-497-5p/MG53 axis. Therefore, we determine that MSCs-derived exosomes prevent sepsis-induced myocardial injury by a circRTN4/miR-497-5p/MG53 pathway. Our data provides novel insight into the regulatory mechanism by which MSCs-derived exosomal circRTN4 regulates sepsis-induced myocardial injury. MSCs-derived exosomal circRTN4 may be applied as a promising therapeutic approach for sepsis-induced myocardial injury.