MiR-183-5p overexpression in bone mesenchymal stem cell-derived exosomes protects against myocardial ischemia/reperfusion injury by targeting FOXO1.

ABSTRACT

OBJECTIVE: Exosomes have been suggested to serve as possible drug delivery vehicles due to their nanometer-size range and capability of transferring biological materials to recipient cells. Thus, whether miR-183-5p-overexpressing bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) could protect against myocardial ischemia/reperfusion (MI/R) injury by targeting FOXO1 was investigated. METHODS: Exosomes were isolated from rat BMSCs, and ischemia/reperfusion (I/R) rat models were established. I/R rats were treated with Exo/NC-Exo/miR-183-5p-Exo/anti-miR-183-5p-Exo. Cardiac function, serum biochemical indices, apoptosis, myocardial infarction size, and the expression of miR-183-5p, FOXO1 and cleaved caspase 3 were assessed. Primary cardiomyocytes were isolated to establish hypoxia/reoxygenation (H/R) models to observe the function of miR-183-5p-Exo in vitro. RESULTS: Rats in the I/R group exhibited a decreased left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS) and left ventricular systolic pressure (LVSP) but an increased left ventricular end-diastolic pressure (LVEDP), myocardial infarct size and apoptosis index (AI). In addition, in I/R rats, miR-183-5p expression was decreased, but FOXO1 and cleaved caspase 3 expression was increased. Both Exo and miR-183-5p-Exo improved the above indices in I/R rats, but miR-183-5p-Exo showed better effects. However, anti-miR-183-5p-Exo reversed the protective effect of Exo. FOXO1 was a target gene of miR-183-5p. Experiments in vitro revealed that Exo and miR-183-5p-Exo suppressed apoptosis and oxidative stress injury in H/R-induced cardiomyocytes, whereas overexpressed FOXO1 reversed the protective role of miR-183-5p-Exo. CONCLUSION: BMSC-derived exosomal miR-183-5p could target FOXO1 to reduce apoptosis and oxidative stress in I/R cardiomyocytes and improve cardiac function, thereby protecting against MI/R injury.