OBJECTIVE Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens.Recent studies have shown that the imbalance of mitochondrial dynamics was associated with the increased reactive oxygen species(ROS)production in endothelial cells,which is a significant contributor to the microvascular complications of diabetes.The present study was designed to determine the involvement of transcription factor FOXO1in diabetic wound healing and investigate underlying mechanisms.METHODS&RESULTS Impaired mitochondrial networks and increased phosphorylation of dynaminrelated protein-1(Drp1)at ser616,a protein required for mitochondrial fission,were observed in human umbilical vein endothelial cells(HUVECs)24 h after exposure to high concentrations of glucose.Inhibition of FOXO1 by si RNA or by FOXO1 selective inhibitor AS1842856 abrogated high glucos-induced alterations in mitochondrial networks and phosphorylation of Drp1.Treatment with AS1842856 or si RNA of FOXO1 could significantly increase the mitochondrial membrane potential and suppress the overproduction of ROS induced by high glucose.Addition of AS1842856 inhibited glucoseinduced apoptosis,ameliorated capillary tube formation in HUVECs.In vivo,AS1842856 dose-dependently rescued the delay of wound closure in diabetic mice,and5 mg·kg-1of AS1842856 treatment significantly increased the mean perfusion rate.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in endothelial cells,inhibition of FOXO1 rescued the delayed wound healing and improved wound angiogenesis in diabetic mice.
