OBJECTIVE Diabetes-induced endothelial cell(EC) dysfunction and neovasculariza.tion impairment constitute vascular complications with limited treatment regimens.Transcription factor FOXO1 is a key angiogenic regulator...OBJECTIVE Diabetes-induced endothelial cell(EC) dysfunction and neovasculariza.tion impairment constitute vascular complications with limited treatment regimens.Transcription factor FOXO1 is a key angiogenic regulator and plays a pathologic role in progression of diabetes.The pres.ent study was designed to determine the involvement of FOXO1 in impaired EC function and post-isch.emic neovascularization in diabetes and investigate underlying mechanisms.RESULTS We found that FOXO1-selective inhibitor AS1842856 improved blood flow recovery and capillary density in ischemic hindlimb,and rescued the delay of wound closure with a concomitant augmentation of mean perfusion rate in diabetic mice.In vitro,treatment with AS1842856 or FOXO1 siRNA abrogated high glucose-in.duced apoptosis and ameliorated capillary tube formation in human umbilical vein endothelial cells(HU.VECs).FOXO1 inhibition relieved alterations in mitochondrial networks and significantly suppressed the over production of mitochondrial reactive oxygen species(mtROS) induced by high glucose in ECs.Expression of dynamin-relatedprotein-1(Drp1) and phosphorylation at Ser616,a protein required for mitochondrial fission,were enhanced by hyperglycemia,which could be neutralized by FOXO1 inhibition.Moreover,the transcription of Rho-associated coiled-coil containing protein kinase 1(ROCK1),which phosphorylates Drp1 at Ser616,was shown by luciferase assay to be directly regulated by FOXO1.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and func.tion in ECs,and FOXO1 may serve as a therapeutic target for microvascular complications of diabetes.展开更多
基金supported by National Natural Science Foundation of China(8167348681373405a+3 种基金30901803) Beijing Natural Science Foundation(7172119) Beijing Higher Education Young Elite Teacher Project(YETP0053) Beijing Golden Bridge Seed Capital Project(ZZ16019)
文摘OBJECTIVE Diabetes-induced endothelial cell(EC) dysfunction and neovasculariza.tion impairment constitute vascular complications with limited treatment regimens.Transcription factor FOXO1 is a key angiogenic regulator and plays a pathologic role in progression of diabetes.The pres.ent study was designed to determine the involvement of FOXO1 in impaired EC function and post-isch.emic neovascularization in diabetes and investigate underlying mechanisms.RESULTS We found that FOXO1-selective inhibitor AS1842856 improved blood flow recovery and capillary density in ischemic hindlimb,and rescued the delay of wound closure with a concomitant augmentation of mean perfusion rate in diabetic mice.In vitro,treatment with AS1842856 or FOXO1 siRNA abrogated high glucose-in.duced apoptosis and ameliorated capillary tube formation in human umbilical vein endothelial cells(HU.VECs).FOXO1 inhibition relieved alterations in mitochondrial networks and significantly suppressed the over production of mitochondrial reactive oxygen species(mtROS) induced by high glucose in ECs.Expression of dynamin-relatedprotein-1(Drp1) and phosphorylation at Ser616,a protein required for mitochondrial fission,were enhanced by hyperglycemia,which could be neutralized by FOXO1 inhibition.Moreover,the transcription of Rho-associated coiled-coil containing protein kinase 1(ROCK1),which phosphorylates Drp1 at Ser616,was shown by luciferase assay to be directly regulated by FOXO1.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and func.tion in ECs,and FOXO1 may serve as a therapeutic target for microvascular complications of diabetes.
