FOXO1 inhibition potentiates endothelial angiogenic functions in diabetes via suppression of ROCK1/Drp1-mediated mitochondrial fission / 中国药理学与毒理学杂志
Chinese Journal of Pharmacology and Toxicology
; (6): 267-267, 2018.
Article
em Zh
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| ID: wpr-705277
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ABSTRACT
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.
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Zh
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Chinese Journal of Pharmacology and Toxicology
Ano de publicação:
2018
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Article