title: Scutellarin inhibits high glucose-induced and hypoxia-mimetic agent-induced angiogenic effects in human retinal endothelial cells through reactive oxygen species/hypoxia-inducible factor-1α/vascular endothelial growth factor pathway.
abstract: Scutellarin inhibits hypoxia-induced and moderately high glucose-induced proliferation and vascular endothelial growth factor (VEGF) expression in human retinal endothelial cells (HRECs); thus, it could be a potential therapy for diabetic retinopathy. However, how scutellarin inhibits VEGF is unknown. In our study, HRECs were treated with high glucose and/or hypoxia-mimetic agent cobalt chloride to stimulate cell proliferation, migration, and angiogenesis, and the effects of scutellarin on these processes were analyzed through cell viability assay, Transwell migration assay and endothelial tube formation assay, respectively. The inhibition of angiogenic factor VEGF by scutellarin was confirmed by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. The mechanisms for VEGF inhibition were examined by luciferase reporter assay, Western blot, immunoprecipitation, and biochemical assays. We found that scutellarin not only concentration-dependently inhibited cell proliferation, migration, and tube formation in HRECs but also decreased their production of VEGF. The reduction of VEGF was due to increased ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α by scutellarin. Furthermore, scutellarin impaired the interaction of HIF-1α with p300, which further decreased the transcriptional activity of HIF-1α. As an inducer of HIF-1α, oxidative stress was attenuated by scutellarin. Our data demonstrate that scutellarin exhibits an antiangiogenic effect via inhibition of oxidative stress, enhancement of HIF-1α degradation, and reduction of VEGF secretion.
authors.affiliation: Departments of *Endocrinology; and †Geriatrics, the First Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Difei
authors.initials: D
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jianqiu
authors.initials: J
authors.lastname: Gu
authors.forename: Huijing
authors.initials: H
authors.lastname: Yang
authors.forename: Nanqi
authors.initials: N
authors.lastname: Liu
authors.forename: Yichen
authors.initials: Y
authors.lastname: Lin
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Shao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D047310:Apigenin / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D005965:Glucuronates / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D005965:Glucuronates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C484876:scutellarin; D003035:Cobalt; D047310:Apigenin; C018021:cobaltous chloride; D005947:Glucose