A Novel Hypoxia-inducible Factor 1α Inhibitor KC7F2 Attenuates Oxygen-induced Retinal Neovascularization.

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  • Additional Information
    • Source:
      Publisher: Association For Research In Vision And Ophthalmology (Arvo) Country of Publication: United States NLM ID: 7703701 Publication Model: Print Cited Medium: Internet ISSN: 1552-5783 (Electronic) Linking ISSN: 01460404 NLM ISO Abbreviation: Invest Ophthalmol Vis Sci Subsets: MEDLINE
    • Publication Information:
      Publication: Brookline Ma : Association For Research In Vision And Ophthalmology (Arvo)
      Original Publication: St. Louis, Mosby.
    • Subject Terms:
      Retinal Neovascularization*/drug therapy ; Retinal Neovascularization*/metabolism ; Retinal Neovascularization*/prevention & control ; Retinopathy of Prematurity*/drug therapy ; Retinopathy of Prematurity*/metabolism ; Retinopathy of Prematurity*/prevention & control; Disulfides/*pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors ; Sulfonamides/*pharmacology; Animals ; Animals, Newborn ; Disease Models, Animal ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Hypoxia ; Infant, Newborn ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic ; Oxygen/metabolism ; Oxygen/toxicity ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A/metabolism
    • Abstract:
      Purpose: KC7F2 is a novel molecule compound that can inhibit the translation of hypoxia-inducible factor 1α (HIF1α). It has been reported to exhibit potential antiangiogenic effect. We hypothesized that KC7F2 could inhibit oxygen-induced retinal neovascularization (RNV). The purpose of this study was to investigate this assumption.
      Methods: Oxygen-induced retinopathy (OIR) models in C57BL/6J mice and Sprague-Dawley rats were used for in vivo study. After intraperitoneal injections of KC7F2, RNV was detected by immunofluorescence and hematoxylin and eosin staining. Retinal inflammation was explored by immunofluorescence. EdU incorporation assay, cell counting kit-8 assay, scratch test, transwell assay, and Matrigel assay were used to evaluate the effect of KC7F2 on the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC) induced by vascular endothelial growth factor (VEGF) in vitro. Protein expression was examined by Western blot.
      Results: KC7F2 treatment (10 mg/kg/d) in OIR mice significantly attenuated pathological neovascularization and decreased the number of preretinal neovascular cell nuclei, without changing the avascular area, which showed the same trends in OIR rats. Consistently, after the KC7F2 intervention (10 µM), cell proliferation was inhibited in VEGF-induced HUVEC, which was in agreement with the trend observed in the retinas of OIR mice. Meanwhile, KC7F2 suppressed VEGF-induced HUVEC migration and tube formation, and decreased the density of leukocytes and microglia colocalizing neovascular areas in the retinas. Moreover, the HIF1α-VEGF pathway activated in retinas of OIR mice and hypoxia-induced HUVEC, was suppressed by KC7F2 treatment.
      Conclusions: The current study revealed that KC7F2 was able to inhibit RNV effectively via HIF1α-VEGF pathway, suggesting that it might be an effective drug for RNV treatment.
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    • Grant Information:
      P30 DK020579 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (Disulfides)
      0 (Hif1a protein, mouse)
      0 (Hypoxia-Inducible Factor 1, alpha Subunit)
      0 (KC7F2 compound)
      0 (Sulfonamides)
      0 (Vascular Endothelial Growth Factor A)
      S88TT14065 (Oxygen)
    • Publication Date:
      Date Created: 20220613 Date Completed: 20220615 Latest Revision: 20221118
    • Publication Date:
      20231215
    • Accession Number:
      PMC9202333
    • Accession Number:
      10.1167/iovs.63.6.13
    • Accession Number:
      35695808