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

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.

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

“…And the administration 10.3389/fnmol.2023.1100254 Frontiers in Molecular Neuroscience frontiersin.org of Celastrol reverses the activation of the miR-17-5p/HIF-1α/VEGF signaling pathway which reduces retinal neovascularization by inhibiting the microglial activation and inflammation; the proliferation, migration and tube formation ability of human retinal microvascular endothelial cells are also inhibited in vitro culture (Zhao et al, 2022). In addition, KC7F2, a novel molecular compound, reduces retinal angiogenesis by reducing the co-localization ratio between microglia and neovascularization and inhibits the activation of the HIF1α/VEGF signaling pathway in human umbilical vein endothelial cells (Tang X. et al, 2022).…”

HIF‐1α in cartilage homeostasis, apoptosis, and glycolysis in mice with steroid‐induced osteonecrosis of the femoral head

“…HY‐Y0873), Tween‐80 (Services, cat. GC204001‐100ml) and saline, diluted to the working concentration, and then administered intraperitoneally (10 mg/kg) every other day (Tang et al, 2022).…”