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International Journal of Molecular Medicine
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Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling

  • Authors:
    • Wen Wu
    • Daimin Zhang
    • Daorong Pan
    • Guangfeng Zuo
    • Xiaomin Ren
    • Shaoliang Chen
  • View Affiliations / Copyright

    Affiliations: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Qinhuai, Nanjing 210006, P.R. China
    Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 911-920
    |
    Published online on: February 18, 2016
       https://doi.org/10.3892/ijmm.2016.2493
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Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2), which is a key determinant of the angiogenecic response, is decreased in diabetic mice under oxidative stress. β-transduction repeat-containing protein (β-TrCP) has been reported to participate in VEGFR-2 degradation in thyroid cancer cells. Additionally, glycogen synthase kinase-3β (GSK‑3β) acts as a mediator in the β-TrCP-induced degradation of several proteins. However, the role played by β-TrCP and GSK‑3β in the degradation of VEGFR-2 in endothelial cells where hyperglycemia had been induced was not fully understood. In the present study, we aimed to analyze the mechanisms of VEGFR-2 degradation by studying excess reactive oxygen species (ROS) induced by hyperglycemia or glucose oxidase (GO). Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of glucose (6.6, 19.8 and 33 mM), mannitol (33 mM) and GO (1 U/ml). Angiogenic function, ROS levels, the co-location of VEGFR-2 and β-TrCP were evaluated. Cells were collected for RT-qPCR and western blot analysis. We noted that angiogenesis was impaired upon increasing the glucose concentration. When HUVECs were in a hyperglycemic state, ROS production increased, comparable to exposure to GO; GO catalyzes oxidation of glucose into H2O2 and D-glucono-δ-lactone. Phosphorylated VEGFR-2 was reduced by hyperglycemia while total VEGFR-2 was almost unaltered. However, VEGFR-2 was reduced when directly exposed to ROS, with resultant co-location of β-TrCP and VEGFR-2. Through a co-immunoprecipitation assay, we noted that ubiquitinated VEGFR-2 was significantly augmented by excess ROS. Decreased VEGFR-2 caused by ROS was ameliorated by β-TrCP siRNA, proteasome inhibitor MG132 and GSK‑3β activity inhibitor (lithium chloride and SB216763). We suggest that redundant ROS reduces VEGFR-2 through β-TrCP-mediated VEGFR-2 degradation, which is postulated to be regulated by GSK-3β.
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Copy and paste a formatted citation
Spandidos Publications style
Wu W, Zhang D, Pan D, Zuo G, Ren X and Chen S: Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling. Int J Mol Med 37: 911-920, 2016.
APA
Wu, W., Zhang, D., Pan, D., Zuo, G., Ren, X., & Chen, S. (2016). Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling. International Journal of Molecular Medicine, 37, 911-920. https://doi.org/10.3892/ijmm.2016.2493
MLA
Wu, W., Zhang, D., Pan, D., Zuo, G., Ren, X., Chen, S."Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling". International Journal of Molecular Medicine 37.4 (2016): 911-920.
Chicago
Wu, W., Zhang, D., Pan, D., Zuo, G., Ren, X., Chen, S."Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling". International Journal of Molecular Medicine 37, no. 4 (2016): 911-920. https://doi.org/10.3892/ijmm.2016.2493
Copy and paste a formatted citation
x
Spandidos Publications style
Wu W, Zhang D, Pan D, Zuo G, Ren X and Chen S: Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling. Int J Mol Med 37: 911-920, 2016.
APA
Wu, W., Zhang, D., Pan, D., Zuo, G., Ren, X., & Chen, S. (2016). Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling. International Journal of Molecular Medicine, 37, 911-920. https://doi.org/10.3892/ijmm.2016.2493
MLA
Wu, W., Zhang, D., Pan, D., Zuo, G., Ren, X., Chen, S."Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling". International Journal of Molecular Medicine 37.4 (2016): 911-920.
Chicago
Wu, W., Zhang, D., Pan, D., Zuo, G., Ren, X., Chen, S."Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by β-transduction repeat-containing protein via glycogen synthase kinase-3β signaling". International Journal of Molecular Medicine 37, no. 4 (2016): 911-920. https://doi.org/10.3892/ijmm.2016.2493
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