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Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity

  • Authors:
    • Ling He
    • Yuting Yang
    • Juan Chen
    • Pengtao Zou
    • Juxiang Li
  • View Affiliations / Copyright

    Affiliations: Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Clinical Medicine, Jiangxi Health Vocational College, Nanchang, Jiangxi 330052, P.R. China
    Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 668
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    Published online on: July 20, 2021
       https://doi.org/10.3892/mmr.2021.12307
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Abstract

It has been shown that ferroptosis is involved in doxorubicin (DOX)‑induced cardiotoxicity and that ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) can protect cardiomyocytes from ferroptosis. Thus, the present study aimed to investigate whether ENPP2 could protect cardiomyocytes from DOX‑induced injury by inhibiting ferroptosis. H9c2 cardiomyocytes were exposed to various concentrations (0.625, 1.25, 2.5, 5 or 10 µM) of DOX for different time periods. Cell viability and ENPP2 expression were determined. ENPP2‑overexpressing H9c2 cells were treated with DOX and subsequently cell viability, oxidative stress, autophagy and ferroptosis were measured using the corresponding assays (MTT assay, commercial kits and western blot analysis). Dual‑luciferase reporter and chromatin immunoprecipitation assays, as well as bioinformatics analysis, were applied to detect the interaction between ENPP2 and FoxO4. Following FoxO4 overexpression in H9c2 cells, the aforementioned cellular processes were assessed. The results indicated that ENPP2 expression was downregulated following treatment of the cells with DOX. DOX also led to the decreased cell viability, reduced autophagy and elevated ferroptosis in H9c2 cells, which were notably reversed by ENPP2 overexpression. In addition, FoxO4 bound to the ENPP2 promoter, resulting in inhibition of its expression. Following FoxO4 overexpression in H9c2 cells, further experiments conducted using commercial kits and western blot analysis revealed that FoxO4 overexpression partially inhibited the effects of ENPP2 overexpression on DOX‑induced oxidative stress, autophagy and ferroptosis in H9c2 cells. In conclusion, the data indicated that ENPP2 was transcriptionally regulated by FoxO4 to protect cardiomyocytes from DOX‑induced toxicity by inhibiting ferroptosis. Therefore, specific treatment approaches targeting the FoxO4/ENPP2 axis and ferroptosis may provide potential therapies for alleviating DOX‑induced cardiotoxicity.
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Copy and paste a formatted citation
Spandidos Publications style
He L, Yang Y, Chen J, Zou P and Li J: Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity. Mol Med Rep 24: 668, 2021.
APA
He, L., Yang, Y., Chen, J., Zou, P., & Li, J. (2021). Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity. Molecular Medicine Reports, 24, 668. https://doi.org/10.3892/mmr.2021.12307
MLA
He, L., Yang, Y., Chen, J., Zou, P., Li, J."Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity". Molecular Medicine Reports 24.3 (2021): 668.
Chicago
He, L., Yang, Y., Chen, J., Zou, P., Li, J."Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity". Molecular Medicine Reports 24, no. 3 (2021): 668. https://doi.org/10.3892/mmr.2021.12307
Copy and paste a formatted citation
x
Spandidos Publications style
He L, Yang Y, Chen J, Zou P and Li J: Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity. Mol Med Rep 24: 668, 2021.
APA
He, L., Yang, Y., Chen, J., Zou, P., & Li, J. (2021). Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity. Molecular Medicine Reports, 24, 668. https://doi.org/10.3892/mmr.2021.12307
MLA
He, L., Yang, Y., Chen, J., Zou, P., Li, J."Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity". Molecular Medicine Reports 24.3 (2021): 668.
Chicago
He, L., Yang, Y., Chen, J., Zou, P., Li, J."Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity". Molecular Medicine Reports 24, no. 3 (2021): 668. https://doi.org/10.3892/mmr.2021.12307
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