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Article Open Access

Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads

  • Authors:
    • Michela Pecoraro
    • Barbara Pala
    • Maria Carmela Di Marcantonio
    • Raffaella Muraro
    • Stefania Marzocco
    • Aldo Pinto
    • Gabriella Mincione
    • Ada Popolo
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacy, University of Salerno, I-84084 Fisciano (SA), Italy, Department of Medical, Oral and Biotechnological Sciences, ‘G. d'Annunzio’ University of Chieti‑Pescara, I-66100 Chieti, Italy
    Copyright: © Pecoraro et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1197-1209
    |
    Published online on: July 6, 2020
       https://doi.org/10.3892/ijmm.2020.4669
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Abstract

Oxidative stress is widely accepted as a key factor of doxorubicin (Doxo)‑induced cardiotoxicity. There is evidence to indicate that nitrosative stress is involved in this process, and that Doxo interacts by amplifying cell damage. Mitochondrial connexin 43 (mitoCx43) can confer cardioprotective effects through the reduction of mitochondrial reactive oxygen species production during Doxo‑induced cardiotoxicity. The present study aimed to evaluate the involvement of mitoCx43 in Doxo‑induced nitrosative stress. Rat H9c2 cardiomyoblasts were treated with Doxo in the absence or presence of radicicol, an inhibitor of Hsp90, the molecular chaperone involved in Cx43 translocation to the mitochondria that underlies its role in cardioprotection. FACS analysis and RT‑qPCR revealed that Doxo increased superoxide dismutase, and catalase gene and protein expression. As shown by hypodiploid nuclei and confirmed by western blot analysis, Doxo increased caspase 9 expression and reduced procaspase 3 levels, which induced cell death. Moreover, a significant increase in the activation of the NF‑κB signaling pathway was observed. It is well known that the increased expression of inducible nitric oxide synthase results in nitric oxide overproduction, which then rapidly reacts with hydrogen peroxide or superoxide generated by the mitochondria, to form highly reactive and harmful peroxynitrite, which ultimately induces nitrotyrosine formation. Herein, these interactions were confirmed and increased effects were observed in the presence of radicicol. On the whole, the data of the present study indicate that an interplay between oxidative and nitrosative stress is involved in Doxo‑induced cardiotoxicity, and that both aspects are responsible for the induction of apoptosis. Furthermore, it is demonstrated that the mechanisms that further increase mitochondrial superoxide generation (e.g., the inhibition of Cx43 translocation into the mitochondria) significantly accelerate the occurrence of cell death.
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Copy and paste a formatted citation
Spandidos Publications style
Pecoraro M, Pala B, Di Marcantonio MC, Muraro R, Marzocco S, Pinto A, Mincione G and Popolo A: Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads. Int J Mol Med 46: 1197-1209, 2020.
APA
Pecoraro, M., Pala, B., Di Marcantonio, M.C., Muraro, R., Marzocco, S., Pinto, A. ... Popolo, A. (2020). Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads. International Journal of Molecular Medicine, 46, 1197-1209. https://doi.org/10.3892/ijmm.2020.4669
MLA
Pecoraro, M., Pala, B., Di Marcantonio, M. C., Muraro, R., Marzocco, S., Pinto, A., Mincione, G., Popolo, A."Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads". International Journal of Molecular Medicine 46.3 (2020): 1197-1209.
Chicago
Pecoraro, M., Pala, B., Di Marcantonio, M. C., Muraro, R., Marzocco, S., Pinto, A., Mincione, G., Popolo, A."Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads". International Journal of Molecular Medicine 46, no. 3 (2020): 1197-1209. https://doi.org/10.3892/ijmm.2020.4669
Copy and paste a formatted citation
x
Spandidos Publications style
Pecoraro M, Pala B, Di Marcantonio MC, Muraro R, Marzocco S, Pinto A, Mincione G and Popolo A: Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads. Int J Mol Med 46: 1197-1209, 2020.
APA
Pecoraro, M., Pala, B., Di Marcantonio, M.C., Muraro, R., Marzocco, S., Pinto, A. ... Popolo, A. (2020). Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads. International Journal of Molecular Medicine, 46, 1197-1209. https://doi.org/10.3892/ijmm.2020.4669
MLA
Pecoraro, M., Pala, B., Di Marcantonio, M. C., Muraro, R., Marzocco, S., Pinto, A., Mincione, G., Popolo, A."Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads". International Journal of Molecular Medicine 46.3 (2020): 1197-1209.
Chicago
Pecoraro, M., Pala, B., Di Marcantonio, M. C., Muraro, R., Marzocco, S., Pinto, A., Mincione, G., Popolo, A."Doxorubicin‑induced oxidative and nitrosative stress: Mitochondrial connexin 43 is at the crossroads". International Journal of Molecular Medicine 46, no. 3 (2020): 1197-1209. https://doi.org/10.3892/ijmm.2020.4669
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