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

  • Published online on: July 6, 2020     https://doi.org/10.3892/ijmm.2020.4669
  • Pages: 1197-1209
  • Copyright: © Pecoraro et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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.

Related Articles

Journal Cover

September-2020
Volume 46 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

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