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Sodium acetate ameliorates doxorubicin-induced cardiac injury via upregulation of Nrf2/HO-1 signaling and downregulation of NFkB-mediated apoptotic signaling in Wistar rats

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Abstract

Despite the effectiveness of doxorubicin (DOX) in the management of a wide range of cancers, a major challenge is its cardio-toxic effect. Oxidative stress, inflammation, and apoptosis are major pathways for the cardiotoxic effect of DOX. On the other hand, acetate reportedly exerts antioxidant, anti-inflammatory, and anti-apoptotic activities. This particular research assessed the impact of acetate on cardiotoxicity induced by DOX. Mechanistically, acetate dramatically inhibited DOX-induced upregulation of xanthine oxidase and uric acid pathway as well as downregulation of Nrf2/HO-1 signaling and its upstream proteins (reduced glutathione peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione, and catalase, glutathione reductase). In addition, acetate markedly attenuated DOX-driven rise inTNF-α, NFkB IL-6 and IL-1β expression, and myeloperoxidase activity. Furthermore, acetate significantly ameliorated DOX-led suppression of Bcl-2 and Ca2+-ATPase activity and upregulation of Bax, caspase 3, and caspase 9 actions. Improved body weight, heart structural integrity, and cardiac function as depicted by cardiac injury markers convoyed these cascades of events. Summarily, the present study demonstrated that acetate protects against DOX-induced cardiotoxicity by upregulating Nrf2/HO-1 signaling and downregulating NFkB-mediated activation of Bax/Bcl-2 and caspase signaling.

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Data availability

The data used to support the findings of the present study are available from the corresponding author upon request.

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Funding

This study was self-funded.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Osun State University, Osogbo, Osun State, Nigeria

    D. H. Adeyemi & O. O. Obembe

  2. Department of Medical Laboratory Sciences, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria

    M. A. Hamed

  3. The Brainwill Laboratories, Osogbo, Osun State, Nigeria

    M. A. Hamed

  4. Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria

    M. A. Hamed & R. E. Akhigbe

  5. Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria

    R. E. Akhigbe

Authors
  1. D. H. Adeyemi
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  2. O. O. Obembe
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  3. M. A. Hamed
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  4. R. E. Akhigbe
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Contributions

Conceptualization and design: ADH, OOO, HMA, and ARE. Data analysis: ADH, OOO, HMA, and ARE. Funding acquisition: ADH, OOO, HMA, and ARE. Investigation: ADH, OOO, HMA, ARE. Methodology: ADH, OOO, HMA, ARE. Project administration: ADH, OOO, HMA, and ARE. Supervision: ADH, OOO, HMA, and ARE. Validation: ADH, OOO, HMA, and ARE. Writing—original draft: ADH, OOO, HMA, and ARE. Writing—review and editing and final approval: ADH, OOO, HMA, and ARE. The authors declare that all data were generated in-house and that no paper mill was used. 

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Correspondence to R. E. Akhigbe.

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Adeyemi, D.H., Obembe, O.O., Hamed, M.A. et al. Sodium acetate ameliorates doxorubicin-induced cardiac injury via upregulation of Nrf2/HO-1 signaling and downregulation of NFkB-mediated apoptotic signaling in Wistar rats. Naunyn-Schmiedeberg's Arch Pharmacol 397, 423–435 (2024). https://doi.org/10.1007/s00210-023-02620-4

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