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Dose-Dependent Cardioprotective Effect of Hemin in Doxorubicin-Induced Cardiotoxicity Via Nrf-2/HO-1 and TLR-5/NF-κB/TNF-α Signaling Pathways

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Abstract

Doxorubicin (DOX) is one of the most widely used chemotherapeutic drugs, but its cardiotoxicity has been shown to be a dose-restricting factor during therapy. Finding new agents for reducing these complications is still in critical need. The current study aimed to evaluate the possible cardioprotective effect of hemin (HEM) in DOX-induced cardiotoxicity and exploring the role of toll like receptor-5/nuclear factor kappa-B/tumor necrosis factor-alpha (TLR-5/NF-κB/TNF-α) and nuclear factor erythroid 2-related factor-2/hemeoxygenase-1 (Nrf-2/HO-1) signaling pathways in mediating such effect. Wistar albino rats were randomly divided into five groups. They were administered DOX by interaperitoneal (i.p.) injection (15 mg/kg) on the 5th day of the experiment with or without HEM in different doses (2.5, 5, 10 mg/kg/day) i.p. for 7 days. Results showed that the DOX group had cardiotoxicity as manifested by a significant increase in cardiac enzymes, malondialdehyde (MDA), TLR-5, NF-κB, TNF-α, and cleaved caspase-3 levels with toxic histopathological changes. Based on these findings, HEM succeeded in reducing DOX-induced cardiotoxicity in a dose-dependent effect by stimulation of Nrf-2/HO-1 and inhibition of TLR-5/NF-κB/TNF-α pathways with subsequent antioxidant, anti-inflammatory, and anti-apoptotic effects.

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Acknowledgements

We'd like to thank Dr. Wedad M. Abdelraheem, Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, El-Minia, Egypt for her generous help in rt-PCR part.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Marwa M. M. Refaie & Seham A. Abdel-Gaber

  2. Department of Cardiology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Sayed Shehata

  3. Department of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Randa Ahmed Ibrahim

  4. Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, 61511, Egypt

    Asmaa M. A. Bayoumi

  5. Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Asmaa M. A. Bayoumi

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Contributions

Dr. MMMR, Dr. SAA-G, and Dr. SS selected the point, performed the experimental part, wrote the manuscript, and sent it for publication. Dr. RAI performed and wrote the histopathology, immunohistochemistry, and revised the manuscript. Dr. AMAB performed and wrote the western blotting part and revised the manuscript.

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Correspondence to Marwa M. M. Refaie.

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Animal handling, medications, and animal sacrifice were carried out following the guidelines for the care of experimental animals and approved by the Institutional Ethical Committee, Faculty of Medicine, Minia University, Egypt according to the NIH Guide for taking care and use of laboratory animals. Approval No. 20:3/2021.

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Refaie, M.M.M., Shehata, S., Ibrahim, R.A. et al. Dose-Dependent Cardioprotective Effect of Hemin in Doxorubicin-Induced Cardiotoxicity Via Nrf-2/HO-1 and TLR-5/NF-κB/TNF-α Signaling Pathways. Cardiovasc Toxicol 21, 1033–1044 (2021). https://doi.org/10.1007/s12012-021-09694-7

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