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The IL-6/STAT Signaling Pathway and PPARα Are Involved in Mediating the Dose-Dependent Cardioprotective Effects of Fenofibrate in 5-Fluorouracil-Induced Cardiotoxicity

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Abstract

Purpose

The cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) is a major complication that challenges their clinical usefulness. Thus there is a critical need to find new protective drugs to defend against these harmful side effects. Up to now, there have been no studies evaluating the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. Therefore, we aimed in the current model to evaluate such an effect of FEN and to explore different mechanisms mediating it.

Methods

We used FEN (25, 50, 100 mg/kg/day) administered orally for 7 days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on the fifth day.

Results

The current study showed that 5FU succeeded in inducing cardiotoxicity, manifested by significantly elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL-6), signal transducer and activator of transcription 4 (STAT4), and caspase-3. Furthermore, the 5FU group showed toxic histopathological changes including marked cardiac damage and a significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC), and peroxisome proliferator-activated receptor alpha (PPARα) expression. FEN reversed 5FU-induced cardiotoxicity by various mechanisms including upregulation of PPARα, inhibition of the IL-6/STAT signaling pathway, and anti-inflammatory, antiapoptotic, and antioxidant properties.

Conclusion

FEN demonstrated a significant cardioprotective effect against 5FU-induced cardiac damage.

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Data Availability

All data are available in Prism files as supplementary material.

Code Availability

Not applicable.

References

  1. Lamberti M, Porto S, Marra M, et al. 5-Fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress. J Exp Clin Cancer Res. 2012;31:60.

    Article  CAS  Google Scholar 

  2. Sara JD, Kaur J, Khodadadi R, et al. 5-Fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1–18.

    Article  Google Scholar 

  3. Wei Bi, Yue Bi, Pengfei Li, Shanshan Hou, Xin Yan, Connor Hensley, Catherine E. Bammert, Yanrong Zhang, K. Michael Gibson, Jingfang Ju, Lanrong Bi, (2018) Indole Alkaloid Derivative B, a Novel Bifunctional Agent That Mitigates 5-Fluorouracil-Induced Cardiotoxicity. ACS Omega 3(11):15850–15864

    Article  CAS  Google Scholar 

  4. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178(5):2623–9.

    Article  CAS  Google Scholar 

  5. Chang H, Zhao F, Xie X, et al. PPARα suppresses Th17 cell differentiation through IL-6/STAT3/RORγt pathway in experimental autoimmune myocarditis. Exp Cell Res. 2019;375(1):22–30.

    Article  CAS  Google Scholar 

  6. Shati AA, El-Kott AF. Acylated ghrelin prevents doxorubicin-induced cardiac intrinsic cell death and fibrosis in rats by restoring IL-6/JAK2/STAT3 signaling pathway and inhibition of STAT1. Naunyn Schmiedeberg's Arch Pharmacol. 2019;392(9):1151–68.

    Article  CAS  Google Scholar 

  7. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374(Pt 1):1–20.

  8. Harrison DA. The Jak/STAT pathway. Cold Spring Harb Perspect Biol. 2012;4(3):a011205.

    Article  Google Scholar 

  9. Kersten S. Integrated physiology and systems biology of PPARα. Mol Metab. 2014;3:354–71.

    Article  CAS  Google Scholar 

  10. Refaie MMM. Upregulation of peroxisome proliferator activated receptor alpha by fenofibrate in induced testicular ischemia reperfusion. Biomed Pharmacother. 2018;98:507–15.

    Article  CAS  Google Scholar 

  11. Al-Asmari AK, Khan AQ, Al-Masri N. Mitigation of 5-fluorouracil-induced liver damage in rats by vitamin C via targeting redox-sensitive transcription factors. Hum Exp Toxicol. 2016;35(11):1203–13.

    Article  CAS  Google Scholar 

  12. Mohamed ET, Safwat GM. Evaluation of cardioprotective activity of Lepidium sativum seed powder in albino rats treated with 5-fluorouracil. Beni –Suef Univ J Basic Appl Sci. 2016;5:208–15.

    Google Scholar 

  13. Rivera-Meza M, Muñoz D, Jerez E, et al. Fenofibrate administration reduces alcohol and saccharin intake in rats: possible effects at peripheral and central levels. Front Behav Neurosci. 2017;11:133.

    Article  Google Scholar 

  14. Sun B, Xie Y, Jiang J, et al. Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia. Lipids Health Dis. 2015;14:27.

    Article  Google Scholar 

  15. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–10.

    Article  CAS  Google Scholar 

  16. Bancroft JD, Gamble M. Theory and practice of histological techniques (Elsevier Health Sciences) 2008; 6th Edition.

  17. Ibrahim MA, Geddawy A, Abdel-Wahab S. Sitagliptin prevents isoproterenol-induced myocardial infarction in rats by modulating nitric oxide synthase enzymes. Eur J Pharmacol. 2018;829:63–9.

    Article  CAS  Google Scholar 

  18. Côté S. Current protocol for light microscopy immunocytochemistry. Immunohistochemistry. 1993;II:148–67.

    Google Scholar 

  19. VanGuilder HD, Vrana KE, Freeman WM. Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques. 2008;44:619–26.

    Article  CAS  Google Scholar 

  20. Ewees MG, Messiha BAS, Abdel-Bakky MS, Bayoumi AMA, Abo-Saif AA. Tempol, a superoxide dismutase mimetic agent, reduces cisplatin-induced nephrotoxicity in rats. Drug Chem Toxicol. 2018:1–8.

  21. Gelen V, Şengül E, Yıldırım S, Atila G. The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Iran J Basic Med Sci. 2018;21(4):404–10.

    PubMed  PubMed Central  Google Scholar 

  22. Desai A, Mohammed T, Patel KN, Almnajam M, Kim AS. 5-Fluorouracil Rechallenge after Cardiotoxicity. Am J Case Rep. 2020;21:e924446.

    Article  Google Scholar 

  23. Durak I, Karaayvaz M, Kavutcu M, et al. Reduced antioxidant defense capacity in myocardial tissue from guinea pigs treated with 5-fluorouracil. J Toxicol Environ Health A. 2000;59:585–9.

    Article  CAS  Google Scholar 

  24. Eskandari MR, Moghaddam F, Shahraki J, Pourahmad J, A comparison of cardiomyocyte cytotoxic mechanisms for 5-fluorouracil and its pro-drug capecitabine. Xenobiotica 2014;1–9.

  25. Aikemu A, Amat N, Yusup A, Shan L, Qi X, Upur H. Attenuation effect of abnormal Savda Munziq on liver and heart toxicity caused by chemotherapy in mice. Exp Ther Med. 2016;12(1):384–90.

    Article  CAS  Google Scholar 

  26. Helmy MM, Helmy MW, El-Mas MM. Additive renoprotection by pioglitazone and fenofibrate against inflammatory, oxidative and apoptotic manifestations of cisplatin nephrotoxicity: modulation by PPARs. PLoS One. 2015;10(11):e0142303.

    Article  Google Scholar 

  27. Rashid S, Ali N, Nafees S, Hasan SK, Sultana S. Mitigation of 5-fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats. Food Chem Toxicol. 2014;66:185–93.

    Article  CAS  Google Scholar 

  28. Refaie MMM, Shehata S, El-Hussieny M, Abdelraheem WM, Bayoumi AMA. Role of ATP-sensitive potassium channel (KATP) and eNOS in mediating the protective effect of nicorandil in cyclophosphamide-induced cardiotoxicity. Cardiovasc Toxicol. 2020;20(1):71–81.

    Article  Google Scholar 

  29. Arab HH, Salama SA, Maghrabi IA. Camel Milk ameliorates 5-fluorouracil-induced renal injury in rats: targeting MAPKs, NF-κB and PI3K/Akt/eNOS pathways. Cell Physiol Biochem. 2018;46(4):1628–42.

    Article  CAS  Google Scholar 

  30. Muhammad RN, Sallam N, El-Abhar HS. Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin. Sci Rep. 2020;10(1):14693.

    Article  CAS  Google Scholar 

  31. Krysiak R, Gilowski W, Szkrobka W, Okopien B. Different effects of fenofibrate on metabolic and cardiovascular risk factors in mixed dyslipidemic women with normal thyroid function and subclinical hypothyroidism. Cardiovasc Ther. 2014;32(6):264–9.

    Article  CAS  Google Scholar 

  32. Jen HL, Yin WH, Chen JW, Lin SJ. Endothelin-1-induced cell hypertrophy in cardiomyocytes is improved by fenofibrate: possible roles of adiponectin. J Atheroscler Thromb. 2017;24(5):508–17.

    Article  CAS  Google Scholar 

  33. Khan V, Sharma S, Bhandari U, Sharma N, Rishi V, Haque SE. Suppression of isoproterenol-induced cardiotoxicity in rats by raspberry ketone via activation of peroxisome proliferator activated receptor-alpha. Eur J Pharmacol. 2019;5(842):157–66.

    Article  Google Scholar 

  34. Wang W, Fang Q, Zhang Z, Wang D, Wu L, Wang Y. PPAR alpha ameliorates doxorubicin-induced cardiotoxicity by reducing mitochondria-dependent apoptosis via regulating MEOX1. Front Pharmacol. 2020;11:528267.

  35. Huang WP, Yin WH, Chen JS, Huang PH, Chen JW, Lin SJ. Fenofibrate attenuates doxorubicin-induced cardiac dysfunction in mice via activating the eNOS/EPC pathway. Sci Rep. 2021;11(1):1159.

    Article  CAS  Google Scholar 

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Acknowledgements

All our thanks and appreciation to Dr. Wedad M. Abdelraheem, Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, El-Minia, Egypt, for helping us in the rt-PCR part.

Funding

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

Author information

Authors and Affiliations

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

    Marwa M. M. Refaie & Walaa Yehia Abdelzaher

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

    Sayed Shehata

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

    Asmaa M. A. Bayoumi

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

    Asmaa M. A. Bayoumi

  5. Department of Histology and Cell biology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Nashwa Fathy Gamal El-Tahawy

Authors
  1. Marwa M. M. Refaie
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  2. Sayed Shehata
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  3. Asmaa M. A. Bayoumi
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  4. Nashwa Fathy Gamal El-Tahawy
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  5. Walaa Yehia Abdelzaher
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Contributions

Dr. Marwa, Dr. Walaa and Dr. Sayed selected the point, performed the experimental part, wrote the manuscript, and submitted it for publication. Dr. Nashwa performed and wrote the histopathology and immunohistochemistry, and revised the manuscript. Dr. Asmaa performed and wrote the part on western blotting and revised the manuscript.

Corresponding author

Correspondence to Marwa M. M. Refaie.

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Ethics

Animal handling, medications, and animal euthanasia 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 the Care and Use of Laboratory Animals. Approval No. 19:3/2021.

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The authors declare that they have no conflict of interest.

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Refaie, M.M.M., Shehata, S., Bayoumi, A.M.A. et al. The IL-6/STAT Signaling Pathway and PPARα Are Involved in Mediating the Dose-Dependent Cardioprotective Effects of Fenofibrate in 5-Fluorouracil-Induced Cardiotoxicity. Cardiovasc Drugs Ther 36, 817–827 (2022). https://doi.org/10.1007/s10557-021-07214-x

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