Skip to main content
Erschienen in: Cardiovascular Drugs and Therapy 5/2022

29.06.2021 | Original Article

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

verfasst von: Marwa M. M. Refaie, Sayed Shehata, Asmaa M. A. Bayoumi, Nashwa Fathy Gamal El-Tahawy, Walaa Yehia Abdelzaher

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 5/2022

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat 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.CrossRef 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.CrossRef
2.
Zurück zum Zitat Sara JD, Kaur J, Khodadadi R, et al. 5-Fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1–18.CrossRef Sara JD, Kaur J, Khodadadi R, et al. 5-Fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1–18.CrossRef
3.
Zurück zum Zitat 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):15850–15864CrossRef 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):15850–15864CrossRef
4.
Zurück zum Zitat Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178(5):2623–9.CrossRef Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178(5):2623–9.CrossRef
5.
Zurück zum Zitat 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.CrossRef 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.CrossRef
6.
Zurück zum Zitat 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.CrossRef 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.CrossRef
7.
Zurück zum Zitat 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. 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.
Zurück zum Zitat Harrison DA. The Jak/STAT pathway. Cold Spring Harb Perspect Biol. 2012;4(3):a011205.CrossRef Harrison DA. The Jak/STAT pathway. Cold Spring Harb Perspect Biol. 2012;4(3):a011205.CrossRef
9.
Zurück zum Zitat Kersten S. Integrated physiology and systems biology of PPARα. Mol Metab. 2014;3:354–71.CrossRef Kersten S. Integrated physiology and systems biology of PPARα. Mol Metab. 2014;3:354–71.CrossRef
10.
Zurück zum Zitat Refaie MMM. Upregulation of peroxisome proliferator activated receptor alpha by fenofibrate in induced testicular ischemia reperfusion. Biomed Pharmacother. 2018;98:507–15.CrossRef Refaie MMM. Upregulation of peroxisome proliferator activated receptor alpha by fenofibrate in induced testicular ischemia reperfusion. Biomed Pharmacother. 2018;98:507–15.CrossRef
11.
Zurück zum Zitat 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.CrossRef 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.CrossRef
12.
Zurück zum Zitat 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. 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.
13.
Zurück zum Zitat 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.CrossRef 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.CrossRef
14.
Zurück zum Zitat Sun B, Xie Y, Jiang J, et al. Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia. Lipids Health Dis. 2015;14:27.CrossRef Sun B, Xie Y, Jiang J, et al. Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia. Lipids Health Dis. 2015;14:27.CrossRef
15.
Zurück zum Zitat Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–10.CrossRef Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–10.CrossRef
16.
Zurück zum Zitat Bancroft JD, Gamble M. Theory and practice of histological techniques (Elsevier Health Sciences) 2008; 6th Edition. Bancroft JD, Gamble M. Theory and practice of histological techniques (Elsevier Health Sciences) 2008; 6th Edition.
17.
Zurück zum Zitat 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.CrossRef 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.CrossRef
18.
Zurück zum Zitat Côté S. Current protocol for light microscopy immunocytochemistry. Immunohistochemistry. 1993;II:148–67. Côté S. Current protocol for light microscopy immunocytochemistry. Immunohistochemistry. 1993;II:148–67.
19.
Zurück zum Zitat VanGuilder HD, Vrana KE, Freeman WM. Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques. 2008;44:619–26.CrossRef VanGuilder HD, Vrana KE, Freeman WM. Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques. 2008;44:619–26.CrossRef
20.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
22.
Zurück zum Zitat Desai A, Mohammed T, Patel KN, Almnajam M, Kim AS. 5-Fluorouracil Rechallenge after Cardiotoxicity. Am J Case Rep. 2020;21:e924446.CrossRef Desai A, Mohammed T, Patel KN, Almnajam M, Kim AS. 5-Fluorouracil Rechallenge after Cardiotoxicity. Am J Case Rep. 2020;21:e924446.CrossRef
23.
Zurück zum Zitat 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.CrossRef 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.CrossRef
24.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.CrossRef 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.CrossRef
26.
Zurück zum Zitat 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.CrossRef 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.CrossRef
27.
Zurück zum Zitat 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.CrossRef 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.CrossRef
28.
Zurück zum Zitat 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.CrossRef 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.CrossRef
29.
Zurück zum Zitat 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.CrossRef 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.CrossRef
30.
Zurück zum Zitat 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.CrossRef 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.CrossRef
31.
Zurück zum Zitat 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.CrossRef 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.CrossRef
32.
Zurück zum Zitat 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.CrossRef 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.CrossRef
33.
Zurück zum Zitat 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.CrossRef 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.CrossRef
34.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.CrossRef 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.CrossRef
Metadaten
Titel
The IL-6/STAT Signaling Pathway and PPARα Are Involved in Mediating the Dose-Dependent Cardioprotective Effects of Fenofibrate in 5-Fluorouracil-Induced Cardiotoxicity
verfasst von
Marwa M. M. Refaie
Sayed Shehata
Asmaa M. A. Bayoumi
Nashwa Fathy Gamal El-Tahawy
Walaa Yehia Abdelzaher
Publikationsdatum
29.06.2021
Verlag
Springer US
Erschienen in
Cardiovascular Drugs and Therapy / Ausgabe 5/2022
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07214-x

Weitere Artikel der Ausgabe 5/2022

Cardiovascular Drugs and Therapy 5/2022 Zur Ausgabe

So beeinflussen Herzinfarkte auf lange Sicht die Sterblichkeit

20.06.2024 ST-Hebungsinfarkt Nachrichten

Wie hoch ist bei Patienten, die nach einem ST-Hebungs-Myokardinfarkt die initiale Hochrisikophase überleben, auf lange Sicht das Sterberisiko? Eine Studie aus Dänemark liefert dazu nun aufschlussreiche Daten.

Protonenpumpenhemmer stoppt Arrhythmie

20.06.2024 Protonenpumpenhemmstoffe Nachrichten

Wenn Nervenfasern aus dem Magen und dem Herzen im Gehirn dicht beieinander liegen, kann auch mal etwas schiefgehen: So lässt sich erklären, weshalb Schmerzen durch einen Magentumor bei einem Mann eine ventrikuläre Extrasystolie auslösen – und PPI diese beenden.

Ob Apixaban nützt oder schadet, entscheidet der CHA2DS2-VASc-Score

20.06.2024 Therapie des Vorhofflimmerns Nachrichten

Patienten mit subklinischem Vorhofflimmern tragen ein erhöhtes Risiko für Schlaganfälle. Da stellt sich die Frage nach einer medikamentösen Antikoagulation. Offenbar hängt es aber vom CHA2DS2-VASc-Score ab, ob die Gabe von Apixaban von Vorteil ist.

Wie SGLT2-Hemmer es schaffen, die Mortalität zu reduzieren

20.06.2024 Kardiologische Therapie Nachrichten

SGLT2-Hemmer verhindern keine Herzinfarkte oder Schlaganfälle. Aber sie reduzieren die kardiovaskuläre Mortalität bei einem breiten Spektrum von Patienten. Wie sie das schaffen, verdeutlicht eine Metaanalyse von Daten aus elf randomisierten Studien.

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.