Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Molecular mechanism of empagliflozin cardioprotection in 5-fluorouracil (5-FU)-induced cardiotoxicity via modulation of SGLT2 and TNFα/TLR/NF-κB signaling pathway in rats

  • Received : 2023.02.22
  • Accepted : 2023.07.26
  • Published : 2024.01.15
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Abstract

One of the commoly used chemotherapeutic agents is 5-Fluorouracil (5-FU). Unfortunately, the clinical administration of 5-FU is complicated with serious cardiotoxic effects and the safe use becomes an urgent task in cardio-oncology. Till now, there are no studies discussed the role of empagliflozin (EMP) against 5-FU cardiotoxicity. Thus, we investigated this effect and the involved mechanisms in 5-FU induced heart injury. Forty male rats of Wistar albino species were used and divided randomly into four groups. Group I is the control group, group II is EMP given group, group III is 5-FU cardiotoxic group and group IV is 5-FU plus EMP group. 5-FU (150 mg/kg) was administered as a single intraperitoneal (i.p.) dose on 1st day to induce cardiotoxicity with or without EMP (30 mg/kg/d) orally for 5 days. The dose of 5-FU is relevant to the human toxic dose. Our data showed that 5-FU given group caused cardiotoxicity with significant increase of serum cardiac enzymes, toll like receptors, enhancement of nuclear factor kappa B (NF-κB), interleukin1β (IL1β), IL6, myeloid-differentiation-factor 88 (MYD88), heart weight, malondialdehyde (MDA), tumor-necrosis-factor-alpha (TNFα), sodium glucose co-transporter 2 (SGLT2), P53 and caspase3 expression with clear histopathological features of cardiotoxicity. Moreover, there is a significant decrease in reduced glutathione (GSH) and total antioxidant capacity (TAC). Interestingly, co-administration of EMP could ameliorate 5-FU induced biochemical and histopathological changes. This effect may be due to modulation of SGLT2, decreasing inflammation, oxidative stress and apoptosis with downregulation of an essential inflammatory cascade that mediates 5-FU cardiotoxicity; TNFα/TLR/NF-κB.

Keywords

Acknowledgement

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). This research received no external funding.

References

  1. Safarpour S, Safarpour S, Pirzadeh M, Moghadamnia AA, Ebrahimpour A, Shirafkan F, Mansoori R, Kazemi S, Hosseini M (2022) Colchicine ameliorates 5-fluorouracil-induced cardiotoxicity in rats. Oxid Med Cell Longev 2022:6194532. https://doi.org/10.1155/2022/6194532
  2. Ghafouri-Fard S, Abak A, Tondro Anamag F, Shoorei H, Fattahi F, Javadinia SA, Basiri A, Taheri M (2021) 5-Fluorouracil: a narrative review on the role of regulatory mechanisms in driving resistance to this chemotherapeutic agent. Front Oncol 11:658636.https://doi.org/10.3389/fonc.2021.658636
  3. Refaie MMM, Shehata S, Bayoumi AMA, El-Tahawy NFG, Abdelzaher WY (2022) 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. https://doi.org/10.1007/s10557-021-07214-x
  4. Shiga T, Hiraide M (2020) Cardiotoxicities of 5-fluorouracil and other fluoropyrimidines. Curr Treat Options Oncol 21:27. https://doi.org/10.1007/s11864-020-0719-1
  5. Liu T, Zhang L, Joo D, Sun C (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:e17023. https://doi.org/10.1038/sigtrans.2017.23
  6. Xinyong C, Zhiyi Z, Lang H, Peng Y, Xiaocheng W, Ping Z, Liang S (2020) The role of toll-like receptors in myocardial toxicity induced by doxorubicin. Immunol Lett 217:56-64. https://doi.org/10.1016/j.imlet.2019.11.001
  7. Refaie MMM, Abdel-Gaber SA, Rahman SAAE, Hafez SMNA, Khalaf HM (2022) Cardioprotective effects of bosentan in 5-fluorouracil-induced cardiotoxicity. Toxicology 465:153042. https://doi.org/10.1016/j.tox.2021.153042
  8. Al-Taher AY, Morsy MA, Rifaai RA, Zenhom NM, Abdel-Gaber SA (2020) Paeonol attenuates methotrexate-induced cardiac toxicity in rats by inhibiting oxidative stress and suppressing tlr4- induced nf-kappab inflammatory pathway. Mediators Inflamm 2020:8641026. https://doi.org/10.1155/2020/8641026
  9. Ala M (2021) SGLT2 inhibition for cardiovascular diseases, chronic kidney disease, and NAFLD. Endocrinology 162:bqab157. https://doi.org/10.1210/endocr/bqab157
  10. Baris VO, Dincsoy AB, Gedikli E, Zirh S, Muftuoglu S, Erdem A (2021) Empagliflozin significantly prevents the doxorubicininduced acute cardiotoxicity via non-antioxidant pathways. Cardiovasc Toxicol 21:747-758. https://doi.org/10.1007/s12012-021-09665-y
  11. Connelly KA, Zhang Y, Desjardins JF, Nghiem L, Visram A, Batchu SN, Yerra VG, Kabir G, Thai K, Advani A, Gilbert RE (2020) Load-independent effects of empaglifozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction. Cardiovasc Diabetol 1:13. https://doi.org/10.1186/s12933-020-0994-y
  12. Gordon M, Meagher P, Connelly KA (2021) Effect of Empagliflozin and liraglutide on the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome in a rodent model of type 2 diabetes mellitus. Can J Diabetes 45:553-556. https://doi.org/10.1016/j.jcjd.2020.11.003
  13. Quagliariello V, De Laurentiis M, Rea D, Barbieri A, Monti MG, Carbone A, Paccone A, Altucci L, Conte M, Canale ML, Botti G, Maurea N (2021) The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin. Cardiovasc Diabetol 20:150. https://doi.org/10.1186/s12933-021-01346-y
  14. Bugga P, Mohammed SA, Alam MJ, Katare P, Meghwani H, Maulik SK, Arava S, Banerjee SK (2022) Empaglifozin prohibits high-fructose diet-induced cardiac dysfunction in rats via attenuation of mitochondria-driven oxidative stress. Life Sci 307:120862. https://doi.org/10.1016/j.lfs.2022.120862
  15. Katsiki N, Kotsa K, Kotsis V (2020) Empaglifozin effects on cardiac remodeling: re-shaping the future of heart failure prevention. Expert Rev Cardiovasc Ther 18:841-842. https://doi.org/10.1080/14779072.2020.1822069
  16. Ren C, Sun K, Zhang Y, Hu Y, Hu B, Zhao J, He Z, Ding R, Wang W, Liang C (2021) Sodium-glucose cotransporter-2 inhibitor empagliflozin ameliorates sunitinib-induced cardiac dysfunction via regulation of ampk-mtor signaling pathwaymediated autophagy. Front Pharmacol 12:664181. https://doi.org/10.3389/fphar.2021.664181
  17. Russo M, Della Sala A, Tocchetti CG, Porporato PE, Ghigo A (2021) Metabolic aspects of anthracycline cardiotoxicity. Curr Treat Options Oncol 22:18. https://doi.org/10.1007/s11864-020-00812-1
  18. Yurista SR, Sillje HHW, Oberdorf-Maass SU, Schouten EM, Pavez Giani MG, Hillebrands JL, van Goor H, van Veldhuisen DJ, de Boer RA, Westenbrink BD (2019) Sodium-glucose cotransporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail 21:862-873. https://doi.org/10.1002/ejhf.1473
  19. Mohamed ET, Safwat GM (2016) Evaluation of cardioprotective activity of Lepidium sativum seed powder in albino rats treated with 5-fluorouracil. Beni-Suef Univ J Basic Appl Sci 5:208-215. https://doi.org/10.1016/j.bjbas.2016.05.001
  20. Miguel M, Muguerza B, Sanchez E, Delado MA, Recio I, Ramos S, Aleixandre MA (2005) Changes in arterial blood pressure caused in hypertensive rats by long-term intake of milk fermented by Enterococcus faecalis CECT 5728. Br J Nutr 93:36-43. https://doi.org/10.1079/bjn20051450
  21. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Meth Enzymol 52:302-310. https://doi.org/10.1016/s0076-6879(78)52032-6
  22. Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 582:67-78. https://doi.org/10.1016/0304-4165(79)90289-7
  23. Chen Y, Zhang Y, Huo Y, Wang D, Hong Y (2016) Adrenomedullin mediates tumor necrosis factor-alpha-induced responses in dorsal root ganglia in rats. Brain Res 1644:183-191. https://doi.org/10.1016/j.brainres.2016.05.021
  24. Chadha S, Wang L, Hancock WW, Beier UH (2019) Sirtuin-1 in immunotherapy: a janus-headed target. J Leukoc Biol 106:337-343. https://doi.org/10.1002/JLB.2RU1118-422R
  25. El-Agamy DS, Elkablawy MA, Abo-Haded HM (2017) Modulation of cyclophosphamide-induced cardiotoxicity by methyl palmitate. Cancer Chemother Pharmacol 79:399-409. https://doi.org/10.1007/s00280-016-3233-1
  26. Nihon-Yanagi Y, Wakayama M, Tochigi N, Saito F, Ogata H, Shibuya K (2021) Immunohistochemical analysis of tolllike receptors, MyD88, and TRIF in human papillary thyroid carcinoma and anaplastic thyroid carcinoma. J Thyroid Res 2021:4226491. https://doi.org/10.1155/2021/4226491
  27. Kauppila JH, Mattila AE, Karttunen TJ, Salo T (2013) Tolllike receptor 5 (TLR5) expression is a novel predictive marker for recurrence and survival in squamous cell carcinoma of the tongue. Br J Cancer 108:638-643. https://doi.org/10.1038/bjc.2012.589
  28. Peng J, Dong C, Wang C, Li W, Yu H, Zhang M, Zhao Q, Zhu B, Zhang J, Li W, Wang F, Wu Q, Zhou W, Yuan Y, Qiu M, Chen G (2018) Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study. Cancer Commun (Lond) 38:22. https://doi.org/10.1186/s40880-018-0292-1
  29. Desai A, Mohammed T, Patel KN, Almnajam M, Kim AS (2020) 5-Fluorouracil rechallenge after cardiotoxicity. Am J Case Rep 21:e924446. https://doi.org/10.12659/AJCR.924446
  30. Pereira-Oliveira M, Reis-Mendes A, Carvalho F, Remiao F, Bastos ML, Costa VM (2019) Doxorubicin is key for the cardiotoxicity of FAC (5-Fluorouracil + adriamycin + cyclophosphamide) combination in differentiated H9c2 cells. Biomolecules 9:21. https:// doi.org/10.3390/biom9010021
  31. Barary M, Hosseinzadeh R, Kazemi S, Liang JJ, Mansoori R, Sio TT, Hosseini M, Moghadamnia AA (2022) The effect of propolis on 5-fluorouracil-induced cardiac toxicity in rats. Sci Rep 12:8661. https://doi.org/10.1038/s41598-022-12735-y
  32. Luo M, Yan D, Sun Q, Tao J, Xu L, Sun H, Zhao H (2020) Ginsenoside Rg1 attenuates cardiomyocyte apoptosis and inflammation via the TLR4/NF-κB/NLRP3 pathway. J Cell Biochem 121:2994-3004. https://doi.org/10.1002/jcb.29556
  33. Muhammad RN, Sallam N, El-Abhar HS (2020) Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin. Sci Rep 10:14693. https://doi.org/10.1038/s41598-020-71531-8
  34. Khezri S, Sabzalipour T, Jahedsani A, Azizian S, Atashbar S, Salimi A (2020) Chrysin ameliorates aluminum phosphideinduced oxidative stress and mitochondrial damages in rat cardiomyocytes and isolated mitochondria. Environ Toxicol 35:1114-1124. https://doi.org/10.1002/tox.22947
  35. Depetris I, Marino D, Bonzano A, Cagnazzo C, Filippi R, Leone AM, F, (2018) Fluoropyrimidine-induced cardiotoxicity. Crit Rev Oncol Hematol 124:1-10. https://doi.org/10.1016/j.critrevonc.2018.02.002
  36. Kanduri J, More LA, Godishala A, Asnani A (2019) Fluoropyrimidine-associated cardiotoxicity. Cardiol Clin 37:399-405. https://doi.org/10.1016/j.ccl.2019.07.004
  37. Arafah A, Rehman MU, Ahmad A, AlKharfy KM, Alqahtani S, Jan BL, Almatroudi NM (2022) Myricetin (3,3',4',5,5',7-hexahydroxyflavone) prevents 5-fluorouracil-induced cardiotoxicity. ACS Omega 7:4514-4524. https://doi.org/10.1021/acsomega.1c06475
  38. Ehrentraut H, Weber C, Ehrentraut S, Schwederski M, Boehm O, Knuefermann P, Meyer R, Baumgarten G (2011) The toll-like receptor 4-antagonist eritoran reduces murine cardiac hypertrophy. Eur J Heart Fail 13:602-610. https://doi.org/10.1093/eurjhf/hfr035
  39. Ma ZG, Kong CY, Wu HM, Song P, Zhang X, Yuan YP, Deng W, Tang QZ (2022) Toll-like receptor 5 deficiency diminishes doxorubicin-induced acute cardiotoxicity in mice. Theranostics 10:11013-11025. https://doi.org/10.7150/thno.47516
  40. Yu L, Feng Z (2018) The role of toll-like receptor signaling in the progression of heart failure. Mediators Inflamm 2018:9874109. https://doi.org/10.1155/2018/9874109
  41. Refaie MMM, Shehata S, Ibrahim RA, Bayoumi AMA, AbdelGaber SA (2021) Dose-dependent cardioprotective efect 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. https://doi.org/10.1007/s12012-021-09694-7
  42. Lrakaybi A, Laubner K, Zhou Q, Hug MJ, Seufert J (2022) Cardiovascular protection by SGLT2 inhibitors-do anti-inflammatory mechanisms play a role? Mol Metab 64:101549. https://doi.org/10.1016/j.molmet.2022.101549
  43. Sabatino J, De Rosa S, Tamme L, Iaconetti C, Sorrentino S, Polimeni A, Mignogna C, Amorosi A, Spaccarotella C, Yasuda M, Indolfi C (2020) Empagliflozin prevents doxorubicin-induced myocardial dysfunction. Cardiovasc Diabetol 19:66. https://doi.org/10.1186/s12933-020-01040-5
  44. Hu Z, Ju F, Du L, Abbott GW (2021) Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death. Cardiovasc Diabetol 20:199. https://doi.org/10.1186/s12933-021-01392-6
  45. Lee TI, Chen YC, Lin YK, Chung CC, Lu YY, Kao YH, Chen YJ (2019) Empagliflozin attenuates myocardial sodium and calcium dysregulation and reverses cardiac remodeling in streptozotocininduced diabetic rats. Int J Mol Sci 20:1680. https://doi.org/10.3390/ijms20071680
  46. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Bohm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F, EMPEROR-Reduced Trial Investigators (2020) Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 383:1413-1424. https://doi.org/10.1056/NEJMoa2022190
  47. Li C, Zhang J, Xue M, Li X, Han F, Liu X, Xu L, Lu Y, Cheng Y, Li T, Yu X, Sun B, Chen L (2019) SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol 18:15. https://doi.org/10.1186/s12933-019-0816-2
  48. Park SH, Farooq MA, Gaertner S, Bruckert C, Qureshi AW, Lee HH, Benrahla D, Pollet B, Stephan D, Ohlmann P, Lessinger JM, Mayoux E, Auger C, Morel O, Schini-Kerth VB (2020) Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat. Cardiovasc Diabetol 19:19. https://doi.org/10.1186/s12933-020-00997-7
  49. Kolijn D, Pabel S, Tian Y, Lodi M, Herwig M, Carrizzo A, Zhazykbayeva S, Kovacs A, Fulop GA, Falcao-Pires I, Reusch PH, Linthout SV, Papp Z, van Heerebeek L, Vecchione C, Maier LS, Ciccarelli M, Tschope C, Mugge A, Bagi Z, Sossalla S, Hamdani N (2021) Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation. Cardiovasc Res 117:495-507. https://doi.org/10.1093/cvr/cvaa123
  50. Lee HC, Shiou YL, Jhuo SJ, Chang CY, Liu PL, Jhuang WJ, Dai ZK, Chen WY, Chen YF, Lee AS (2019) The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol 18:45. https://doi.org/10.1186/s12933-019-0849-6
  51. Lopaschuk GD, Verma S (2020) Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci 5:632-644. https://doi.org/10.1016/j.jacbts.2020.02.004
  52. Garcia-Ropero A, Santos-Gallego CG, Badimon JJ (2019) SGLT receptors and myocardial ischaemia-reperfusion injury: inhibition of SGLT-1, SGLT-2, or both? Cardiovasc Res 115:1572-1573. https://doi.org/10.1093/cvr/cvz077
  53. Uthman L, Baartscheer A, Schumacher CA, Fiolet JWT, Kuschma MC, Hollmann MW, Coronel R, Weber NC, Zuurbier CJ (2018) Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients. Front Physiol 9:1575. https://doi.org/10.3389/fphys.2018.01575
  54. Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Jancev M, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ (2018) Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia 61:722-726. https://doi.org/10.1007/s00125-017-4509-7
  55. Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, Herrmann J, Lerman A, Grothey A (2018) 5-Fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol 10:11-18. https://doi.org/10.1177/1758835918780140