Fumarate attenuated doxorubicin-induced cardiac injury through modulation of endothelial nitric oxide synthase expression and transforming growth factor-β1 signaling
DOI:
https://doi.org/10.56782/pps.677Keywords:
Cardiac injury, doxorubicin, fumarate, endothelial nitric oxide synthase, transforming growth factorβ1, troponinAbstract
Doxorubicin (dox) is an anticancer agent with adverse effects, such as cardiac injury. Fumarate, a tricarboxylic acid cycle metabolite, has been shown to ameliorate cardiac injury. This study investigated the possible cardioprotective action of fumarate in dox-induced cardiac injury. Male Wistar rats were divided into four groups (n=8); control (distilled water 10 mL/kg, po), dox (10 mg/kg, ip), dox (10 mg/kg, ip) + fumarate (50 mg/kg, po) and dox (10 mg/kg, ip) + fumarate (100 mg/kg, po). The animals were treated for 10 days and euthanized. Blood was withdrawn, the hearts were excised, and immediately frozen for biochemical and molecular analyses. Fumarate reduced serum levels of troponin-T (57.5 %, p<0.05) at 50 mg/kg and (55 % p<0.05) at 100 mg/kg in the dox group. Malondialdehyde formation was reduced from 69.6±3.6 mmol/mg in the dox group to 52.4±3.4 nmol MDA/mg protein at 50 mg/kg and 39.4±0.9 nmol MDA/mg protein at 100 mg/kg in fumarate-treated dox rats (p<0.001). Similarly, catalase (CAT) (9-fold), superoxide dismutase (SOD) (3-fold), and glutathione peroxidase (GPx) (3-fold) activity, which was significantly decreased in the dox group, was reversed by fumarate at 100 mg/kg. Transforming growth factor (TGF) β1 expression was reduced by fumarate (p<0.001). The expression of endothelial nitric oxide synthase (eNOS) was reduced with the administration of fumarate at 100 mg/kg (26.2±1.6, p<0.001) in dox-treated rats. The data have shown that fumarate ameliorated the dox-induced cardiomyopathy by increasing CAT, SOD, and GPx activities and by a reduction in TGFβ1 and eNOS expression.
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1. Lu, C.W.J.; Gao, C.; Sun, M.; Dong, D.; and Mu, Z. Molecular signaling pathways in doxorubicin-induced nephrotoxicity and potential therapeutic agents. Int. Immunopharmacol. 2025, 144, 113-373. DOI: 10.1016/j.intimp.2024.113373
2. Altun, İ.; Sonkaya, A. The Most Common Side Effects Experienced by Patients Were Receiving First Cycle of Chemotherapy. Iran J. Public Health 2018, 47, 12-18.
3. Boire, A.; Burke, K.; Cox, T.R.; Guise, T.; Jamal-Hanjani, M.; Janowitz, T.; Kaplan, R.; Lee, R.; Swanton, C.; Vander Heiden, M.; Sahai, E. Why do patients with cancer die? Nat. Rev. Cancer. 2024, 24(8), 578-589. DOI: 10.1038/s41568-024-00708-4
4. Hanna, T.P.; Kangolle, A.C. Cancer control in developing countries: using health data and health services research to measure and improve access, quality and efficiency. BMC Int. Health Hum. Rights 2010, 10, 24-34. DOI: 10.1186/1472-698X-10-24
5. Rawat, P.S.; Jaiswal, A.; Khurana, A.; Bhatti, J.; Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed. Pharmacother. 2021, 139, 111-131. DOI: 10.1016/j.biopha.2021.111708
6. Christidi, E.; Brunham, L.R. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis. 2021, 12, Art. No: 339. DOI: 10.1038/s41419-021-03614-x
7. Zhang, J.; Sun, Z.; Lin, N.; Lin, N.; Lu, W.; Huang, X.; Weng, J.; Sun, S.; Zhang, C.; Yang, Q.; Zhou, G.; Guo, H.; Chi, J. Fucoidan from Fucus vesiculosus attenuates doxorubicin-induced acute cardiotoxicity by regulating JAK2/STAT3-mediated apoptosis and autophagy. Biomed. Pharmacother. 2020, 130, 135-148. DOI: 10.1016/j.biopha.2020.110534
8. Dulf, P.L.; Mocan, M.; Coadă, C.A.; Dulf, D.; Moldovan, R.; Baldea, I.; Farcas, A.; Blendea, D.; Filip, A. Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model. Naunyn Schmiedebergs Arch. Pharmacol. 2023, 396, 1105–1115. DOI: 10.1007/s00210-023-02382-z
9. Adeyemi, D.H.; Obembe, O.O.; Hamed, M.A.; Akhigbe, R. 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 Schmiedebergs Arch. Pharmacol. 2024, 397, 423–435. DOI: 10.1007/s00210-023-02620-4
10. Qi, W.; Boliang, W.; Xiaoxi, T.; Guoqiang, F.; Jianbo, X.; Gang, W. Cardamonin protects against doxorubicin-induced cardiotoxicity in mice by restraining oxidative stress and inflammation associated with Nrf2 signaling. Biomed. Pharmacother. 2020, 122, 100-115. DOI: 10.1016/j.biopha.2019.109547
11. Jiang, Y.; Zhang, Q. Catalpol ameliorates doxorubicin induced inflammation and oxidative stress in H9C2 cells through PPAR γ activation. Exp. Ther. Med. 2020, 20, 1003–1011. DOI: 0.3892/etm.2020.8743
12. Ashrafian, H.; Czibik, G,; Bellahcene, M.; ksentijević, D.; Smith, A.; Mitchell, S.; Dodd, M.; Kirwan, J.; Byrne, J.; Ludwig, C.; et al. Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway. Cell Metab. 2012, 15, 361–371. DOI: 10.1016/j.cmet.2012.01.017
13. Hou, E.; Sun, N.; Zhang, F.; Zhao, C.; Usa, K.; Liang, M.; Tian, Z. Malate and Aspartate Increase L-Arginine and Nitric Oxide and Attenuate Hypertension. Cell Rep. 2017, 19, 1631–1639. DOI: 10.1016/j.celrep.2017.04.071
14. Tian, Z.; Liang, M. Renal metabolism and hypertension. Nat. Commun. 2021, 12, 963-973. DOI: 10.1038/s41467-021-21301-5
15. Edosuyi, O.; Choi, M.; Igbe, I.; Oyekan, A. Role of peroxisome proliferator-activated receptor (PPARα) in mediating renoprotective effects of fumarate. J. Pharm. Biores. 2025, 22, 37–44. DOI: 10.4314/jpb.v22i1.4
16. Edosuyi, O.; Igbe, I.; Oyekan, A. Fumarate and its downstream signalling pathways in the cardiorenal system: Recent insights and novel expositions in the etiology of hypertension. Eur. J. Pharmacol. 2023, 961, 176-186. DOI: 10.1016/j.ejphar.2023.176186
17. Renu, K.; Abilash, V.G.; Tirapathi Pichiah, P.B.; Arunachalam, S. Molecular mechanism of doxorubicin-induced cardiomyopathy – An update. Eur. J. Pharmacol. 2018, 818, 241–253. DOI: 10.1016/j.ejphar.2017.10.043
18. Edosuyi, O.; Choi, M.; Igbe, I.; Oyekan, A. Fumarate exerted an antihypertensive effect and reduced kidney injury molecule (KIM)-1 expression in deoxycorticosterone acetate-salt hypertension. Clin. Exp. Hypertens. 2021, 43, 555–564. DOI: 10.1080/10641963.2021.1916943
19. Yilmaz, A.; Yalta, K.; Turgut, OO.; Yilmaz, M.; Ozyol, A.; Kendirlioglu, O.; Karadas, F.; Tandogan, I. Clinical Importance of Elevated CK-MB and Troponin I Levels in Congestive Heart Failure. Adv. Ther. 2006, 23, 1060-1067. DOI: 10.1007/BF02850226
20. Ravkilde, J.; Nissen, H.; Horder, M.; Thygesen, K.; Aaehus, F. Independent Prognostic Value of Serum Creatine Kinase Isoenzyme MB Mass, Cardiac Troponin T and Myosin Light Chain Levels in Suspected Acute Myocardial Infarction Analysis of 28 Months of Follow.Up in 196 Patients. J. Am. Coll. Cardiol. 1995, 25(3), 574-581. DOI: 10.1016/0735-1097(94)00430-X
21. Edosuyi, O.; Omo-Erhabor, A.J. Effects of fumarate on cardiorenal injury markers in normotensive Wistar rats. J. Pharm. Allied Sci. 2024, 21, 4064–4070.
22. Omo-Erhabor, A.J.; Edosuyi, O. Fumarate ameliorated doxorubicin-induced nephrotoxicity: The role of pro-inflammatory cytokines and endothelial nitric oxide synthase signaling pathway. Trop. J. Drug Res. 2024, 1(1), 30-36. DOI: 10.26538/tjdr/v1i1.4
23. Edosuyi, O.; Choi, M.; Edosuyi, V.; Igbe, I.; Oyekan, A. Malate reduced kidney injury molecule (KIM-1) expression and selectively upregulated the renal nitric oxide production in obstructive nephropathy. Bratislava Med. J. 2023, 124, 151–157. DOI: 10.4149/BLL_2023_024
24. Koroliuk, M.A.; Ivanova, L.I.; Maĭorova, I.G.; Tokarev, V. A method of determining catalase activity. Lab. Delo. 1988, 1, 16-19.
25. Bahrami, S.; Shahriari, A.; Tavalla, M.; Azadmanesh, S.; Hamidinejat, H. Blood Levels of Oxidant/Antioxidant Parameters in Rats Infected with Toxoplasma gondii. Oxid. Med. Cell Longev. 2016, 2016, Art. No: 8045969. DOI: 10.1155/2016/8045969
26. Paglia, D.E.; Valentine, W.N.; Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. 1967, 70, 158–69.
27 Ibrahim, M.M.; AL Sahli, A.A.A.; Alaraidh, I.A.; Al-Homaidan, A.; Mostafa, E.; El-Gaaly, G. Assessment of antioxidant activities in roots of Miswak (Salvadora persica) plants grown at two different locations in Saudi Arabia. Saudi J Biol. Sci. 2015, 22, 168–175. DOI: 10.1016/j.sjbs.2014.11.019
28. Olumegbon, L.T.; Lawal, A.O.; Oluyede, D.M.; Adebimpe, M.; Elekofehinti, O.; Umar, H. Hesperetin protects against diesel exhaust particles-induced cardiovascular oxidative stress and inflammation in Wistar rats. Environ. Sci. Pol. Res. 2022, 29, 52574–52589. DOI: 10.1007/s11356-022-19494-3
29. Elekofehinti, O.O.; Lawal, A.O.; Ejelonu, O.C.; Molehin, O.; Famusiwa, C. Involvement of fat mass and obesity gene (FTO) in the anti-obesity action of Annona muricata Annonaceae: in silico and in vivo studies. J. Diabetes Metab. Disord. 2020, 19, 197–204. DOI: 10.1007/s40200-020-00491-7.
30. Baracos, V.E.; Martin, L.; Korc, M.; Guttridge, D.; Fearon, K. Cancer-associated cachexia. Nat. Rev. Dis. Primers 2018, 4, Art. No: 17105. DOI: 10.1038/nrdp.2017.105
31. Hu, C.M.; Chen, Y.H.; Chiang, M.T.; Chau, L. Heme oxygenase-1 inhibits angiotensin II-induced cardiac hypertrophy in vitro and in vivo. Circulation 2004, 110, 309–316. DOI: 10.1161/01.CIR.0000135475.35758.23
32. Rasola, A.; Bernardi, P. Cell Calcium Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis. Cell Cal. 2011, 50, 222–233. DOI: 10.1016/j.ceca.2011.04.007
33. Jiang, X.; Qiao, L.; Feng, X.; Liu, L.; Wei, Q.; Wang, X.; Yu, W.; Qiao, L.; Feng, X.; Liu, L.; Wei, Q.; Wang, X. Rotenone induces nephrotoxicity in rats : oxidative damage and apoptosis. Toxicol. Mech. Methods 2017, 27(7), 528-536. DOI: 10.1080/15376516.2017.1333553
34. Omóbòwálé, T.O.; Oyagbemi, A.A.; Folasire, A.M.; Ajibade, T.; Asenuga, E.; Adejumobi, O.; Ola-Davies, O.; Oyetola, O.; James, G.; Adedapo, A.; Yakubu, M. Ameliorative effect of gallic acid on doxorubicin-induced cardiac dysfunction in rats. J. Basic Clin. Physiol. Pharmacol. 2018, 29, 19–27. DOI: 10.1515/jbcpp-2016-0194
35. Pan, D.S.; Li, B.; Wan, S.L. Evaluation of biomarkers for doxorubicin induced cardiac injury in rats. Exp. Ther. Med. 2022, 24(6), Art. No: 712. DOI: 10.3892/etm.2022.11648
36. Loboda, Y.V.; Korokin, M.V.; Kuznetsov, A.V.; Malorodova, T.; Danilenko, A.; Peresypkina, A.; Gudyrev, T.; Kopeva, O.; Pokrovskaya, T.; Korokina, L.; Khruslova, V.; Nazarenko, V.; Avtina, T.; Deikin, A.; Dolzhikov, A.; Puzanova, T.; Danilenko, L. Novel derivative of nicotinic acid ameliorates doxorubicin-induced cardiac injury via regulation of redox homeostasis. Res. Res. Pharmacol. 2024, 10(3), 85–93. DOI: 10.18413/rrpharmacology.10.514
37. Ahmad, A. The Role of the Endogenous Antioxidant Enzymes and Malondialdehyde in Essential Hypertension. J. Clin. Diagnostic Res. 2013, 7, 987–990. DOI: 10.7860/JCDR/2013/5829.3091
38. Jacob, R.; Khan, M. Cardiac Biomarkers: What Is and What Can Be. Indian J. Cardiovasc. Dis. 2018, 03, 240–244. DOI: 10.1055/s-0039-1679104
39. Kim, K.; Chini, N.; Fairchild, D.G.; Engle, S.; Reagan, W.; Summers, S.; Mirsalis, J. Evaluation of Cardiac Toxicity Biomarkers in Rats from Different Laboratories. Toxicol. Pathol. 2016, 44, 1072–1083. DOI: 10.1177/0192623316668276
40. Chen, P.Y.; Qin, L.; Simons, M. TGFβ signaling pathways in human health and disease. Front. Mol. Biosci. 2023, 10(6), Art. No: 1113061. DOI: 10.3389/fmolb.2023.1113061
41. Jackson, J.W.; Streich Jr, F.C.; Pal, A.; Coricor, G.; Boston, C.; Brueckner, C.; Canonico, K.; Chapron, C.; Cote, S.; Dagbay, K.; Danehy Jr, F.; Kavosi, M.; Kumar, S.; Lin, S.; Littlefield, C.; Looby, K.; Manohar, R.; Martin, C.; Wood, M.; Zawadzka, A.; Wawersik, S.; Nicholis, S. An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis. Sci. Signal. 2024, 17(844), Art. No: eadn6052. DOI: 10.1126/scisignal.adn6052
42. Förstermann, U.; Münzel, T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 2006, 113, 1708–1714. DOI: 10.1161/CIRCULATIONAHA.105.602532
43. Octavia, Y., Tocchetti, C.G.; Gabrielson, K.L.; Janssens, S.; Crijns, H.; Moens, A. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J. Mol. Cell Cardiol. 2012, 52, 1213–1225. DOI: 10.1016/j.yjmcc.2012.03.006.
44. Radi, R. Peroxynitrite, a stealthy biological oxidant. J. Biol. Chem. 2013, 288, 26464–26472. DOI: 10.1074/jbc.r113.472936
45. Pacher, P.; Josehph, S.; Beckman, L.L. Nitric Oxide and Peroxynitrite in Health and Disease PA´. Physiol. Rev. 1995, 87, 315–424. DOI: 10.1152/physrev.00029.2006.
46. Zheng, X.; Tian, Z. Fumarate hydratase as a potential target to ameliorate salt sensitive hypertension. Int. J. Cardiol. Cardiovasc. Dis. 2022, 2(1), 14-16. DOI: 10.46439/cardiology.2.020
47. Anderson, N.M.; Mucka, P.; Kern, J.G.; Kem, J.; Feng, H. The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2018, 9, 216–237. DOI: 10.1007/s13238-017-0451-1
48. Saura, M.; Zaragoza, C.; Herranz, B.; Griera, M.; Diez-Marques, L.; Rodriguez-Puyol, D.; Rodriguez-PuyolM. Nitric oxide regulates transforming growth factor-β signaling in endothelial cells. Circ. Res. 2005, 97, 115–1123. DOI: 10.1161/01.RES.0000191538.76771.66
49. Hasić, S.; Jadrić, R.; Kiseljaković, E.; Mornjaković, Z.; Winterhalter-Jadrić, M. Troponin t and histological characteristics of rat myocardial infarction induced by isoproterenol. Bos. J. Basic Med. Sci. 2007, 7, 212-217. DOI: 10.17305/bjbms.2007.3046
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Copyright (c) 2025 Osaze Edosuyi, Eghosa B. Osagiede, Nosakhare Eguasa, Samuel O. Ayodele, Eze A. Eunice, Elaigwu R. Ojonugba, Vashti Edosuyi, Olusola O. Elekofehinti, Aladuna J. Omo-Erhabor, Ighodaro Igbe
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