Daneshvar Medicine

Daneshvar Medicine

The effect of Troxerutin combined with high intensity interval training on heart injury and expression of antioxidant genes in doxorubicin-induced cardiac toxicity in male rats

Document Type : Original Article

Authors
Aboalghasem Taghavi Holagh 1
Hosein Aabednatanzi 1
Reza Badalzadeh 2
Farshad Ghazalian 3
1 Department of Physical Education and Sports Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.
2 Department of Physiology, School of Medicine and Molecular Medical Research Center and Applied Pharmaceutical Research, Tabriz University of Medical Sciences, Tabriz, Iran.
3 Department of Physical Education and Sports Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
10.22070/daneshmed.2021.13863.1039
Abstract
Background and Objective: Cancers represent an important cause of morbidity and mortality, cause more than 12% of deaths in the world. Doxorubicin (DOX) is an effective drug in the treatment of various cancers whose usage has been limited due to cardiac toxicity. Troxerutin (TRX) is derived from rutin flavonoids and has multiplex pharmacological properties. The present study aimed to investigate the combined effect of troxerutin and high-intensity interval training (HIIT) on DOX-induced cardiac toxicity and the expression of antioxidant genes in rat hearts.
Materials and Methods: Male Wistar rats were randomly divided into five groups (n = 10): 1) Control, 2) DOX, 3) HIIT + DOX, 4) TRX + DOX, and 5) HIIT + TRX + DOX. After the last session of HIIT, the trained and time-matched control rats were injected with DOX (20 mg/kg, ip). The Creatine kinase (CKMB) and Lactate­dehydrogenase (LDH) changes were measured by spectrophotometry and ELISA. Expression of antioxidant genes was measured by Real-Time PCR.
Results: DOX injection increased serum CKMB and LDH in rats in comparison to the control group (p < 0.05) and (P <0.01), respectively. HIIT exercise and troxerutin, alone or in combination, reduced the serum CKMB and LDH levels (p < 0.05) and their combined effect was greater than those of individual treatments (p < 0.01). DOX injection decreased the expression of Nrf2 and Foxo1 antioxidant genes as compared with a control group (P <0.01). HIIT exercise and troxerutin consumption alone increased the expression of the Foxo1 gene as compared with the DOX group (P <0.05) and their combined effect was greater than either alone (P <0.01). HIIT exercise and troxergotTroxerutin consumption alone increased the expression of the Nrf2 gene insignificantly, but their combined effect was significantly increased (P <0.01).
Conclusion: The combined effect of HIIT exercise and troxerutin is a promising strategy to prevent DOX-induced cardiac toxicity and increase the expression of antioxidant genes in rat hearts.
Keywords
Doxorubicin
High-intensity interval training
Troxerutin
Cardiac Toxicity
Antioxidant genes
  1. Tauan Nunes Maia, Gustavo Bento Ribeiro de Araujo, José Antônio Caldas Teixeira, Edmundo de Drummond, Alves Junior, Kátia Pedreira Dias. Cardiotoxicity of Doxorubicin Treatment and Physical Activity: A Systematic Review. Int J Cardiovascular Sciences 2017; 30(1):70-80. DOI: 10.5935/2359-4802.20170004
  2. Li M, Xiongzh G. Ion channels as targets for cancer therapy. Int J Physiol Pathophysiol Pharmacol 2011; 3(2):156-166. PMCID: PMC3134009
  3. Dolinsky VW, Rogan KJ, Sung MM, Zordoky BN, Haykowsky MJ, Young ME, et al. Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. Am J Physiol Endocrinol Metab 2013;305:E243-253. DOI: org/10.1152/ajpendo.00044.2013
  4. Ahmet I, Sawa Y, Iwata K, Matsuda H. Gene transfection of hepatocyte growth factor attenuates cardiac remodeling in the canine heart: A novel gene therapy for cardiomyopathy. J Thorac Cardiovasc Surg2002;124(5):957-63. DOI: org/10.1067/mtc.2002.126655
  5. Koleini N and Kardami E. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget 2017;8 (28):46663-46680. DOI: 10.18632%2Foncotarget.16944
  6. Singal P, Kumar D, Danelisen I, Iliskovic N. Adriamycin-induced heart failure: mechanisms and modulation.  Mol Cell Biochem 2000;207(1-2):77-86. DOI: 10.1023/a:1007094214460
  7. Parra V, Eisner V, Chiong M, Criollo A, Moraga F, Garcia A, et al. Changes in mitochondrial dynamics during ceramide- induced cardiomyocyte early apoptosis. Cardiovasc Res 2008;77:387-397. DOI: 10.1093/cvr/cvm029
  8. Wu S, Zhou F, Zhang Z, Xing D. Mitochondrial oxidative stress causes mitochondrial fragmentation via differential modulation of mitochondrial fission–fusion proteins. FEBS j 2011;278(6):941-54. DOI: 10.1111%2Fj.1742-4658.2011.08010.x
  9. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003; 97(11):2869–79. doi:10.1002/cncr.11407. DOI: 10.1002/cncr.11407
  10. Elwia S, Elnoury H, Muhammad M. Forskolin Effect on FOXO1 Expression and Relatonship of FOXO1 Actvaton to Oxidatve Stress: From Molecular to Therapeutc Strategy. Biomarkers J ISSN 2018;4(2:11):2472-1646. DOI: 10.21767/2472-1646.100049
  11. Narasimhan M, Rajasekaran N. Exercise, Nrf2 and Antioxidant Signaling in Cardiac Aging. Front Physiol 2016; 7:241. doi: 10.3389/fphys.2016.00241
  12. Kavazis AN, Smuder AJ, Powers SK. Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle. Journal of Applied Physiology 2014;117(3):223–30.   doi: 10.1152/japplphysiol.00210.2014
  13. Starnes J. W. and R. P Taylor. Exercise-induced cardioprotection: endogenous mechanisms. Med Medicine & Science in Sports & Exercise 2007;39(9): 1537-1543. DOI: 10.1249/mss.0b013e3180d099d4 
  14. Kavazis A, McClung J, Hood D and Powers S. Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli. American Journal of Physiology-Heart and Circulatory Physiology 2008;294(2): H928-935. DOI: 10.1152/ajpheart.01231.2007
  15. Ascensao A, Ferreira PJ Oliveira and Magalhaes J. Effects of endurance training and acute Doxorubicin treatment on rat heart mitochondrial alterations induced by in vitro anoxia-reoxygenation.Cardiovascular Toxicology 2006;6(3-4):159-172. DOI: 10.1385/ct:6:3:159
  16. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. Journal of Clinical Investigation 2000; Oct;106(7):847-56. DOI: 10.1172/JCI10268
  17. Guiraud T, Nigam A, Gremeaux V, Meyer P, Juneau M, Bosquet L. High-intensity interval training in cardiac rehabilitation. Sports Medicine 2012; 42(7):587-605.  DOI: 10.2165/11631910-000000000-00000
  18. Jarrett CL, D’Lugos AC, Mahmood TN, Gonzales RJ, Hale TM, Carroll CC, et al(2016). Effect of high intensity exercise preconditioning and training on antioxidant enzymes in cardiomyocytes during doxorubicin treatment.FASEB Journal2016;30(1_supplement):lb601. DOI: 10.1096/fasebj.30.1_supplement.lb601
  19. Ebrahimi Kh, Choobineh S, Badalzadeh R, Soori R. Protective Effect of Aerobic High-Intensity Interval Training Against Doxorubicin-Induced Cardiotoxicity in Rats. Journal of Knowledge & Health 2018;13(1). DOI: 10.22100/jkh.v13i3.2040. (Persian)
  20. Zhou S, Starkov A, Froberg MK, Leino RL and Wallace KB. Cumulative and Irreversible Cardiac Mitochondrial Dysfunction Induced by Doxorubicin. Cancer Research 2001;61(2):771–777. DOI:  Published January 2001
  21. whiteside H, Nagabandi A, Jyothidasan A, Brown K, Thormton J. Acute anthracycline induced cardiotoxicity: A rare and reversible cause of acute systolic heart failure. Journals of the American College of Cardiology 2018;71(11):A2356. DOI:10.1016/50735-1097(18)32897-3.
  22. Shirinbayan V and Roshan VD. Pretreatment effect of running exercise on HSP70 and DOXinduced cardiotoxicity. Asian Pacific Journal of Cancer Prevention 2012;13:5849-5855.  DOI: 10.7314/apjcp.2012.13.11.5849
  23. Ebrahimi KH, Choobineh S, Soori R and Badalzadeh R. Cardioprotective Effect of High-Intensity Aerobic Interval Training against Adriamycin-Induced Cardiac Toxicity in Rats. Journal of Clinical Research in Paramedical Science 2019;8(1):e83850. Published online 2019 March 17. DOI: 10.5812/jcrps.83850.
  24. Geetha R, Yogalakshmi B, Sreeja S, Bhavani K, Anuradha CV. Troxerutin suppresses lipid abnormalities in the heart of high-fat-high-fructose diet-fed mice. Molecular and Cellular Biochemistry 2014;387(1-2):123-34. DOI: https://doi.org/10.1007/s11010-013-1877-2
  25. Subastri A, Ramamurthy CH, Suyavaran A, Mareeswaran R, Lokeswara Rao P, Harikrishna M, et al. Spectroscopic and molecular docking studies on the interaction of troxerutin with DNA. International Journal of Biological Macromolecules 2015;78:122-9.  DOI: 10.1016/j.ijbiomac.2015.03.036
  26. Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Current Vascular Pharmacology 2009;7(3):303-308. DOI: 10.2174/157016109788340758
  27. Haram PM, Kemi OJ, Lee SJ, Bendheim M, Al-Share QY, Waldum HL, et al. Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity. Cardiovascular Research 2009;81(4):723-32. DOI: 10.1093/cvr/cvn332
  28. Babri S, Amani M, Mohaddes G, Alihemmati A, Ebrahimi H. Protective effects of troxerutin on β-amyloid (1-42)-induced impairments of spatial learning and memory in rats. Neuropathy 2012;44(5):387-93. doi: 10.22038/IJBMS.2018.28170.6901
  29. Hoydal MA, Wisloff U, Kemi OJ, Ellingsen O. Running speed and maximal oxygen uptake in rats and mice: Practical implications for exercise training. European Journal of Cardiovascular Prevention and Rehabilitation 2007;14(6):753–60. DOI: 10.1097/HJR.0b013e3281eacef1
  30. Ascensão A, Magalhães J, Soares JM, Ferreira R, Neuparth MJ, Marques F, Duarte JA. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. American Journal of Physiology-Heart and Circulatory Physiology 2005;289(2):722-731. DOI: 10.1152/ajpheart.01249.2004 
  31. . Kemp M, Donovan J, Higham H, Hooper J. Biochemical markers of myocardial injury. British Journal of Anaesthesia 2004;93(1):63-73. DOI.org/10.1093/bja/aeh148
  32. Badalzadeh R, Azimi A, Alihemmati A, Yousefi B. Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury. Journal of Physiology and Biochemistry 2017;73:111–120. DOI: 10.1007/s13105-016-0530-4
  33. Asadi M, Shanehbandi D, Mohammadpour H, Hashemzadeh S, Sepehri B. Expression Level of miR-34a in Tumor Tissue from Patients with Esophageal Squamous Cell Carcinoma. Journal of Gastroenterology2018; 1-4. DOI: 10.1007/s12029-018-0060-0
  34. Yavari R, Badalzadeh R, Alipour M, Tabatabae S M. Modulation of hippocampal gene expression of microRNA-146a/microRNA-155-nuclear factor-kappa B inflammatory signaling by troxerutin in healthy and diabetic rats. Indian Journal of Pharmacology 2016; 48(6): 675–680. DOI: 10.4103/0253-7613.194847
  35. Félix DNM. Effects of voluntary physical activity and endurance training on cardiac mitochondrial function of rats sub-chronically treated with doxorubicin [dissertation]. University of Porto; 2013.
  36. Marques-Alexio. Chronic exercise mitigates Doxorubicin-induced cardiac and brain mitochondrial activity, oxidative stress, apoptic signaling, mitochondrial dynamics and quality control. Tese de Doutorento em Atividade Fisica e Saude. Centro de investigacao em Atividade Fisica, Saude e Lazer. Faculdade de Desporto. Universidade do porto 2014.
  37. Marques-Aleixo I, Santos-Alves E, Mariani D, Rizo-Roca D, Padrão AI, RochaRodrigues S, et al. Physical exercise prior and during treatment reduces subchronic doxorubicin-induced mitochondrial toxicity and oxidative stress. Mitochondrion 2015;20:22–33. DOI: 10.1016/j.mito.2014.10.008
  38. Jiang HK, Miao Y, Wang YH, Zhao M, Feng ZH, Yu XJ, et al. Aerobic interval training protects against myocardial infarction‐induced oxidative injury by enhancing antioxidase system and mitochondrial biosynthesis. Clinical and Experimental Pharmacology and Physiology 2014: 41(3):192-201. DOI: 10.1111/1440-1681.12211
  39. Wang L, Gao K,Wang D. Exercise training has restorative potential on myocardial energy metabolism in rats with chronic heart failure. Iranian Journal of Basic Medical Sciences 2018; 21(8):818–23. doi: 10.22038/IJBMS.2018.29294.7076. DOI:  10.22038/IJBMS.2018.29294.7076
  40. Heidarzadeh F, Badalzadeh R and Hatami H. The effect of troxerutin on lipid peroxidation and tissue injury induced by myocardial ischemia reperfusion injury in diabetic rat. Razi Journal of Medical Sciences 2014;21(125):37-45. (Persian)
  41. Badalzadeh R, Layeghzadeh N, Alihemmati A, Mohammadi M. Beneficial Effect of Troxerutin on Diabetes-Induced Vascular Damages in Rat Aorta: Histopathological Alterations and Antioxidation Mechanism.International Journal of Endocrinology and Metabolism 2015;13(2):e25969.DOI: 10.5812/ijem.25969
Daneshvar Medicine
Volume 29, Issue 2 - Serial Number 153
July and August 2021
Pages 79-90