Document Type : Research Paper


1 Ph.D. Student of Sport Physiology, Department of Physical Education, Tabriz branch, Islamic Azad University, Tabriz, Iran

2 Assistant Professor of Sport Physiology, Tabriz branch, Islamic Azad University, Tabriz, Iran

3 Assistant Professor of Vet, Tabriz branch, Islamic Azad University, Tabriz, Iran

4 Associate Professor of Sport Physiology, Tabriz branch, Islamic Azad University, Tabriz, Iran

5 Associate Professor of Sport Physiology, Azarbaijan Shahid Madani University, Tabriz, Iran


The aim of this study was to investigate the effects of HIIT and curcumin supplementation on cardiac tissue caspase 3 content and also expression of miR-1 and miR-133 in rats exposed to arsenic. Forty-eight (age: 16 weeks, weight: 340.31 ± 24.77 gr) male rats were randomized into six groups including on Arsenic-Training (HIIT), Arsenic-Curcumin (Curcumin), Arsenic – Training + Curcumin (Concomitant), Arsenic (Arsenic), Ethanol Control and Normal Control (pure water). Arsenic 5 mg/ and Curcumin 15 mg/ were consumed orally for six weeks. HIIT were conducted for six weeks (5 d/w) including on 60 min interval running/session (each interval bout was consisted of 4 min running at 85-90% of v Vo2max with 2 min recovery between work intervals at 50-60% of v Vo2max). Cardiac Caspase 3 and miRNAs expression levels were evaluated by western blot and RT-PCR analysis methods respectively. Cardiac mir-1 expression level (P=0.001) and also caspase 3 content (P=0.001) were higher, however; mir-133 expression level was lower (P=0.001) in the Arsenic group than the Normal Control. While no differences were observed in miR-1(P=0.20) and miR-133 (P=0.45) expressions as well as caspase 3 content (P=0.26) between the HIIT and Arsenic groups; lower caspase 3 content was observed in Curcumin group than the Arsenic counterparts (P=0.001). However, in Concomitant group, there were a lower mir-1 expression (P=0.042) and caspase 3 content (P=0.001) in accompany with a higher mir-133 (P=0.010) expression compared to the Arsenic group. Arsenic exposure predisposes cardiomyocytes to apoptosis via modifications in both miR-1 and miR-133 expressions which is associated with cardiac diseases. While physical training could not fully overcome arsenic toxicity in cardiomyocytes, curcumin supplementation and mostly the concomitant effect have more benefits. However, more research warranted to be done because of the lack of similar evidence and also limitations in this study.


Main Subjects

  1. Singh AP, Goel RK, Kaur T. Mechanisms pertaining to arsenic toxicity. Toxicol Int. 2011;18(2):87-93.
  2. Alamolhodaei NS, Shirani K, Karimi G. Arsenic cardiotoxicity: an overview. Environ Toxicol Pharmacol. 2015;40(3):1005-14.
  3. Shan H, Zhang Y, Cai B, Chen X, Fan Y, Yang L, et al. Upregulation of microRNA-1 and microRNA-133 contributes to arsenic-induced cardiac electrical remodeling. Int J Cardiol. 2013;167(6):2798-805.
  4. van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA, De Windt LJ. Myocyte apoptosis in heart failure. Cardiovasc Res. 2005;67(1):21-9.
  5. Chiong M, Wang Z, Pedrozo Z, Cao D, Troncoso R, Ibacache M, et al. Cardiomyocyte death: mechanisms and translational implications. Cell Death Dis. 2011;2(12):e244.
  6. Mani K. Programmed cell death in cardiac myocytes: strategies to maximize post-ischemic salvage. Heart Fail Rev. 2008;13(2):193-209.
  7. Ghajari H, Hosseini SA, Farsi S. The effect of endurance training along with cadmium consumption on Bcl-2 and Bax gene expressions in heart tissue of rats. Annals of Military and Health Sciences Research. 2019;17(1):e86795.
  8. Zhao Y, Fu J, Gao B. Effects of different intensity exercise training on apoptosis-related microRNAs and the targeted proteins in cardiomyocytes. Chinese Journal of Applied Physiology. 2018;34(1):93-6.
  9. Jiang H-K, Wang Y-H, Sun L, He X, Zhao M, Feng Z-H, et al. Aerobic interval training attenuates mitochondrial dysfunction in rats' post-myocardial infarction: roles of mitochondrial network dynamics. Int J Mol Sci. 2014;15(4):5304-22.
  10. Pace C, Dagda R, Angermann J. Antioxidants Protect against arsenic induced mitochondrial cardio-toxicity. Toxics. 2017;5(4):38-46.
  11. Gorzi A, Ekradi s. The effect of intake duration of curcumin supplementation during strenuous endurance training on GPX activity and MDA levels of liver, heart and skeletal muscle in male Wistar rats. Sport Physiology. 2020 (In Press).
  12. Shehzad A, Lee YS. Molecular mechanisms of curcumin action: Signal transduction. BioFactors. 2013;39(1):27-36.
  13. Ren X, Gaile DP, Gong Z, Qiu W, Ge Y, Zhang C, et al. Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress. Toxicol Appl Pharmacol. 2015;283(3):198-209.
  14. Sturchio E, Colombo T, Boccia P, Carucci N, Meconi C, Minoia C, et al. Arsenic exposure triggers a shift in microRNA expression. Sci Total Environ. 2014;472:672-80.
  15. Li N, Zhou H, Tang Q. miR-133: A Suppressor of cardiac remodeling? Frontiers in Pharmacology. 2018;9:903.
  16. Xu C, Lu Y, Pan Z, Chu W, Luo X, Lin H, et al. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. J Cell Sci. 2007;120(Pt 17):3045-52.
  17. Hemmati AA, Olapour S, Varzi HN, Khodayar MJ, Dianat M, Mohammadian B, et al. Ellagic acid protects against arsenic trioxide–induced cardiotoxicity in rat. Hum Exp Toxicol. 2017;37(4):412-9.
  18. Biswas J, Roy S, Mukherjee S, Sinha D, Roy MJAPjocpA. Indian spice curcumin may be an effective strategy to combat the genotoxicity of arsenic in Swiss albino mice. Asian Pac J Cancer Prev. 2010;11(1):239.
  19. Hoydal M, Wisloff U, Kemi O, Ellindsen O. Running speed and maximal oxygen uptake in rats and mice: practical omplications for exercise training. Eur J Cardiovasc Prev Rehabil. 2007;14(6):753-60.
  20. Waring CD, Vicinanza C, Papalamprou A, Smith AJ, Purushothaman S, Goldspink DF, et al. The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. Eur Heart J. 2012;35(39):2722-31.
  21. Kraljevic J, Marinovic J, Pravdic D, Zubin P, Dujic Z, Wisloff U, et al. Aerobic interval training attenuates remodelling and mitochondrial dysfunction in the post-infarction failing rat heart. Cardiovasc Res. 2013;99(1):55-64.
  22. Hafstad AD, Boardman NT, Lund J, Hagve M, Khalid AM, Wisløff U, et al. High intensity interval training alters substrate utilization and reduces oxygen consumption in the heart. Appl Physiol. 2011;111(5):1235-41.
  23. Hafstad AD, Lund J, Hadler-Olsen E, Höper AC, Larsen TS, Aasum E. High-and moderate-intensity training normalizes ventricular function and mechanoenergetics in mice with diet-induced obesity. Diabetes. 2013;62(7):2287-94.
  24. Liou C-M, Tsai S-C, Kuo C-H, Ting H, Lee S-D. Cardiac Fas-Dependent and Mitochondria-Dependent Apoptosis after Chronic Cocaine Abuse. Int J Mol Sci. 2014;15(4):5988-6001.
  25. Sun L, Sun S, Zeng S, Li Y, Pan W, Zhang Z. Expression of circulating microRNA-1 and microRNA-133 in pediatric patients with tachycardia. Mol Med Rep. 2015;11(6):4039-46.
  26. Ruíz-Vera T, Ochoa-Martínez ÁC, Zarazúa S, Carrizales-Yáñez L, Pérez-Maldonado IN. Circulating miRNA-126, -145 and -155 levels in Mexican women exposed to inorganic arsenic via drinking water. Environ Toxicol Pharmacol. 2019;67:79-86.
  27. Wu X-D, Zeng K, Liu W-L, Gao Y-G, Gong C-S, Zhang C-X, et al. Effect of aerobic exercise on miRNA-TLR4 signaling in atherosclerosis. 2014;35(04):344-50.
  28. Yan B, Wang H, Tan Y, Fu WJCTiMC. microRNAs in Cardiovascular Disease: Small Molecules but Big Roles. Curr Top Med Chem. 2019;19(21):1918-47.
  29. Liu Y, Liang Y, Zhang J-f, Fu W-m. MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications. Exp Cell Res. 2017;354(2):65-70.
  30. Zheng J, Cai Y, Cong H, Zhou JJTMJ. Down Regulation Microrna-1 Can Protect H2O2 injured Cardiomyocytes. Int J Clin Exp Pathol. 2014;(8):737-40.
  31. Li Q, Song X-W, Zou J, Wang G-K, Kremneva E, Li X-Q, et al. Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy. J Cell Sci. 2010;123(14):2444-52.
  32. Karakikes I, Chaanine AH, Kang S, Mukete BN, Jeong D, Zhang S, et al. Therapeutic cardiac‐targeted delivery of miR‐1 reverses pressure overload–induced cardiac hypertrophy and attenuates pathological remodeling. J Am Heart Assoc. 2013;2(2):e000078.
  33. Beck R, Bommarito P, Douillet C, Kanke M, Del Razo LM, García-Vargas G, et al. Circulating miRNAs associated with arsenic exposure. Environ Sci Technol. 2018;52(24):14487-95.
  34. Sassi Y, Avramopoulos P, Ramanujam D, Grüter L, Werfel S, Giosele S, et al. Cardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling. Nat Commun. 2017;8(1):1-11.
  35. Tonevitsky AG, Maltseva DV, Abbasi A, Samatov TR, Sakharov DA, Shkurnikov MU, et al. Dynamically regulated miRNA-mRNA networks revealed by exercise. BMC Physiol. 2013;13(1):9-18.
  36. Bolboli L, Sattari M, Hakimi V. Effect of High Intensity Interval Training and Moderate Intensity Continuous Training on Electrocardiographic Indices in Sedentary Men. Journal of Applied Health Studies in Sport Physiology. 2020;7(2):53-8.
  37. Yang Y, Li Z-h, Liu H, Zhang J. Inhibitory effect of tetramethylpyrazine preconditioning on overload training-induced myocardial apoptosis in rats. Chin J Integr Med. 2015;21(6):423-30.
  38. Afousi AG, Gaeini A, Rakhshan K, Naderi N, Azar AD, Aboutaleb N. Targeting necroptotic cell death pathway by high-intensity interval training (HIIT) decreases development of post-ischemic adverse remodelling after myocardial ischemia/reperfusion injury. J Cell Commun Signal. 2019: 13(2): 255-267.
  39. Gao S, Duan X, Wang X, Dong D, Liu D, Li X, et al. Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food Chem Toxicol. 2013;59:739-47.
  40. Rauf A, Imran M, Orhan IE, Bawazeer S. Health perspectives of a bioactive compound curcumin: A review. Trends Food Sci Technol. 2018;74:33-45.
  41. Lee S-W, Nah S-S, Byon J-S, Ko HJ, Park S-H, Lee S-J, et al. Transient complete atrioventricular block associated with curcumin intake. Int J Cardiol. 2011;150(2):e50-e2.
  42. Pichler G, Grau-Perez M, Tellez-Plaza M, Umans J, Best L, Cole S, et al. Association of arsenic exposure with cardiac geometry and left ventricular function in young adults. Circ Cardiovasc Imaging. 2019;12(5):e009018.
  43. Chowdhury R, van Daalen K. Arsenic: a metal that might break your heart. Circ Cardiovasc Imaging. 2019;12:12:e009185.
  44. Phan NN, Wang C-Y, Lin Y-CJT. The novel regulations of MEF2A, CAMKK2, CALM3, and TNNI3 in ventricular hypertrophy induced by arsenic exposure in rats. Toxicology. 2014;324:123-35.
  45. Nozohour Y, Jalilzadeh-Amin GJJoABR. Histopathological changes and antioxidant enzymes status in oxidative stress induction using Sodium arsenite in rats. Journal of Applies Biotechnology Reports. 2019;6(1):40-4.
  46. Srivastava P, Yadav RS, Chandravanshi LP, Shukla RK, Dhuriya YK, Chauhan LKS, et al. Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats. Toxicol Appl Pharmacol. 2014;279(3):428-40.