The effects of mid and long-term endurance exercise on heart angiogenesis and oxidative stress

Document Type: Original Article


Department of Sport Sciences, Faculty of Humanities Damghan University, Semnan, Iran


Objective(s): Long-term, irregular endurance exercise may result in disturbance to the angiogenesis of heart muscles and blood supply. The aim of the present study is to evaluate the effects of mid- and long-term endurance exercise on the process of angiogenesis.
Materials and Methods: Eighteen male Wister rats of 220±10 g, were randomly assigned to three groups of 6 rats including: Control, Mid, and Long Group. After the training sessions, the rats were weighed and sacrificed.
Results: In comparison to the Control Group, the both groups, indicated remarkable increase in the weight of heart and significantly higher serum LDH and CK activity (P<0.01). In addition, after the training sessions, weakened antioxidant heart system (TAC, total thiol groups, and GPX activity) and increased oxidative stress markers (MDA and NO) were remarkably observed in Mid Group and particularly in those in the Long Group in comparison to the Control Group (P<0.05). Finally, significant increase in VEGF-B, MEF-2C and MMP-2 gene expression was found for both experimental groups, associated with the up-regulation of ANGPT-1 and HDAC4 in the Mid Group (P<0.05). While the longer exercise period induced significantly upper VEGF-B, MEF-2C, and MMP-2 and significantly lower ANGPT-1 and HDAC4 in the Long Group (P<0.05).    
Conclusion: In this study, higher oxidative status and upper angiogenic gene expression with higher VEGF-B, MEF-2c, and MMP-2 and lower ANGPT-1 and HDAC4 were traced as effects of long-term endurance exercise. These results point to the dis-regulation of blood supply in the presence of angiogenesis resulting from long-term exercise.


Main Subjects

1.Siddiqui NI, Nessa A, Hossain MA. Regular physical exercise: way to healthy life. Mymensingh Med J 2010; 19:154-158.

2.Lee IM, Hsieh CC, Paffenbarger RS. Exercise intensity and longevity in men: The Harvard Alumni Health Study. Jama 1995; 273:1179-1184.

3.Quinn TJ, Sprague HA, Van Huss WD, Olson HW. Caloric expenditure, life status, and disease in former male athletes and non-athletes. Med Sci Sports Exerc 1990; 22:742-750.

4.Han GS. Endurance exercise effects on cardiac hypertrophy in mice. J Phys Therap Sci 2013; 25:1525-1527.

5.Rosano JM, Cheheltani R, Wang B, Vora H, Kiani MF, Crabbe DL. Targeted delivery of VEGF after a myocardial infarction reduces collagen deposition and improves cardiac function. Cardiovasc Eng Technol 2012; 3:237-247.

6.Maiti D, Xu Z, Duh EJ. Vascular endothelial growth factor induces MEF2C and MEF2-dependent activity in endothelial cells. Invest Ophthalmol Vis Sci 2008; 49:3640-3648.

7.Wang Z, Qin G, Zhao TC. Histone deacetylase 4 (HDAC4): mechanism of regulations and biological functions. Epigenomics 2014; 6:139-150.

8.Kim YW, Byzova TV. Oxidative stress in angiogenesis and vascular disease. Blood 2014; 123:625-631.

9.Sjodin B, Westing YH, Apple FS. Biochemical mechanisms for oxygen free radical formation during exercise. Sports Med 1990; 10:236-254.

10.Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Phys rev 2008; 88:1243-1276.

11.Radosinska J, Barancik M, Vrbjar N. Heart failure and role of circulating MMP-2 and MMP-9. Panminerva Med 2017; 59:241-253.

12.Zhu Y, Lee C, Shen F, Du R, Young WL, Yang GY. Angiopoietin-2 facilitates vascular endothelial growth factor-induced angiogenesis in the mature mouse brain. Stroke 2005; 36:1533-1537.

13.Ogonovszky H, Berkes I, Kumagai S, Kaneko T, Tahara S, Goto S, et al. The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain. Neurochem Int 2005; 46:635-640.

14.Farriol M, Rosselló J, Schwartz S. Body surface area in sprague-dawley rats. J Animal Phys Anim Nut 1997; 77:61-65.

15.Bahabadi M, Mohammadalipour A, Karimi J, Sheikh N, Solghi G, Goudarzi F, et al. Hepatoprotective effect of parthenolide in rat model of nonalcoholic fatty liver disease. Immunopharmacol Immunotoxicol 2017; 39:233-242.

16.Hu ML. Measurement of protein thiol groups and glutathione in plasma. Methods Enzymol 1994; 233:380-385.

17.Kalantar GH, Kalantar H, Asadi M, Goudarzi M. Protective effect of hydroalcoholic extract of Lavandula Officinalis L. on gentamicin induced nephrotoxicity in rats. J Babol Univ Med Sci  2016; 18:62-67.

18.Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem 1996; 239:70-76.

19.Malekshah OM, Bahrami AR, Afshari JT, Mosaffa F, Behravan J. Correlation between PXR and ABCG2 patterns of mRNA expression in a MCF7 breast carcinoma cell derivative upon induction by proinflammatory cytokines. DNA cell biol 2011; 30:25-31.

20.Hyatt HW, Smuder AJ, Sollanek KJ, Morton AB, Roberts MD, Kavazis AN. Comparative changes in antioxidant enzymes and oxidative stress in cardiac, fast twitch and slow twitch skeletal muscles following endurance exercise training. Int J Physiol Pathophysiol Pharmacol 2016; 8:160-168.

21.Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis – an overview for clinicians. Critical Care 2005; 9:158-169.

22.Luck RP, Verbin S. Rhabdomyolysis: a review of clinical presentation, etiology, diagnosis, and management. Pediatr Emerg Care 2008; 24:262-268.

23.Baird MF, Graham SM, Baker JS, Bickerstaff GF. Creatine-kinase and exercise-related muscle damage implications for muscle performance and recovery. J Clin Nutr Metab 2012; 2012:13.

24.Brancaccio P, Lippi G, Maffulli N. Biochemical markers of muscular damage. Clin Chem Lab Med 2010; 48:757-767.

25.Chang Q, Miao X, Ju X, Zhu L, Huang C, Huang T, et al. Effects of pulse current on endurance exercise and its anti-fatigue properties in the hepatic tissue of trained rats. PLoS One 2013; 8:e75093.

26.Zamanian M, Hajizadeh MR, Esmaeili Nadimi A, Shamsizadeh A, Allahtavakoli M. Antifatigue effects of troxerutin on exercise endurance capacity, oxidative stress and matrix metalloproteinase-9 levels in trained male rats. Fundam Clin Pharmacol 2017; 31:447-455.

27.Powers SK, Nelson WB, Hudson MB. Exercise-induced oxidative stress in humans: cause and consequences. Free Radic Biol Med 2011; 51:942-950.

28.Borges LS, Dermargos A, da Silva Junior EP, Weimann E, Lambertucci RH, Hatanaka E. Melatonin decreases muscular oxidative stress and inflammation induced by strenuous exercise and stimulates growth factor synthesis. J Pineal Res 2015; 58:166-172.

29.Angeli A, Minetto M, Dovio A, Paccotti P. The overtraining syndrome in athletes: a stress-related disorder. J Endocrinol Invest 2004; 27:603-612.

30.Powers SK, DeRuisseau KC, Quindry J, Hamilton KL. Dietary antioxidants and exercise. J Sports Sci 2004; 22:81-94.

31.Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 2010; 86:236-242.

32.Keramidas ME, Stavrou NAM, Kounalakis SN, Eiken O, Mekjavic IB. Severe hypoxia during incremental exercise to exhaustion provokes negative post-exercise affects. Physiol Behav 2016; 156:171-176.

33.Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 2004; 56:549-580.

34.Ushio-Fukai M. Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 2006; 71:226-235.

35.Wu H, Naya FJ, McKinsey TA, Mercer B, Shelton JM, Chin ER, et al. MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type. The EMBO Journal 2000; 19:1963-1973.

36.Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, et al. Increased vascularization in mice overexpressing angiopoietin-1. Science 1998; 282:468-471.

37.Nykanen AI, Pajusola K, Krebs R, Keranen MA, Raisky O, Koskinen PK, et al. Common protective and diverse smooth muscle cell effects of AAV-mediated angiopoietin-1 and -2 expression in rat cardiac allograft vasculopathy. Circ Res 2006; 98:1373-1380.

38.Webb AH, Gao BT, Goldsmith ZK, Irvine AS, Saleh N, Lee RP, et al. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer 2017; 17:434.

39.Tsukiyama T, Wu C. Chromatin remodeling and transcription. Curr Opin Genet Dev 1997; 7:182-191.

40.Sun X, Wei L, Chen Q, Terek RM. HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity. J Biol Chem 2009; 284:21881-21890.

41.Liu J, Zhou X, Li Q, Zhou SM, Hu B, Hu G-W, et al. Role of phosphorylated HDAC4 in stroke-induced angiogenesis. BioMed Res Int 2017; 2017:2957538.

42.Kwon TG, Zhao X, Yang Q, Li Y, Ge C, Zhao G, et al. Physical and functional interactions between Runx2 and HIF-1α induce vascular endothelial growth factor gene expression. J Cell Biochem 2011; 112:3582-3593.