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Effects of four weeks lasting aerobic physical activity on cardiovascular biomarkers, oxidative stress and histomorphometric changes of heart and aorta in rats with experimentally induced hyperhomocysteinemia

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Abstract

The aim of this study was to examine the effects of hyperhomocysteinemia and aerobic physical activity on changes of cardiovascular biomarkers in sera, oxidative stress in cardiac tissue, and histomorphometric parameters of heart and aorta in rats. Experiments were conducted on male Wistar albino rats organized into four groups (n = 10, per group): C (control group): 0.9% NaCl 0.2 mL/day; H (homocysteine group): homocysteine 0.45 µmol/g b.w./day; CPA (control + physical activity group): 0.9% NaCl 0.2 mL/day and a program of physical activity on a treadmill; and HPA (homocysteine + physical activity group) homocysteine 0.45 µmol/g b.w./day and a program of physical activity on a treadmill. Substances were applied subcutaneously twice a day. Lipid peroxidation and relative activity of Mn-superoxide dismutase isoform were significantly higher in active hyperhomocysteinemic rats in comparison to sedentary animals. Atherosclerotic plaques were detected in aorta samples of active hyperhomocysteinemic rats and also, they had increased left ventricle wall and interventricular septum, and transverse diameter of cardiomyocytes compared to sedentary groups. Aerobic physical activity in the condition of hyperhomocysteinemia can lead to increased oxidative stress in cardiac tissue and changes in histomorphometric parameters of the heart and aorta, as well increased lipid parameters and cardiac damage biomarkers in sera of rats.

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The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

References

  1. Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R, Angayarkanni N (2006) Biochemistry of homocysteine in health and diseases. Indian J Biochem Biophys 43:275–283

  2. McCully KS (2015) Homocysteine and the pathogenesis of atherosclerosis. Expert Rev Clin Pharmacol 8:211–219. https://doi.org/10.1586/17512433.2015.1010516

    Article  CAS  Google Scholar 

  3. Guldener CV, Stehouwer CDA (2007) Homocysteine and large arteries. Adv Cardiol 44:278–301. https://doi.org/10.1159/000096748

    Article  Google Scholar 

  4. Balint B, Kosgei Jepchumba V, Guéant JL, Guéant-Rodriguez RM (2020) Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall. Biochimie 173:100–106. https://doi.org/10.1016/j.biochi.2020.02.012

    Article  CAS  Google Scholar 

  5. Lai WKC, Yin Kan M (2015) Homocysteine-induced endothelial dysfunction. Ann NutrMetab 67:1–12. https://doi.org/10.1159/000437098

    Article  CAS  Google Scholar 

  6. Azad MAK, Huang P, Liu G, Ren W, Teklebrh T, Yan W, Zhou X, Yin Y (2018) Hyperhomocysteinemia and cardiovascular disease in animal model. Amino Acids 50:3–9. https://doi.org/10.1007/s00726-017-2503-5

    Article  CAS  Google Scholar 

  7. Ashfield-Watt PA, Moat SJ, Doshi SN, McDowell IF (2001) Folate, homocysteine, endothelial function and cardiovascular disease. What is the link? Biomed Pharmacother 55:425–433. https://doi.org/10.1016/s0753-3322(01)00125-1

    Article  CAS  Google Scholar 

  8. Son P, Hyperhomocysteinemia LL (2021) StatPearls [Internet]. StatPearls Publishing, Treasure Island

    Google Scholar 

  9. Yuan S, Mason AM, Carter P, Burgess S, Larsson SC (2021) Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study. BMC Med 19:97. https://doi.org/10.1186/s12916-021-01977-8

    Article  CAS  Google Scholar 

  10. Kim J, Kim H, Roh H, Kwon Y (2018) Causes of hyperhomocysteinemia and its pathological significance. Arch Pharm Res 41:372–383. https://doi.org/10.1007/s12272-018-1016-4

    Article  CAS  Google Scholar 

  11. McDowell IFW, Lang D (2000) Homocysteine and endothelial dysfunction: a link with cardiovascular disease. J Nutr 130(2S Suppl):369S-372S. https://doi.org/10.1093/jn/130.2.369S

    Article  CAS  Google Scholar 

  12. McCully KS (2009) Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci 39:219–232

    CAS  Google Scholar 

  13. Ganguly P, Alam SF (2015) Role of homocysteine in the development of cardiovascular disease. Nutr J 14:6. https://doi.org/10.1186/1475-2891-14-6

    Article  CAS  Google Scholar 

  14. Tribouilloy CM, Peltier M, Iannetta Peltier MC, Trojette F, Andrejak M, Lesbre JPM (2000) Plasma homocysteine and severity of thoracic aortic atherosclerosis. Chest 118(6):1685–1689. https://doi.org/10.1378/chest.118.6.1685

    Article  CAS  Google Scholar 

  15. McCully KS, Wilson RB (1975) Homocysteine theory of arteriosclerosis. Atherosclerosis 22(2):215–227. https://doi.org/10.1016/0021-9150(75)90004-0

    Article  CAS  Google Scholar 

  16. Perna AF, Ingrosso D, De Santo NG (2003) Homocysteine and oxidative stress. Amino Acids 25:409–417. https://doi.org/10.1007/s00726-003-0026-8

    Article  CAS  Google Scholar 

  17. Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC (2005) Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol 289:H2649-2656. https://doi.org/10.1152/ajpheart.00548.2005

    Article  CAS  Google Scholar 

  18. Vanzin CS, BrondaniBiancini G, Sitta A, Yasin Wayhs CA, Netto Pereira I, Rockenbach F, Garcia SC, De Souza Wyse AT, Doederlein Schwartz IV, Wajner M, Regla Vargas C (2011) Experimental evidence of oxidative stress in plasma of homocystinuric patients: a possible role for homocysteine. Mol Genet Metab 104:112–117. https://doi.org/10.1016/j.ymgme.2011.06.013

    Article  CAS  Google Scholar 

  19. Esse R, Barroso M, Tavares de Almeida I, Castro R (2019) The contribution of homocysteine metabolism disruption to endothelial dysfunction: state-of-the-art. Int J Mol Sci 20(4):867. https://doi.org/10.3390/ijms20040867

    Article  CAS  Google Scholar 

  20. Ma SC, Hao YJ, Jiao Y, Wang YH, Xu LB, Mao CY, Yang XL, Yang AN, Tian J, Zhang MH, Jin SJ, Xu H, Jiang YD, Zhang HP (2017) Homocysteine-induced oxidative stress through TLR4/NF-κB/DNMT1-mediated LOX-1 DNA methylation in endothelial cells. Mol Med Rep 16(6):9181–9188. https://doi.org/10.3892/mmr.2017.7753

    Article  CAS  Google Scholar 

  21. Kang JY (2011) Copper and homocysteine in cardiovascular diseases. Pharmacol Ther 129(3):321–331. https://doi.org/10.1016/j.pharmthera.2010.11.004

    Article  CAS  Google Scholar 

  22. Resstel LBM, De Andrade CR, Haddad R, Eberlin MN, De Oliveira AM, Corrêa FMA (2008) Hyperhomocysteinaemia-induced cardiovascular changes in rats. Clin Exp Pharmacol Physiol 35(8):949–956. https://doi.org/10.1111/j.1440-1681.2008.04940.x

    Article  CAS  Google Scholar 

  23. Czajkowska A, Lutoslawska G, Mazurek K, Ambroszkiewicz J, Zmijewski P (2011) Plasma homocysteine levels, physical activity and macronutrient intake in young healthy men. Pediatr Endocrinol Diabetes Metab 17:30–34

    CAS  Google Scholar 

  24. Hayward R, Ruangthai R, Karnilaw P, Chicco A, Strange R, McCarty H, Westerlind KC (2003) Attenuation of homocysteine-induced endothelial dysfunction by exercise training. Patophysiology 9(4):207–214. https://doi.org/10.1016/s0928-4680(03)00023-3

    Article  CAS  Google Scholar 

  25. Joubert LM, Manore MM (2006) Exercise, nutrition, and homocysteine. Int J Sport Nutr Exerc Metab 16(4):341–361. https://doi.org/10.1123/ijsnem.16.4.341

    Article  CAS  Google Scholar 

  26. Deminice R, Ribeiro DF, TrevisanFrajacomo FT (2016) The effects of acute exercise and exercise training on plasma homocysteine: a meta-analysis. PLoS ONE 11:e0151653. https://doi.org/10.1371/journal.pone.0151653

    Article  CAS  Google Scholar 

  27. Maroto-Sánchez B, Lopez-Torres O, Palacios G, González-Gross M (2016) What do we know about homocysteine and exercise? A review from the literature. Clin Chem Lab Med 54:1561–1577. https://doi.org/10.1515/cclm-2015-1040

    Article  CAS  Google Scholar 

  28. Pavlikova M, Kovalska M, Tatarkova Z, Sivonova-Kmetova M, Kaplan P, Lehotsky J (2011) Response of secretory pathways Ca2+ ATPase gene expression to hyperhomocysteinemia and/or ischemic preconditioning in rat cerebral cortex and hippocampus. Gen Physiol Biophys 30:S61–S69. https://doi.org/10.4149/gpb_2011_SI1_61

    Article  Google Scholar 

  29. Contarteze RV, de Alencar Mota CS, de Oliveira CA, de Almeida Leme JA, Bottcher LB, de Mello MA, Luciano E (2009) Exercise test and glucose homeostasis in rats treated with alloxan during the neonatal period or fed a high calorie diet. J Diabetes 1:65–72. https://doi.org/10.1111/j.1753-0407.2008.00003.x

    Article  CAS  Google Scholar 

  30. Rouet-Benzineb P, Buhler JM, Dreyfus P, Delcourt A, Dorent R, Perennec J, Crozatier B, Harf A, Lafuma C (1999) Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation. Eur J Heart Fail 1:337–352. https://doi.org/10.1016/s1388-9842(99)00048-3

    Article  CAS  Google Scholar 

  31. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. https://doi.org/10.1016/0003-2697(76)90527-3

    Article  CAS  Google Scholar 

  32. Beers RF Jr, Sizer IW (1952) A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem 195:133–140

    Article  CAS  Google Scholar 

  33. Draper H, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431. https://doi.org/10.1016/0076-6879(90)86135-i

    Article  CAS  Google Scholar 

  34. Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175

    Article  CAS  Google Scholar 

  35. Flohé L, Otting F (1984) Superoxide dismutase assays. Methods Enzymol 105:93–104. https://doi.org/10.1016/s0076-6879(84)05013-8

    Article  Google Scholar 

  36. van Son JA, Smedts F, de Wilde PC, Pijls NH, Wong-Alcala L, Kubat K, Tavilla G, Lacquet LK (1993) Histological study of the internal mammary artery with emphasis on its suitability as a coronary artery bypass graft. Ann Thorac Surg 55:106–113. https://doi.org/10.1016/0003-4975(93)90483-x

    Article  Google Scholar 

  37. Chaouad B, Moudilou EN, Ghoul A, Zerrouk F, Moulahoum A, Othmani-Mecif K, El HadiCherifi M, Exbrayat JM, Benazzoug Y (2019) Hyperhomocysteinemia and myocardial remodeling in the sand rat. Psammomysobesus Acta Histochem 121:823–832. https://doi.org/10.1016/j.acthis.2019.07.008

    Article  CAS  Google Scholar 

  38. Eleftheriadou I, Grigoropoulou P, Moyssakis I, Kokkinos A, Perrea D, Toutouzas K, Katsilambros N, Tentolouris N (2013) The effect of hyperhomocysteinemia on aortic distensibility in healthy individuals. Nutrition 29:876–880. https://doi.org/10.1016/j.nut.2012.12.026

    Article  CAS  Google Scholar 

  39. Steed MM, Tyagi SC (2011) Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid Redox Signal 15:1927–1943. https://doi.org/10.1089/ars.2010.3721

    Article  CAS  Google Scholar 

  40. Carnicer R, Navarro MA, Arbonés-Mainar JM, Arnal C, Surra JC, Acín S, Sarría A, Blanco-Vaca F, Maeda N, Osada J (2007) Genetically based hypertension generated through interaction of mild hypoalphalipoproteinemia and mild hyperhomocysteinemia. J Hypertens 25:1597–1607. https://doi.org/10.1097/HJH.0b013e3281ab6c3d

    Article  CAS  Google Scholar 

  41. Alter P, Rupp H, Rominger MB, Figiel JH, Renz H, Klose KJ, Maisch B (2010) Association of hyperhomocysteinemia with left ventricular dilatation and mass in human heart. Clin Chem Lab Med 48:555–560. https://doi.org/10.1515/CCLM.2010.102

    Article  CAS  Google Scholar 

  42. Joseph J, Joseph L, Shekhawat NS, Devi S, Wang J, Melchert RB, Hauer-Jensen M, Kennedy RH (2003) Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats. Am J Physiol Heart Circ Physiol 285:H679-686. https://doi.org/10.1152/ajpheart.00145.2003

    Article  CAS  Google Scholar 

  43. Weiss N, Heydrick SJ, Postea O, Keller C, Keaney JF Jr, Loscalzo J (2003) Influence of hyperhomocysteinemia on the cellular redox state-impact on homocysteine-induced endothelial dysfunction. Clin Chem Lab Med 41:1455–1461. https://doi.org/10.1515/CCLM.2003.223

    Article  CAS  Google Scholar 

  44. Lehotsky J, Petras M, Kovalska M, Tothova B, Drgova A, Kaplan P (2015) Mechanisms involved in the ischemic tolerance in brain: effect of the homocysteine. Cell Mol Neurobiol 35:7–15. https://doi.org/10.1007/s10571-014-0112-3

    Article  CAS  Google Scholar 

  45. Lubos E, Loscalzo J, Handy DE (2007) Homocysteine and glutathione peroxidase-1. Antioxid Redox Signal 9:1923–1940. https://doi.org/10.1089/ars.2007.1771

    Article  CAS  Google Scholar 

  46. Yuyun MF, Ng LL, Ng GA (2018) Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy? Microvasc Res 119:7–12. https://doi.org/10.1016/j.mvr.2018.03.012

    Article  CAS  Google Scholar 

  47. Barroso M, Kao D, Blom HJ, Tavares de Almeida I, Castro R, Loscalzo J, Handy DE (2016) S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation. Biochim Biophys Acta Mol Basis Dis 1862:82–92. https://doi.org/10.1016/j.bbadis.2015.10.019

    Article  CAS  Google Scholar 

  48. Li T, Yu B, Liu Z, Li J, Ma M, Wang Y, Zhu M, Yin H, Wang X, Fu Y, Yu F, Wang X, Fang X, Sun J, Kong W (2018) Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury. Nat Commun 9:11. https://doi.org/10.1038/s41467-017-02401-7

    Article  CAS  Google Scholar 

  49. Sun T, Ghosh AK, Eren M, Miyata T, Vaughan DE (2019) PAI-1 contributes to homocysteine-induced cellular senescence. Cell Signal 64:109394. https://doi.org/10.1016/j.cellsig.2019.109394

    Article  CAS  Google Scholar 

  50. Derouiche F, Bôle-Feysot C, Naïmi D, Coëffier M (2014) Hyperhomocysteinemia-induced oxidative stress differentially alters proteasome composition and activities in heart and aorta. Biochem Biophys Res Commun 452:740–745. https://doi.org/10.1016/j.bbrc.2014.08.141

    Article  CAS  Google Scholar 

  51. Endo N, Nishiyama K, Otsuka A, Kanouchi H, Taga M, Oka T (2006) Antioxidant activity of vitamin B6 delays homocysteine-induced atherosclerosis in rats. Br J Nutr 95:1088–1093. https://doi.org/10.1079/bjn20061764

    Article  CAS  Google Scholar 

  52. Leng YP, Ma YS, Li XG, Chen RF, Zeng PY, Li XH, Qiu CF, Li YP, Zhang Z, Chen AF (2018) l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia. Br J Pharmacol 175:1157–1172. https://doi.org/10.1111/bph.13920

    Article  CAS  Google Scholar 

  53. Xi H, Zhang Y, Xu Y, Yang WY, Jiang X, Sha X, Cheng X, Wang J, Qin X, Yu J, Ji Y, Yang X, Wang H (2016) Caspase-1 inflammasome activation mediates homocysteine-induced pyrop-apoptosis in endothelial cells. Circ Res 118:1525–1539. https://doi.org/10.1161/CIRCRESAHA.116.308501

    Article  CAS  Google Scholar 

  54. Leng Y, Chen R, Chen R, He S, Shi X, Zhou X, Zhang Z, Chen AF (2020) HMGB1 mediates homocysteine-induced endothelial cells pyroptosis via cathepsin V-dependent pathway. Biochem Biophys Res Commun 532:640–646. https://doi.org/10.1016/j.bbrc.2020.08.091

    Article  CAS  Google Scholar 

  55. Sato K, Nishii T, Sato A, Tatsunami R (2020) Autophagy activation is required for homocysteine-induced apoptosis in bovine aorta endothelial cells. Heliyon 6:e03315. https://doi.org/10.1016/j.heliyon.2020.e03315

    Article  Google Scholar 

  56. Todorovic D, Stojanovic M, Medic A, Gopcevic K, Mutavdzin S, Stankovic S, Djuric D (2021) Four weeks of aerobic training affects cardiac tissue matrix metalloproteinase, lactate dehydrogenase and malate dehydrogenase enzymes activities, and hepatorenal biomarkers in experimental hyperhomocysteinemia in rats. Int J Mol Sci 22:6792. https://doi.org/10.3390/ijms22136792

    Article  CAS  Google Scholar 

  57. Kim YN, Hwang JH, Cho YO (2016) The effects of exercise training and acute exercise duration on plasma folate and vitamin B12. Nurs Res Pract 10:161–166. https://doi.org/10.4162/nrp.2016.10.2.161

    Article  CAS  Google Scholar 

  58. Choi EY, Cho YO (2014) The influence of different durations of aerobic exercise on fuel utilization, lactate level and antioxidant defense system in trained rats. Nutr Res Pract 8:27–32. https://doi.org/10.4162/nrp.2014.8.1.27

    Article  Google Scholar 

  59. Jackson MJ, Vasilaki A, McArdle A (2016) Cellular mechanisms underlying oxidative stress in human exercise. Free Radic Biol Med 98:13–17. https://doi.org/10.1016/j.freeradbiomed.2016.02.023

    Article  CAS  Google Scholar 

  60. Zhao X, Bey EA, Wientjes FB, Cathcart MK (2002) Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. cPLA2 affects translocation but not phosphorylation of p67phox and p47phox. J Biol Chem 277:25385–25392. https://doi.org/10.1074/jbc.M203630200

    Article  CAS  Google Scholar 

  61. Ward CW, Prosser BL, Lederer WJ (2014) Mechanical stretch-induced activation of ROS/RNS signaling in striated muscle. Antioxid Redox Signal 20:929–936. https://doi.org/10.1089/ars.2013.5517

    Article  CAS  Google Scholar 

  62. Gong MC, Arbogast S, Guo Z, Mathenia J, Su W, Reid MB (2006) Calciumindependent phospholipase A2 modulates cytosolic oxidant activity andcontractile function in murine skeletal muscle cells. J Appl Physiol 100:399–405. https://doi.org/10.1152/japplphysiol.00873.2005

  63. Nethery D, Stofan D, Callahan L, DiMarco A, Supinski G (1999) Formation of reactive oxygen species by the contracting diaphragm is PLA2 dependent. J Appl Physiol 87:792–800. https://doi.org/10.1152/jappl.1999.87.2.792

    Article  CAS  Google Scholar 

  64. Powers SK, Deminice R, Ozdemir M, Yoshihara T, Bomkamp MP, Hyatt H (2020) Exercise-induced oxidative stress: friend or foe? J Sport Health Sci 9:415–425. https://doi.org/10.1016/j.jshs.2020.04.001

    Article  Google Scholar 

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Funding

This research was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No. 175043 and No. 200110).

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DD contributed to the study conception, design, organization and funding. Material preparation, data collection and analysis were performed by DT, MS, AM, SS, and MLB. The first draft of the manuscript was written by DT and BK. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Dragan Djuric.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The study has been approved by the Ethical Council for the Welfare of Experimental Animals, Ministry of Agriculture, Forestry and Water Management, Veterinary Directorate, Republic of Serbia No: 323-07-02523/2018-05.

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Todorovic, D., Stojanovic, M., Gopcevic, K. et al. Effects of four weeks lasting aerobic physical activity on cardiovascular biomarkers, oxidative stress and histomorphometric changes of heart and aorta in rats with experimentally induced hyperhomocysteinemia. Mol Cell Biochem 478, 161–172 (2023). https://doi.org/10.1007/s11010-022-04503-3

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