HYPERHOMOCYSTEINEMIA AND ISCHEMIC STROKE
https://doi.org/10.21518/2079-701X-2017-10-12-17
Abstract
The article deals with the role of homocysteine in the human body. The amino acid homocysteine is a product of methionine demethylation. When the level of homocysteine increases, it damages the tissue structures of the arteries, initiating the release of cytokine, cyclins and other mediators of the inflammation. Its accumulation results in the loosening of arterial walls, formation of local defects in endothelium, which in turn leads to deposition on the cardiovascular wall of cholesterol and calcium. Hyperhomocysteinemia as a consequence of disturbed homocysteine metabolism is considered an independent factor in the risk of human stroke. The role of neuroprotective therapy in interrupting or decelerating the sequence of damaging biochemical and molecular processes capable of causing irreversible coronary damage to the brain is demonstrated.
About the Authors
N. V. Pizova
Yaroslavl State Medical University
Russian Federation
Russian Federation
MD, Prof.
N. A. Pizo
Yaroslavl State Medical University
Russian Federation
Russian Federation
References
1. Champe P, Harvey R. Biochemistry. Lippincott’s Illustrated Reviews 4th ed. Philadelphia: Lippincott Williams and Wilkins, 2008: 261-276.
2. McCully KS. Chemical Pathology of Homocysteine. IV. Excitotoxicity, Oxidative Stress, Endothelial Dysfunction, and Inflammation. Ann Clin. Lab. Sci,. 2009, 39(3): 219-232.
3. Dietrich-Muszalska A, Malinowska J, Olas B et al. The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients. Neurochem. Res., 2012, 37(5): 1057-62.
4. Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation, 2015, 132: e6-9.
5. Elanchezhian R, Palsamy P, Madson CJ, Lynch DW, Shinohara T. Age-related cataracts: homocysteine coupled endoplasmic reticulum stress and suppression of Nrf2-dependent antioxidant protection. Chem Biol Interact, 2012, 200: 1-10.
6. Zhang D, Fang P, Jiang X, Nelson J, Moore JK, Kruger WD, Berretta RM, Houser SR, Yang X, Wang H. Severe hyperhomocysteinemia promotes bone marrowderived and resident inflammatory monocyte differentiation and atherosclerosis in LDLr/CBS-deficient mice. Circ Res,2012, 111: 37-49.
7. Wang X, Cui L, Joseph J, Jiang B, Pimental D, Handy DE, Liao R, Loscalzo J: Homocysteine induces cardiomyocyte dysfunction and apoptosis through p38 MAPK-mediated increase in oxidant stress. J Mol Cell Cardiol, 2012, 52: 753-760.
8. Zhong C, Xu T, Xu T, Peng Y, Wang A, Wang J, Peng H, Li Q, Geng D, Zhang D, Zhang Y, Zhang Y, Gao X, He J, Groups CI. Plasma Homocysteine and Prognosis of Acute Ischemic Stroke: a GenderSpecific Analysis From CATIS Randomized Clinical Trial. Mol Neurobiol, DOI: 10.1007/s12035-016-9799-0.
9. Han L, Wu Q, Wang C, Hao Y, Zhao J, Zhang L, Fan R, Liu Y, Li R, Chen Z, Zhang T, Chen S, Ma J, Liu S, Peng X, Duan S. Homocysteine, Ischemic Stroke, and Coronary Heart Disease in Hypertensive Patients: A Population-Based, Prospective Cohort Study. Stroke, 2015, 46: 1777-1786.
10. Zhou BS, Bu GY, Li M, Chang BG, Zhou YP: Tagging SNPs in the MTHFR gene and risk of ischemic stroke in a Chinese population. Int J Mol Sci, 2014, 15: 8931-8940.
11. Qin X, Li Y, Yuan H et al. Relationship of MTHFR gene 677C –> T polymorphism, homocysteine, and estimated glomerular filtration rate levels with the risk of new-onset diabetes. Medicine (Baltimore), 2015, 94: e563.
12. Yildiz SH, Ozdemir Erdogan M, Solak M et al. Lack of association between the methylenetetrahydropholate reductase gene A1298C polymorphism and neural tube defects in a Turkish study group. Genet Mol Res, 2016, 15.
13. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet, 2005, 365: 224–232.
14. Dichgans M. Genetics of ischaemic stroke. Lancet Neurol, 2007, 6: 149–161.
15. van Meurs JB, Pare G, Schwartz SM, Hazra A, Tanaka T, Vermeulen SH, Cotlarciuc I, Yuan X, Malarstig A, Bandinelli S, Bis JC, Blom H, Brown MJ, Chen C, Chen YD, Clarke RJ, Dehghan A, Erdmann J, Ferrucci L, Hamsten A, Hofman A, Hunter DJ, Goel A, Johnson AD, Kathiresan S, Kampman E, Kiel DP, Kiemeney LA, Chambers JC, Kraft P, Lindemans J, McKnight B, et al. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. Am J Clin Nutr, 2013, 98: 668-676.
16. Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, Tang G, Wang B, Chen D, He M, Fu J, Cai Y, Shi X, Zhang Y, Cui Y, Sun N, Li X, Cheng X, Wang J, Yang X, Yang T, Xiao C, Zhao G, Dong Q, Zhu D, Wang X, Ge J, Zhao L, Hu D, Liu L, Hou FF, Investigators C. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA, 2015, 313: 1325-1335.
17. Tasdemir S, Erdem HB, Sahin I et al. Correlation with Platelet Parameters and Genetic Markers of Thrombophilia Panel (Factor II g.20210G>A, Factor V Leiden, MTHFR (C677T, A1298C), PAI-1, betaFibrinogen, Factor XIIIA (V34L), Glycoprotein IIIa (L33P)) in Ischemic Strokes. Neuromolecular Med, 2016, 18: 170-176.
18. Ho GY, Eikelboom JW, Hankey GJ et al. Methylenetetrahydrofolate reductase polymorphisms and homocysteine-lowering effect of vitamin therapy in Singaporean stroke patients. Stroke, 2006, 37: 456-460.
19. Nilsson TK, Hurtig-Wennlof A, Sjostrom M, Herrmann W, Obeid R, Owen JR, Zeisel S: Plasma 1-carbon metabolites and academic achievement in 15-yr-old adolescents. FASEB J, 2016, 30: 1683-1688.
20. Mehlig K, Leander K, de Faire U, Nyberg F, Berg C, Rosengren A, Bjorck L, Zetterberg H, Blennow K, Tognon G, Toren K, Strandhagen E, Lissner L, Thelle D. The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism. Heart, 2013, 99: 1761-1765.
21. van Beynum IM, Smeitink JA, den Heijer M, te Poele Pothoff MT, Blom HJ: Hyperhomocysteinemia: a risk factor for ischemic stroke in children. Circulation, 1999, 99: 2070-2072.
22. Perna AF, Ingrosso D, De Santo NG. Homocysteine and oxidative stress. Amino Acids, 2003, 25(3–4): 409-417.
23. Markus C, Stuhlinger PS, Tsao Jeng-Horng Her, Kimoto M et al. Homocysteine Impairs the Nitric Oxide Synthase Pathway. Circulation, 2001, 104: 2569-2575.
24. Karolczak K, Olas B. Mechanism of Action of Homocysteine and Its Thiolactone in Hemostasis System. Physiology, 2009, 58: 623-633.
25. Liao D, Tan H, Hui R, Wang H. Hyperhomocysteinemia decreasescirculating high-density lipoprotein by inhibiting apolipoprotein A-Iprotein synthesis and enhancing HDL cholesterol clearance. Circ. Res., 2006, 99: 598-606.
26. Loscalo J. The oxidant stress of hyperhomocysteinemia. J. Clin. Invest., 1996, 98: 5-7.
27. Aygul R, Kotan D, Yildirim A, Ulvi H, Akcay F. Plasma and cerebrospinal fluid homocysteine, nitric oxide and malondialdehyde levels in acute ischemic stroke: possible role of free radicals in the development of brain injury. Eur. J. Gen. Med., 2008, 5(2): 57-63.
28. Shirodaria C, Antoniades C, Lee J, Moat SJ. Global improvement of vascular function and redox state with low-dose folic acid: implicationsfor folate therapy in patients with coronary artery disease. Circulation, 2007, 115: 2262-2270.
29. Seshadri S et al. Association of Plasma Homocysteine Levels with Subclinical Brain Injury: Cerebral Volumes, White Matter Hyperintensity and Silent Brain Infarcts on Volumetric MRI in the Framingham Offspring Study. Arch. Neurol., 2008, 65(5): 642-649.
30. Vermeer SE, Van Dijk EJ, Koudstaal PJ, Oudkerk M, Hofman A, Clarke R, Breteler MM. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Annals of neurology, 2002, 51(3): 285-289.
31. Wang H, Fan D, Zhang H, Fu Y, Zhang J, Shen Y. Serum level ofhomocysteine is correlated to carotid artery atherosclerosis in Chinesewith ischemic stroke. Neurol. Res., 2006, 28: 25-30.
32. Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, Hinchey JA, Howard VJ, Jauch EC, Levine SR, Meschia JF, Moore WS, Nixon JV, Pearson TA. Guidelines for the primary prevention of stroke. A guideline for bhealthcare professionals from the American Heart Association/ AmericanStroke Association. Stroke, 2010: 6.
33. Meng R, Li ZY, Ji X, Ding Y, Meng S, Wang X. Antithrombin III associated with fibrinogen predicts the risk of cerebral ischemic stroke. Clin. Neurol. Neurosurg., 2011, 113(5): 380-386.
34. Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb. Haemost., 2005, 94(5): 907-15.
35. Williams KT, Schalinske KL. Homocysteine metabolism and its relation to health and disease. Biofactors, 2010, 36: 19-24.
36. Zhang F, Slungaarg A, Vercellotti GM, Iadecola C. Superoxide-dependent cerebrovascular effects of homocysteine. Am. J. Physiol,. 1998, 274: 1704-11.
37. Schneede J, Refsum H, Ueland PM. Biological and environmental determinants of plasma homocysteine. Semin Thromb Hemost, 2000, 26(3): 263-79.
38. Bots ML, Launer LJ, Lindemans J et al. Homocysteine and short term risk of myocardial infarction and stroke in the elderly. Arch. Intern. Med., 1999, 159: 38–44.
39. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet, 2007, 369: 1876-1882.
40. Graham IM, Daly LE, Refsum HM et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA, 1997, 277(22): 1775-81.
41. Refsum H, Ueland PM, Nygard O, and Vollset SE. Homocysteine and cardiovascular disease. Annu. Rev. Med., 1998, 49: 31–62.
42. Steele ML, Fuller S, Maczurek AE, Kersaitis C, Ooi L, and Münch G. Chronic inflammation alters production and release of glutathione and related thiols in human U373 astroglial cells. Cell. Mol. Neurobiol., 2013, 33: 19–30.
43. Kwon HM, Lee YS, Bae HJ, Kang DW. Homocysteine as a predictor of early neurological deterioration in acute ischemic stroke. Stroke, 2014, 45: 871–873.
44. Petras M, Tatarkova Z, Kovalska M, Mokra D, Dobrota D, Lehotsky J, et al. Hyperhomocysteinemia as a risk factor for the neuronal system disorders. J. Physiol. Pharmacol., 2014, 65: 15–23.
45. Williams SR, Yang Q, Chen F, Liu X, Keene KL, Jacques P et al. Genomics and Randomized Trials Network, Framingham Heart Study. Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke. PLoS Genet, 2014, 10: e1004214. doi: 10.1371/journal.pgen.1004214.
46. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA, 2002, 288: 2015–2022.
47. Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke, 2004, 35: 345–347.
48. Mudd SH, Levy HL, Scovby F. Disorders of transulfuration. In: Scriver C.L., Beaudet A.L., Sly W.S. eds. The Metabolic and Molecular Bases of Inherited Disease. 7 ed. New York: McGraw-Hill. 1995: 1279-327.
49. Clarke R, Daly L, Robinson K et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med, 1991, 324(17): 1149-55.
50. Iso H, Moriyama Y, Sato S, Kitamura A, Tanigawa T, Yamagishi K, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation, 2004, 109: 2766–2772.
51. Khan U, Crossley C, Kalra L, Rudd A, Wolfe CD, Collinson P, et al. Homocysteine and its relationship to stroke subtypes in a UK black population: the south London ethnicity and stroke study. Stroke, 2008, 39: 2943–2949.
52. Hassan A, Hunt BJ, O’Sullivan M, Bell R, D’Souza R, Jeffery S, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain, 2004, 127(pt 1): 212–219.
53. Parnetti L, Caso V, Santucci A, Corea F, Lanari A, Floridi A, et al. Mild hyperhomocysteinemia is a risk-factor in all etiological subtypes of stroke. Neurol Sci, 2004, 25: 13–17.
54. Tay SY, Ampil ER, Chen CP, Auchus AP. The relationship between homocysteine, cognition and stroke subtypes in acute stroke. J Neurol Sci, 2006, 250: 58–61.
55. Aronow WS, Ahn C, Schoenfeld MR. Association between plasma homocyst(e)ine and extracranial carotid arterial disease in older persons. Am J Cardiol, 1997, 149: 1432–1433.
56. Selhub J, Jacques PF, Bostom AG et al. Association between plasma homocyst(e)ine concentrations and extracranial carotid stenosis. N Engl J Med, 1995, 332: 286–91.
57. Sen S, Reddy PL, Grewal RP et al. Hyperhomocysteinemia is associated with aortic atheroma progression in stroke/TIA patients. Front Neurol, 2010, 1: 131.
58. Sacco RL, Anand K, Lee HS, Boden-Albala B, Stabler S, Allen R, et al. Homocysteine and the risk of ischemic stroke in a triethnic cohort: the NOrthern MAnhattan Study. Stroke, 2004, 35: 2263–2269.
59. Cui R, Moriyama Y, Koike KA, Date C, Kikuchi S, Tamakoshi A, et al. JACC Study group. Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: The JACC study. Atherosclerosis, 2008, 198: 412–418.
60. Shi Z, Guan Y, Huo YR, Liu S, Zhang M, Lu H, Yue W, Wang J, Ji Y. Elevated Total Homocysteine Levels in Acute Ischemic Stroke Are Associated With Long-Term Mortality. Stroke, 2015 Sep, 46(9): 2419-25.
61. The European Stroke Organization (ESO) Executive Committee and the ESO Writing Committee: Guidelines for management of ischaemic stroke and transient ischaemic attacks 2008. Cerebrovasc Dis, 2008, 25: 457–507.
62. Суслина З.А., Танашян М.М. Антитромботическая терапия в ангионеврологии. М.: Медицинская книга, 2004.
63. Аметов А.С., Дадаева Е.Е., Строков И.А. и др. Актовегин в лечении заболеваний центральной и периферической нервной системы. РМЖ, 2007, 15(24): 1824-1827.
64. Бояринов Г.А., Пенкнович А.А., Мухина И.В. Метаболические эффекты нейротропного действия Актовегина в условиях гипоксии. Эксп. клин. фармакол., 1999, 62(2): 61-63.
65. Reichel H, Weiss C, Leichtweiss HP. The effects of a blood extract on the oxygen uptake of isolated artificially perfused kidneys and skeletal muscles in rats. Arzneim-Forsch, 1965, 15(756): 757.
66. Kuninaka T, Senga Y, Senga H, Weiner M. Nature of enhanced mitochondrial oxidative metabolism by a calf blood extract. J Cell Physiol, 1991, 146(1): 148-155.
67. Строков И.А., Моргоева Ф.Э., Строков К.И. и др. Терапевтическая коррекция диабетической полиневропатии и энцефалопатии Актовегином. Междунар. неврол. журн., 2007, 2: 33-38.
68. Machicao F, Muresanu DF, Hundsberger H, Pflüger M, Guekht A. Pleiotropic neuroprotective and metabolic effects of Actovegin’s mode of action. J Neurol Sci, 2012, 322(1): 222-227.
69. Юринская М.М., Винокуров М.Г., Грачев С.В., Асташкин Е.И. Актовегин снижает апоптоз клеток нейробластомы SK-N-SH, индуцированный пероксидом водорода, в результате ингибирования p38MAPK и PI-3K. Доклады Академии Наук, 2014, 456(5): 618-621.
70. Hoyer S, Betz K. Elimination of the delayed postischemic energy deficit in cerebral cortex and hippocampus of aged rats with a dried, deproteinized blood extract (Actovegin). Arch Gerontol Geriatr, 1989, 2(9): 181–92.
71. Гусев Е.И., Скворцова В.И., Платонова И.А. Терапия ишемического инсульта. Сonsilium medicum. Спец. Выпуск, 2003: 18–25.
72. Румянцева С.А. Актовегин в комплексной терапии критических состояний неврологического генеза. Неотложные состояния в неврологии. Орел, 2002: 376–83.
73. Стаховская Л.В., Квасова О.В., Гудкова В.В. и др. Применение Актовегина на разных этапах лечения больных с ишемическим инсультом. Consilium medicum, 2007, 9(8): 22–25.
74. Федин А.И., Румянцева С.А. Принципы антигипоксической терапии у больных с инсультом. Интенсивная терапия ишемического инсульта. Руководство для врачей. М., 2004: 251–60.
75. Федин А.И., Румянцева С.А. Избранные вопросы базисной интенсивной терапии нарушений мозгового кровообращения Методические указания. М., 2002, 169–96.
76. Любшина О.В., Талибов О.Б., Верткин А.Л. Алгоритм диагностики инсульта на догоспитальном этапе. Сonsilium medicum, 2004, 6(8): 606–9.
77. Чуканова Е.И. Актовегин в лечении больных с дисциркуляторной энцефалопатией. Фарматека, 2005, 17: 71–6.
78. Филимонов Д.А. Гипергомоцистеинемия как прокоагулянтный фактор риска у пациентов с атеротромботическим ишемическим инсультом и возможности лечебной коррекции. Нейронауки: теоретические и клинические аспекты, 2012, 8(2): 204-208.
79. Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, et al. CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015, 313: 1325–1335.
80. Cavalieri M, Schmidt R, Chen C, Mok V, de Freitas GR, Song S, et al. VITATOPS Trial Study Group. B vitamins and magnetic resonance imagingdetected ischemic brain lesions in patients with recent transient ischemic attack or stroke: the VITAmins TO Prevent Stroke (VITATOPS) MRIsubstudy. Stroke, 2012, 43: 3266–3270.
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Pizova NV, Pizo NA. HYPERHOMOCYSTEINEMIA AND ISCHEMIC STROKE. Meditsinskiy sovet = Medical Council. 2017;(10):12-17. (In Russ.) https://doi.org/10.21518/2079-701X-2017-10-12-17
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