Abstract
Dysregulation of the oxidant-antioxidant system contributes to the pathogenesis of cerebral stroke (CS). Epigenetic changes of redox homeostasis genes, such as glutamate-cysteine ligase (GCLM), glutathione-S-transferase-P1 (GSTP1), thioredoxin reductase 1 (TXNRD1), and myeloperoxidase (MPO), may be biomarkers of CS. In this study, we assessed the association of DNA methylation levels of these genes with CS and clinical features of CS. We quantitatively analyzed DNA methylation patterns in the promoter or regulatory regions of 4 genes (GCLM, GSTP1, TXNRD1, and MPO) in peripheral blood leukocytes of 59 patients with CS in the acute phase and in 83 relatively healthy individuals (controls) without cardiovascular and cerebrovascular diseases. We found that in both groups, the methylation level of CpG sites in genes TXNRD1 and GSTP1 was ≤ 5%. Lower methylation levels were registered at a CpG site (chr1:94,374,293, GRCh37 [hg19]) in GCLM in patients with ischemic stroke compared with the control group (9% [7%; 11.6%] (median and interquartile range) versus 14.7% [10.4%; 23%], respectively, p < 0.05). In the leukocytes of patients with CS, the methylation level of CpG sites in the analyzed region of MPO (chr17:56,356,470, GRCh3 [hg19]) on average was significantly lower (23.5% [19.3%; 26.7%]) than that in the control group (35.6% [30.4%; 42.6%], p < 0.05). We also found increased methylation of MPO in smokers with CS (27.2% [23.5%; 31.1%]) compared with nonsmokers with CS (21.7% [18.1%; 24.8%]). Thus, hypomethylation of CpG sites in GCLM and MPO in blood leukocytes is associated with CS in the acute phase.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of Data and Material/Code Availability
All data and materials as well as software application and custom code support authors’ published claims and comply with field standards.
References
Allen CL, Bayraktutan U (2009) Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 4(6):461–470. https://doi.org/10.1111/j.1747-4949.2009.00387.x
Arnér ES, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem Oct;267(20):6102–6109. https://doi.org/10.1046/j.1432-1327.2000.01701.x
Barciszewska AM (2018) Global DNA demethylation as an epigenetic marker of human brain metastases. Biosci Rep 38(5):BSR20180731. https://doi.org/10.1042/BSR20180731
Baum L, Chen X, Cheung WS, Cheung CK, Cheung LW, Chiu KF, Wen HM, Poon P, Woo KS, Ng HK, Wong KS (2007) Polymorphisms and vascular cognitive impairment after ischemic stroke. J Geriatr Psychiatry Neurol 20(2):93–99. https://doi.org/10.1177/0891988706298627
Buck BH, Liebeskind DS, Saver JL, Bang OY, Yun SW, Starkman S, Ali LK, Kim D, Villablanca JP, Salamon N, Razinia T, Ovbiagele B (2008) Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke 39(2):355–360. https://doi.org/10.1161/STROKEAHA.107.490128
Bushueva O, Solodilova M, Ivanov V, Polonikov A (2015) Gender-specific protective effect of the -463G>A polymorphism of myeloperoxidase gene against the risk of essential hypertension in Russians. J Am Soc Hypertens 9(11):902–906. https://doi.org/10.1016/j.jash.2015.08.006
Caplan LR (2004) Treatment of acute stroke: still struggling. JAMA 292(15):1883–1885. https://doi.org/10.1001/jama.292.15.1883
Choi J, Liu RM, Kundu RK, Sangiorgi F, Wu W, Maxson R, Forman HJ (2000) Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice. J Biol Chem 275(5):3693–3698. https://doi.org/10.1074/jbc.275.5.3693
Ciavatta DJ, Yang J, Preston GA, Badhwar AK, Xiao H, Hewins P, Nester CM, Pendergraft WF 3rd, Magnuson TR, Jennette JC, Falk RJ (2010) Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest 120(9):3209–3219. https://doi.org/10.1172/JCI40034
Cojocaru IM, Cojocaru M, Iliescu I, Botnaru L, Gurban CV, Sfrijan F, Tănăsescu R (2010) Plasma myeloperoxidase levels in patients with acute ischemic stroke. Rom J Intern Med 48(1):101–104
Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62(6):649–671. https://doi.org/10.1016/s0301-0082(99)00060-x
Ebrahimian T, Touyz RM (2008) Thioredoxin in vascular biology: role in hypertension. Antioxid Redox Signal 10(6):1127–1136. https://doi.org/10.1089/ars.2007.1985
Fu X, Kassim SY, Parks WC, Heinecke JW (2001) Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem 276(44):41279–41287. https://doi.org/10.1074/jbc.M106958200
Ganz P, Amarenco P, Goldstein LB, Sillesen H, Bao W, Preston GM, Welch KMA, Steering Committee SPARCL (2017) Association of osteopontin, neopterin, and myeloperoxidase with stroke risk in patients with prior stroke or transient ischemic attacks: results of an analysis of 13 biomarkers from the stroke prevention by aggressive reduction in cholesterol levels trial. Stroke 48(12):3223–3231. https://doi.org/10.1161/STROKEAHA.117.017965
Gao X, Gào X, Zhang Y, Holleczek B, Schöttker B, Brenner H (2019) Oxidative stress and epigenetic mortality risk score: associations with all-cause mortality among elderly people. Eur J Epidemiol 34(5):451–462. https://doi.org/10.1007/s10654-019-00493-7
Gómez-Úriz AM, Milagro FI, Mansego ML, Cordero P, Abete I, De Arce A, Goyenechea E, Blázquez V, Martínez-Zabaleta M, Martínez JA, López De Munain A, Campión J (2015) Obesity and ischemic stroke modulate the methylation levels of KCNQ1 in white blood cells. Hum Mol Genet 24(5):1432–1440. https://doi.org/10.1093/hmg/ddu559
Gorudko IV, Sokolov AV, Shamova EV, Grudinina NA, Drozd ES, Shishlo LM, Grigorieva DV, Bushuk SB, Bushuk BA, Chizhik SA, Cherenkevich SN, Vasilyev VB, Panasenko OM (2013) Myeloperoxidase modulates human platelet aggregation via actin cytoskeleton reorganization and store-operated calcium entry. Biol Open 2(9):916–923. https://doi.org/10.1242/bio.20135314
Green PS, Mendez AJ, Jacob JS, Crowley JR, Growdon W, Hyman BT, Heinecke JW (2004) Neuronal expression of myeloperoxidase is increased in Alzheimer’s disease. J Neurochem 90(3):724–733. https://doi.org/10.1111/j.1471-4159.2004.02527.x
Gupta S, Jaworska K, Jakubowska A, Wojdacz TK, Hansen LL, Lubiński J (2012) Constitutional methylation of cancer-related and selenoprotein coding genes in breast carcinoma in Polish population. Hered Cancer Clin Pract 10(Suppl 4):A13. https://doi.org/10.1186/1897-4287-10-S4-A13
Hajjar DP, Gotto AM Jr (2013) Biological relevance of inflammation and oxidative stress in the pathogenesis of arterial diseases. Am J Pathol 182(5):1474–1481. https://doi.org/10.1016/j.ajpath.2013.01.010
Inazawa J, Inoue K, Nishigaki H, Tsuda S, Taniwaki M, Misawa S, Abe T (1989) Assignment of the human myeloperoxidase gene (MPO) to bands q21.3----q23 of chromosome 17. Cytogenet Cell Genet 50(2–3):135–136. https://doi.org/10.1159/000132742
Jickling GC, Liu D, Ander BP, Stamova B, Zhan X, Sharp FR (2015) Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab 35(6):888–901. https://doi.org/10.1038/jcbfm.2015.45
Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–789. https://doi.org/10.1189/jlb.1109766
Kasugai I, Yamada M (1986) Regulation of myeloperoxidase gene expression by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in human leukemia HL-60 cells. J Biochem 100(2):381–388. https://doi.org/10.1093/oxfordjournals.jbchem.a121725
Khalil A, Medfai H, Poelvoorde P, Kazan MF, Delporte C, Van Antwerpen P, El-Makhour Y, Biston P, Delrée P, Badran B, Vanhamme L, Boudjeltia KZ (2018) Myeloperoxidase promotes tube formation, triggers ERK1/2 and Akt pathways and is expressed endogenously in endothelial cells. Arch Biochem Biophys 654:55–69. https://doi.org/10.1016/j.abb.2018.07.011
Kim J, Song TJ, Park JH, Lee HS, Nam CM, Nam HS, Kim YD, Heo JH (2012) Different prognostic value of white blood cell subtypes in patients with acute cerebral infarction. Atherosclerosis 222(2):464–467. https://doi.org/10.1016/j.atherosclerosis.2012.02.042
Kumar AD, Boehme AK, Siegler JE, Gillette M, Albright KC, Martin-Schild S (2013) Leukocytosis in patients with neurologic deterioration after acute ischemic stroke is associated with poor outcomes. J Stroke Cerebrovasc Dis 22(7):e111–e117. https://doi.org/10.1016/j.jstrokecerebrovasdis.2012.08.008
Li P, Stetler RA, Leak RK, Shi Y, Li Y, Yu W, Bennett MVL, Chen J (2018) Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology 134(Pt B):208–217. https://doi.org/10.1016/j.neuropharm.2017.11.011
Liu D, Liu L, Song Z, Hu Z, Liu J, Hou D (2017) Genetic variations of oxidative stress related genes ALOX5, ALOX5AP and MPO modulate ischemic stroke susceptibility through main effects and epistatic interactions in a Chinese population. Cell Physiol Biochem 43(4):1588–1602. https://doi.org/10.1159/000482023
Liu Y, Min JW, Feng S, Subedi K, Qiao F, Mammenga E, Callegari E, Wang H (2020) Therapeutic role of a cysteine precursor, OTC, in ischemic stroke is mediated by improved proteostasis in mice. Transl Stroke Res 11(1):147–160. https://doi.org/10.1007/s12975-019-00707-w
Lu SC (2009) Regulation of glutathione synthesis. Mol Aspects Med 30(1–2):42–59. https://doi.org/10.1016/j.mam.2008.05.005
Lübbert M, Miller CW, Koeffler HP (1991) Changes of DNA methylation and chromatin structure in the human myeloperoxidase gene during myeloid differentiation. Blood 78(2):345–356
Maestrini I, Tagzirt M, Gautier S, Dupont A, Mendyk AM, Susen S, Tailleux A, Vallez E, Staels B, Cordonnier C, Leys D, Bordet R (2020) Analysis of the association of MPO and MMP-9 with stroke severity and outcome: Cohort study. Neurology 95(1):e97–e108. https://doi.org/10.1212/WNL.0000000000009179
Maki RA, Tyurin VA, Lyon RC, Hamilton RL, DeKosky ST, Kagan VE, Reynolds WF (2009) Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease. J Biol Chem 284(5):3158–3169. https://doi.org/10.1074/jbc.M807731200
Manchanda K, Kolarova H, Kerkenpaß C, Mollenhauer M, Vitecek J, Rudolph V, Kubala L, Baldus S, Adam M, Klinke A (2018) MPO (Myeloperoxidase) reduces endothelial glycocalyx thickness dependent on its cationic charge. Arterioscler Thromb Vasc Biol 38(8):1859–1867. https://doi.org/10.1161/ATVBAHA.118.311143
Mendelson MM, Marioni RE, Joehanes R, Liu C, Hedman ÅK, Aslibekyan S, Demerath EW, Guan W, Zhi D, Yao C, Huan T, Willinger C, Chen B, Courchesne P, Multhaup M, Irvin MR, Cohain A, Schadt EE, Grove ML, Bressler J, North K, Sundström J, Gustafsson S, Shah S, McRae AF, Harris SE, Gibson J, Redmond P, Corley J, Murphy L, Starr JM, Kleinbrink E, Lipovich L, Visscher PM, Wray NR, Krauss RM, Fallin D, Feinberg A, Absher DM, Fornage M, Pankow JS, Lind L, Fox C, Ingelsson E, Arnett DK, Boerwinkle E, Liang L, Levy D, Deary IJ (2017) Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: a mendelian randomization approach. PLoS Med 14(1):e1002215. https://doi.org/10.1371/journal.pmed.1002215
Mendis S, Davis S, Norrving B (2015) Organizational update: the world health organization global status report on noncommunicable diseases 2014; one more landmark step in the combat against stroke and vascular disease. Stroke 46(5):e121–e122. https://doi.org/10.1161/STROKEAHA.115.008097
Montaner J, Ramiro L, Simats A, Tiedt S, Makris K, Jickling GC, Debette S, Sanchez JC, Bustamante A (2020) Multilevel omics for the discovery of biomarkers and therapeutic targets for stroke. Nat Rev Neurol 16(5):247–264. https://doi.org/10.1038/s41582-020-0350-6
Na HK, Kim M, Chang SS, Kim SY, Park JY, Chung MW, Yang M (2015) Tobacco smoking-response genes in blood and buccal cells. Toxicol Lett 232(2):429–437. https://doi.org/10.1016/j.toxlet.2014.10.005
Nagra RM, Becher B, Tourtellotte WW, Antel JP, Gold D, Paladino T, Smith RA, Nelson JR, Reynolds WF (1997) Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis. J Neuroimmunol 78(1–2):97–107. https://doi.org/10.1016/s0165-5728(97)00089-1
Nauseef WM (2018) Biosynthesis of human myeloperoxidase. Arch Biochem Biophys 642:1–9. https://doi.org/10.1016/j.abb.2018.02.001
O’Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, Clements EG, Cai Y, Van Neste L, Easwaran H, Casero RA, Sears CL, Baylin SB (2011) Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20(5):606–619. https://doi.org/10.1016/j.ccr.2011.09.012
Okada SS, de Oliveira EM, de Araújo TH, Rodrigues MR, Albuquerque RC, Mortara RA, Taniwaki NN, Nakaya HI, Campa A, Moreno AC (2016) Myeloperoxidase in human peripheral blood lymphocytes: production and subcellular localization. Cell Immunol 300:18–25. https://doi.org/10.1016/j.cellimm.2015.11.003
Orhan G, Elkama A, Mungan SÖ, Eruyar E, Karahalil B (2016) The impact of detoxifying and repair gene polymorphisms on oxidative stress in ischemic stroke. Neurol Sci 37(6):955–961. https://doi.org/10.1007/s10072-016-2524-y
Palm F, Pussinen PJ, Safer A, Tervahartiala T, Sorsa T, Urbanek C, Becher H, Grau AJ (2018) Serum matrix metalloproteinase-8, tissue inhibitor of metalloproteinase and myeloperoxidase in ischemic stroke. Atherosclerosis 271:9–14. https://doi.org/10.1016/j.atherosclerosis.2018.02.012
Polonikov A, Rymarova L, Klyosova E, Volkova A, Azarova I, Bushueva O, Bykanova M, Bocharova I, Zhabin S, Churnosov M, Laskov V, Solodilova M (2019) Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease. J Cell Biochem 120(10):16467–16482. https://doi.org/10.1002/jcb.28815
Polonikov A, Vialykh E, Vasil’eva O, Bulgakova I, Bushueva O, Illig T, Solodilova M (2012a) Genetic variation in glutathione S-transferase genes and risk of nonfatal cerebral stroke in patients suffering from essential hypertension. J Mol Neurosci 47(3):511–513. https://doi.org/10.1007/s12031-012-9764-y
Polonikov AV, Vialykh EK, Churnosov MI, Illig T, Freidin MB, Vasil’eva OV, Bushueva OY, Ryzhaeva VN, Bulgakova IV, Solodilova MA (2012b) The C718T polymorphism in the 3’-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension. Hypertens Res 35(5):507–512. https://doi.org/10.1038/hr.2011.213
Pravalika K, Sarmah D, Kaur H, Vats K, Saraf J, Wanve M, Kalia K, Borah A, Yavagal DR, Dave KR, Bhattacharya P (2019) Trigonelline therapy confers neuroprotection by reduced glutathione mediated myeloperoxidase expression in animal model of ischemic stroke. Life Sci 216:49–58. https://doi.org/10.1016/j.lfs.2018.11.014
Ren J, Dai S, Wang X, Liu P (2016) The clinical significance of serum MPO in patients with acute ischemic cerebral stroke. Int J Lab Med 37(20):2854–2856
Ross AM, Hurn P, Perrin N, Wood L, Carlini W, Potempa K (2007) Evidence of the peripheral inflammatory response in patients with transient ischemic attack. J Stroke Cerebrovasc Dis 16(5):203–207. https://doi.org/10.1016/j.jstrokecerebrovasdis.2007.05.002
Saeed SA, Shad KF, Saleem T, Javed F, Khan MU (2007) Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Exp Brain Res 182(1):1–10. https://doi.org/10.1007/s00221-007-1050-9
Shao B, Oda MN, Oram JF, Heinecke JW (2010) Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein. Chem Res Toxicol 23(3):447–454. https://doi.org/10.1021/tx9003775
Shichita T, Sakaguchi R, Suzuki M, Yoshimura A (2012) Post-ischemic inflammation in the brain. Front Immunol 3:132. https://doi.org/10.3389/fimmu.2012.00132
Soriano-Tárraga C, Jiménez-Conde J, Giralt-Steinhauer E, Mola-Caminal M, Vivanco-Hidalgo RM, Ois A, Rodríguez-Campello A, Cuadrado-Godia E, Sayols-Baixeras S, Elosua R, Roquer J, GENESTROKE Consortium (2016) Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia. Hum Mol Genet 25(3):609–619. https://doi.org/10.1093/hmg/ddv493
Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P (2004) Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler Thromb Vasc Biol 24(7):1309–1314. https://doi.org/10.1161/01.ATV.0000131784.50633.4f
Sun MS, Jin H, Sun X, Huang S, Zhang FL, Guo ZN, Yang Y (2018) Free radical damage in ischemia-reperfusion injury: an obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev 2018:3804979. https://doi.org/10.1155/2018/3804979
Tang C, Wang C, Zhang Y, Xue L, Li Y, Ju C, Zhang C (2019) Recognition, intervention, and monitoring of neutrophils in acute ischemic stroke. Nano Lett 19(7):4470–4477. https://doi.org/10.1021/acs.nanolett.9b01282
Tao L, Gao E, Hu A, Coletti C, Wang Y, Christopher TA, Lopez BL, Koch W, Ma XL (2006) Thioredoxin reduces post-ischemic myocardial apoptosis by reducing oxidative/nitrative stress. Br J Pharmacol 149(3):311–318. https://doi.org/10.1038/sj.bjp.0706853
Tobler A, Miller CW, Johnson KR, Selsted ME, Rovera G, Koeffler HP (1988) Regulation of gene expression of myeloperoxidase during myeloid differentiation. J Cell Physiol 136(2):215–225. https://doi.org/10.1002/jcp.1041360203
Tost J, Gut IG (2007) Analysis of gene-specific DNA methylation patterns by pyrosequencing technology. Methods Mol Biol 373:89–102. https://doi.org/10.1385/1-59745-377-3:89
Turoczi T, Chang VW, Engelman RM, Maulik N, Ho YS, Das DK (2003) Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1. J Mol Cell Cardiol 35(6):695–704. https://doi.org/10.1016/s0022-2828(03)00117-2
Valinluck V, Sowers LC (2007) Inflammation-mediated cytosine damage: a mechanistic link between inflammation and the epigenetic alterations in human cancers. Cancer Res 67(12):5583–5586. https://doi.org/10.1158/0008-5472.CAN-07-0846
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160(1):1–40. https://doi.org/10.1016/j.cbi.2005.12.009
Vialykh EK, Solidolova MA, Bushueva OIu, Bulgakova IV, Polonikov AV (2012) Catalase gene polymorphism is associated with increased risk of cerebral stroke in hypertensive patients. Zh Nevrol Psikhiatr Im S S Korsakova 112(8 Pt 2):3–7 (In Russian)
Vita JA, Brennan ML, Gokce N, Mann SA, Goormastic M, Shishehbor MH, Penn MS, Keaney JF Jr, Hazen SL (2004) Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation 110(9):1134–1139. https://doi.org/10.1161/01.CIR.0000140262.20831.8F
Voetsch B, Jin RC, Bierl C, Benke KS, Kenet G, Simioni P, Ottaviano F, Damasceno BP, Annichino-Bizacchi JM, Handy DE, Loscalzo J (2007) Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke 38(1):41–49. https://doi.org/10.1161/01.STR.0000252027.53766.2b
Wang Y, Rosen H, Madtes DK, Shao B, Martin TR, Heinecke JW, Fu X (2007) Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue: an oxidative mechanism for regulating proteolysis during inflammation. J Biol Chem 282(44):31826–31834. https://doi.org/10.1074/jbc.M704894200
Weiss SJ, Peppin G, Ortiz X, Ragsdale C, Test ST (1985) Oxidative autoactivation of latent collagenase by human neutrophils. Science 227(4688):747–749. https://doi.org/10.1126/science.2982211
Yang J, Cheng Y, Ji R, Zhang C (2006) Novel model of inflammatory neointima formation reveals a potential role of myeloperoxidase in neointimal hyperplasia. Am J Physiol Heart Circ Physiol 291(6):H3087–H3093. https://doi.org/10.1152/ajpheart.00412.2006
Zaina S, Gonçalves I, Carmona FJ, Gomez A, Heyn H, Mollet IG, Moran S, Varol N, Esteller M (2015) DNA methylation dynamics in human carotid plaques after cerebrovascular events. Arterioscler Thromb Vasc Biol 35(8):1835–1842. https://doi.org/10.1161/ATVBAHA.115.305630
Zhang K, Tu M, Gao W, Cai X, Song F, Chen Z, Zhang Q, Wang J, Jin C, Shi J, Yang X, Zhu Y, Gu W, Hu B, Zheng Y, Zhang H, Tian M (2019) Hollow Prussian blue nanozymes drive neuroprotection against ischemic stroke via attenuating oxidative stress, counteracting inflammation, and suppressing cell apoptosis. Nano Lett 19(5):2812–2823. https://doi.org/10.1021/acs.nanolett.8b04729
Zheng GR, Chen B, Shen J, Qiu SZ, Yin HM, Mao W, Wang HX, Gao JB (2018) Serum myeloperoxidase concentrations for outcome prediction in acute intracerebral hemorrhage. Clin Chim Acta 487:330–336. https://doi.org/10.1016/j.cca.2018.10.026
Zhou B, Zu L, Chen Y, Zheng X, Wang Y, Pan B, Dong M, Zhou E, Zhao M, Zhang Y, Zheng L, Gao W (2017) Myeloperoxidase-oxidized high density lipoprotein impairs atherosclerotic plaque stability by inhibiting smooth muscle cell migration. Lipids Health Dis 16(1):3. https://doi.org/10.1186/s12944-016-0388-z
Žitňanová I, Šiarnik P, Kollár B, Chomová M, Pazderová P, Andrezálová L, Ježovičová M, Koňariková K, Laubertová L, Krivošíková Z, Slezáková L, Turčáni P (2016) Oxidative stress markers and their dynamic changes in patients after acute ischemic stroke. Oxid Med Cell Longev 2016:9761697. https://doi.org/10.1155/2016/9761697
Acknowledgements
We express our gratitude to all the patients, healthy volunteers, and psychiatrists for their help in recruiting patients and diagnosing of CS.
Funding
The study was supported by Federal State Budgetary Educational Institution of Higher Education “Kursk State Medical University” of the Ministry of Healthcare of the Russian Federation.
Author information
Authors and Affiliations
Contributions
Bushueva Olga performed experiments, analyzed data, and wrote the manuscript. Barysheva Ekaterina performed experiments and collected data. Markov Anton performed the bioinformatic analysis. Belykh Andrey performed the statistical analysis. Koroleva Iuliia and Churkin Egor performed experiments. Polonikov Alexey and Ivanov Vladimir developed the concept of the study. Nazarenko Maria designed the study and revised the manuscript.
Corresponding author
Ethics declarations
Ethical Approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Kursk State Medical University (Date: 07.12.2015).
Consent to Participate
Informed consent was obtained from all individual participants included in the study.
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bushueva, O., Barysheva, E., Markov, A. et al. DNA Hypomethylation of the MPO Gene in Peripheral Blood Leukocytes Is Associated with Cerebral Stroke in the Acute Phase. J Mol Neurosci 71, 1914–1932 (2021). https://doi.org/10.1007/s12031-021-01840-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-021-01840-8