Platelet mitochondrial DNA methylation: a potential new marker of cardiovascular disease

Clinical Epigenetics

Hyang-Min Byun²  Andrea A Baccarelli¹ 

[1] Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston 02115, MA, USA;Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK

关键词: Cardiovascular disease;    Platelet;    DNA methylation;    Mitochondrial epigenetics;   

Others  :  1210210
DOI  :  10.1186/s13148-015-0078-0

 received in 2015-03-02, accepted in 2015-04-01,  发布年份 2015

【 摘 要 】

Background

Platelets are critical in the etiology of cardiovascular disease (CVD), and the mitochondria in these cells serve as an energy source for platelet function. Epigenetic factors, especially DNA methylation, have been employed as markers of CVD. Unlike nuclear DNA methylation, mitochondrial DNA (mtDNA) methylation has not been widely studied, in part, due to debate about its existence and role. In this study, we examined platelet mtDNA methylation in relation to CVD.

Results

We measured mtDNA methylation in platelets by bisulfite-PCR pyrosequencing and examined associations of CVD with methylation in mitochondrial genes; cytochrome c oxidase (MT-CO1, MT-CO2, and MT-CO3); tRNA leucine 1 (MT-TL1); ATP synthase (MT-ATP6 and MT-ATP8); and NADH dehydrogenase (MT-MD5). We report that CVD patients have significantly higher mtDNA methylation than healthy controls in MT-CO1 (18.53%, P < 0.0001), MT-CO2 (3.33%, P = 0.0001), MT-CO3 (0.92%, P < 0.0001), and MT-TL1 (1.67%, P = 0.0001), which are involved in ATP synthesis. Platelet mtDNA methylation was not related with age, BMI, and race in this study.

Conclusions

Our results suggest that platelet mtDNA methylation, which could serve as non-invasive and easy-to-obtain markers, may be implicated in the etiology of CVD.

【 授权许可】

   
2015 Baccarelli and Byun; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al.: Heart disease and stroke statistics - 2014 update: a report from the American Heart Association. Circulation 2014, 129(3):e28-292.
• [2]Brookmeyer R, Gray S, Kawas C: Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998, 88(9):1337-42.
• [3]Gregg D, Goldschmidt-Clermont PJ: Cardiology patient page. Platelets and cardiovascular disease. Circulation 2003, 108(13):e88-90.
• [4]Kottke-Marchant K: Importance of platelets and platelet response in acute coronary syndromes. Cleve Clin J Med 2009, 76(Suppl 1):S2-7.
• [5]Salky N, Dugdale M: Platelet abnormalities in ischemic heart disease. Am J Cardiol 1973, 32(5):612-7.
• [6]Willoughby S, Holmes A, Loscalzo J: Platelets and cardiovascular disease. Eur J Cardiovasc Nurs 2002, 1(4):273-88.
• [7]Akkerman JW: Regulation of carbohydrate metabolism in platelets: a review. Thromb Haemost 1978, 39(3):712-24.
• [8]Akkerman JW, Holmsen H, Loughnane M: Simultaneous measurement of aggregation, secretion, oxygen uptake, proton production, and intracellular metabolites in the same platelet suspension. Anal Biochem 1979, 97(2):387-93.
• [9]Akkerman JW, Holmsen H: Interrelationships among platelet responses: studies on the burst in proton liberation, lactate production, and oxygen uptake during platelet aggregation and Ca2+ secretion. Blood 1981, 57(5):956-66.
• [10]Byun HM, Panni T, Motta V, Hou L, Nordio F, Apostoli P, et al.: Effects of airborne pollutants on mitochondrial DNA methylation. Part Fibre Toxicol 2013, 10:18. BioMed Central Full Text
• [11]Byun HM, Baccarelli AA: Environmental exposure and mitochondrial epigenetics: study design and analytical challenges. Hum Genet 2014, 133(3):247-57.
• [12]Infantino V, Castegna A, Iacobazzi F, Spera I, Scala I, Andria G, et al.: Impairment of methyl cycle affects mitochondrial methyl availability and glutathione level in Down’s syndrome. Mol Genet Metab 2011, 102(3):378-82.
• [13]Feng S, Xiong L, Ji Z, Cheng W, Yang H: Correlation between increased ND2 expression and demethylated displacement loop of mtDNA in colorectal cancer. Mol Med Rep 2012, 6(1):125-30.
• [14]Ramos A, Barbena E, Mateiu L, del Mar GM, Mairal Q, Lima M, et al.: Nuclear insertions of mitochondrial origin: database updating and usefulness in cancer studies. Mitochondrion 2011, 11(6):946-53.
• [15]Vanyushin BF, Kiryanov GI, Kudryashova IB, Belozersky AN: DNA-methylase in loach embryos (Misgurnus fossilis). FEBS Lett 1971, 15(4):313-6.
• [16]Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM: DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci U S A 2011, 108(9):3630-5.
• [17]Iacobazzi V, Castegna A, Infantino V, Andria G: Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Mol Genet Metab 2013, 110(1–2):25-34.
• [18]Baccarelli A, Rienstra M, Benjamin EJ: Cardiovascular epigenetics: basic concepts and results from animal and human studies. Circ Cardiovasc Genet 2010, 3(6):567-73.
• [19]Baccarelli A, Wright R, Bollati V, Litonjua A, Zanobetti A, Tarantini L, et al.: Ischemic heart disease and stroke in relation to blood DNA methylation. Epidemiology 2010, 21(6):819-28.
• [20]Castro R, Rivera I, Struys EA, Jansen EE, Ravasco P, Camilo ME, et al.: Tavares de Almeida I: increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin Chem 2003, 49(8):1292-6.
• [21]Kim M, Long TI, Arakawa K, Wang R, Yu MC, Laird PW: DNA methylation as a biomarker for cardiovascular disease risk. PLoS One 2010., 5(3) Article ID e9692
• [22]Houseman A, Accomando P, Koestler C, Christensen C, Marsit J, Nelson H, et al.: DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics 2012, 13:86. BioMed Central Full Text
• [23]Jaffe AE, Irizarry RA: Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol 2014, 15(2):R31. BioMed Central Full Text
• [24]Waterhouse DF, Cahill RA, Sheehan F, McCreery C: Prediction of calculated future cardiovascular disease by monocyte count in an asymptomatic population. Vasc Health Risk Manag 2008, 4(1):177-87.
• [25]Maekawa M, Taniguchi T, Higashi H, Sugimura H, Sugano K, Kanno T: Methylation of mitochondrial DNA is not a useful marker for cancer detection. Clin Chem 2004, 50(8):1480-1.
• [26]Wong M, Gertz B, Chestnut BA, Martin LJ: Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front Cell Neurosci 2013, 7:279.
• [27]Finsterer J: Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol Scand 2007, 116(1):1-14.
• [28]Reardon W, Ross RJ, Sweeney MG, Luxon LM, Pembrey ME, Harding AE, et al.: Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 1992, 340(8832):1376-9.
• [29]Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K: Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J Biol Chem 2000, 275(6):4251-7.
• [30]Xin M, Olson EN, Bassel-Duby R: Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol 2013, 14(8):529-41.
• [31]Movassagh M, Choy MK, Goddard M, Bennett MR, Down TA, Foo RS: Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One 2010., 5(1) Article ID e8564
• [32]Bauereisen E, Hauck G, Jacob R, Peiper U: Endhdiastolic pressure-volume relationships and the work diagram of the intact heart during natural circulation depending on heart frequency, adrenalin effect and vagus stimulation. Pflugers Arch Gesamte Physiol Menschen Tiere 1964, 281:216-30.
• [33]Griffiths EJ: Mitochondria and heart disease. Adv Exp Med Biol 2012, 942:249-67.
• [34]Pecina P, Houstkova H, Hansikova H, Zeman J, Houstek J: Genetic defects of cytochrome c oxidase assembly. Physiol Res 2004, 53(Suppl 1):S213-23.
• [35]Lorente L, Martin MM, Lopez-Gallardo E, Iceta R, Blanquer J, Sole-Violan J, et al.: Higher platelet cytochrome oxidase specific activity in surviving than in non-surviving septic patients. Crit Care 2014, 18(3):R136. BioMed Central Full Text
• [36]Despres JP: Body fat distribution and risk of cardiovascular disease: an update. Circulation 2012, 126(10):1301-13.
• [37]Collins ML, Eng S, Hoh R, Hellerstein MK: Measurement of mitochondrial DNA synthesis in vivo using a stable isotope-mass spectrometric technique. J Appl Physiol (1985) 2003, 94(6):2203-11.
• [38]Fukami MH, Salganicoff L: Isolation and properties of human platelet mitochondria. Blood 1973, 42(6):913-8.
• [39]Boudreau LH, Duchez AC, Cloutier N, Soulet D, Martin N, Bollinger J, et al.: Platelets release mitochondria serving as substrate for bactericidal group IIA secreted phospholipase A2 to promote inflammation. Blood 2014, 124(14):2173-83.
• [40]Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR: Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis. J Biol Chem 2010, 285(28):21590-9.
• [41]Byun HM, Heo K, Mitchell KJ, Yang AS: Mono-allelic retrotransposon insertion addresses epigenetic transcriptional repression in human genome. J Biomed Sci 2012, 19:13. BioMed Central Full Text
• [42]Li LC, Dahiya R: MethPrimer: designing primers for methylation PCRs. Bioinformatics 2002, 18(11):1427-31.