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The potential role of homocysteine mediated DNA methylation and associated epigenetic changes in abdominal aortic aneurysm formation

      Abstract

      Previous studies have suggested that homocysteine (Hcy) has wide-ranging biological effects, including accelerating atherosclerosis, impairing post injury endothelial repair and function, deregulating lipid metabolism and inducing thrombosis. However, the biochemical basis by which hyperhomocysteinemia (HHcy) contributes to cardiovascular diseases (CVDs) remains largely unknown. Several case–control studies have reported an association between HHcy and the presence of abdominal aortic aneurysms (AAA) and there are supportive data from animal models. Genotypic data concerning the association between variants of genes involved in the methionine cycle and AAA are conflicting probably due to problems such as reverse causality and confounding. The multifactorial nature of AAA suggests the involvement of additional epigenetic factors in disease formation. Elevated Hcy levels have been previously linked to altered DNA methylation levels in various diseases. Folate or vitamin B12 based methods of lowering Hcy have had disappointingly limited effects in reducing CVD events. One possible reason for the limited efficacy of such therapy is that they have failed to reverse epigenetic changes induced by HHcy. It is possible that individuals with HHcy have an “Hcy memory effect” due to epigenetic alterations which continue to promote progression of cardiovascular complications even after Hcy levels are lowered. It is possible that deleterious effect of prior, extended exposure to elevated Hcy concentrations have long-lasting effects on target organs and genes, hence underestimating the benefit of Hcy lowering therapies in CVD patients. Therapies targeting the epigenetic machinery as well as lowering circulating Hcy concentrations may have a more efficacious effect in reducing the incidence of cardiovascular complications.

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      References

        • Fuster V.
        • Voute J.
        MDGs: chronic diseases are not on the agenda.
        Lancet. 2005; 366: 1512-1514
        • Lopez A.D.
        • Mathers C.D.
        • Ezzati M.
        • Jamison D.T.
        • Murray C.J.
        Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.
        Lancet. 2006; 367: 1747-1757
        • Paradis G.
        • Chiolero A.
        The cardiovascular and chronic diseases epidemic in low- and middle-income countries a global health challenge.
        J Am Coll Cardiol. 2011; 57: 1775-1777
        • Smith Jr., S.C.
        • Amsterdam E.
        • Balady G.J.
        • et al.
        Prevention conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: tests for silent and inducible ischemia: Writing Group II.
        Circulation. 2000; 101: E12-E16
        • Moxon J.V.
        • Parr A.
        • Emeto T.I.
        • Walker P.
        • Norman P.E.
        • Golledge J.
        Diagnosis and monitoring of abdominal aortic aneurysm: current status and future prospects.
        Curr Probl Cardiol. 2010; 35: 512-548
        • Lindsay M.E.
        • Dietz H.C.
        Lessons on the pathogenesis of aneurysm from heritable conditions.
        Nature. 2011; 473: 308-316
        • Golledge J.
        • Muller J.
        • Daugherty A.
        • Norman P.
        Abdominal aortic aneurysm: pathogenesis and implications for management.
        Arterioscler Thromb Vasc Biol. 2006; 26: 2605-2613
        • Lederle F.A.
        • Wilson S.E.
        • Johnson G.R.
        • et al.
        Immediate repair compared with surveillance of small abdominal aortic aneurysms.
        N Engl J Med. 2002; 346: 1437-1444
        • Wang Y.X.
        • Martin-McNulty B.
        • da Cunha V.
        • et al.
        Fasudil, a Rho-kinase inhibitor, attenuates angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice by inhibiting apoptosis and proteolysis.
        Circulation. 2005; 111: 2219-2226
        • Yoshimura K.
        • Aoki H.
        • Ikeda Y.
        • et al.
        Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.
        Nat Med. 2005; 11: 1330-1338
        • Lindeman J.H.
        • Abdul-Hussien H.
        • van Bockel J.H.
        • Wolterbeek R.
        • Kleemann R.
        Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells.
        Circulation. 2009 Apr 28; 119: 2209-2216
        • Kajimoto K.
        • Miyauchi K.
        • Kasai T.
        • et al.
        Short-term 20-mg atorvastatin therapy reduces key inflammatory factors including c-Jun N-terminal kinase and dendritic cells and matrix metalloproteinase expression in human abdominal aortic aneurysmal wall.
        Atherosclerosis. 2009 Oct; 206: 505-511
        • Liu O.
        • Jia L.
        • Liu X.
        • et al.
        Clopidogrel, a platelet P2Y12 receptor inhibitor, reduces vascular inflammation and angiotensin II induced-abdominal aortic aneurysm progression.
        PLoS One. 2012; 7: e51707
        • Krishna S.M.
        • Dear A.E.
        • Norman P.E.
        • Golledge J.
        Genetic and epigenetic mechanisms and their possible role in abdominal aortic aneurysm.
        Atherosclerosis. 2010; 212: 16-29
        • Giles W.H.
        • Kittner S.J.
        • Anda R.F.
        • Croft J.B.
        • Casper M.L.
        Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study.
        Stroke. 1995; 26: 1166-1170
        • Brattstrom L.
        • Wilcken D.E.
        Homocysteine and cardiovascular disease: cause or effect?.
        Am J Clin Nutr. 2000; 72: 315-323
        • Joseph J.
        • Handy D.E.
        • Loscalzo J.
        Quo vadis: whither homocysteine research?.
        Cardiovasc Toxicol. 2009; 9: 53-63
        • Becker A.
        • Kostense P.J.
        • Bos G.
        • et al.
        Hyperhomocysteinaemia is associated with coronary events in type 2 diabetes.
        J Intern Med. 2003; 253: 293-300
        • Ambrosi P.
        • Rolland P.H.
        • Bodard H.
        • et al.
        Effects of folate supplementation in hyperhomocysteinemic pigs.
        J Am Coll Cardiol. 1999; 34: 274-279
        • Hofmann M.A.
        • Lalla E.
        • Lu Y.
        • et al.
        Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.
        J Clin Invest. 2001; 107: 675-683
        • Zhou J.
        • Moller J.
        • Danielsen C.C.
        • et al.
        Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1470-1476
        • Fujimoto S.
        • Togane Y.
        • Matsuzaki C.
        • et al.
        Effects of long-term administration of methionine on vascular endothelium in rabbits.
        Nutr Metab Cardiovasc Dis. 2003; 13: 20-27
        • Matthias D.
        • Becker C.H.
        • Riezler R.
        • Kindling P.H.
        Homocysteine induced arteriosclerosis-like alterations of the aorta in normotensive and hypertensive rats following application of high doses of methionine.
        Atherosclerosis. 1996; 122: 201-216
        • Zhang R.
        • Ma J.
        • Xia M.
        • Zhu H.
        • Ling W.
        Mild hyperhomocysteinemia induced by feeding rats diets rich in methionine or deficient in folate promotes early atherosclerotic inflammatory processes.
        J Nutr. 2004; 134: 825-830
        • Zulli A.
        • Hare D.L.
        • Buxton B.F.
        • Black M.J.
        High dietary methionine plus cholesterol exacerbates atherosclerosis formation in the left main coronary artery of rabbits.
        Atherosclerosis. 2004; 176: 83-89
        • Chang P.Y.
        • Lu S.C.
        • Lee C.M.
        • et al.
        Homocysteine inhibits arterial endothelial cell growth through transcriptional downregulation of fibroblast growth factor-2 involving G protein and DNA methylation.
        Circ Res. 2008; 102: 933-941
        • Wald D.S.
        • Law M.
        • Morris J.K.
        Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.
        BMJ. 2002; 325: 1202
        • Den Heijer M.
        • Lewington S.
        • Clarke R.
        Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies.
        J Thromb Haemost. 2005; 3: 292-299
        • Homocysteine Studies Collaboration
        Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.
        JAMA. 2002 Oct 23–30; 288: 2015-2022
        • Stampfer M.J.
        • Malinow M.R.
        • Willett W.C.
        • et al.
        A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.
        JAMA. 1992; 268: 877-881
        • Faraci F.M.
        • Lentz S.R.
        Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction.
        Stroke. 2004; 35: 345-347
        • Ungvari Z.
        • Csiszar A.
        • Edwards J.G.
        • et al.
        Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase.
        Arterioscler Thromb Vasc Biol. 2003; 23: 418-424
        • Eberhardt R.T.
        • Forgione M.A.
        • Cap A.
        • et al.
        Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia.
        J Clin Invest. 2000; 106: 483-491
        • Lentz S.R.
        • Erger R.A.
        • Dayal S.
        • et al.
        Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta-synthase-deficient mice.
        Am J Physiol Heart Circ Physiol. 2000; 279: H970-H975
        • Riba R.
        • Nicolaou A.
        • Troxler M.
        • Homer-Vaniasinkam S.
        • Naseem K.M.
        Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels.
        Atherosclerosis. 2004; 175: 69-75
        • Schroecksnadel K.
        • Frick B.
        • Winkler C.
        • Leblhuber F.
        • Wirleitner B.
        • Fuchs D.
        Hyperhomocysteinemia and immune activation.
        Clin Chem Lab Med. 2003; 41: 1438-1443
        • Yideng J.
        • Jianzhong Z.
        • Ying H.
        • et al.
        Homocysteine-mediated expression of SAHH, DNMTs, MBD2, and DNA hypomethylation potential pathogenic mechanism in VSMCs.
        DNA Cell Biol. 2007; 26: 603-611
        • Majors A.
        • Ehrhart L.A.
        • Pezacka E.H.
        Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells.
        Arterioscler Thromb Vasc Biol. 1997; 17: 2074-2081
        • Chen N.C.
        • Yang F.
        • Capecci L.M.
        • et al.
        Regulation of homocysteine metabolism and methylation in human and mouse tissues.
        FASEB J. 2010; 24: 2804-2817
        • Zhang D.
        • Jiang X.
        • Fang P.
        • et al.
        Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice.
        Circulation. 2009; 120: 1893-1902
        • Van Campenhout A.
        • Moran C.S.
        • Parr A.
        • et al.
        Role of homocysteine in aortic calcification and osteogenic cell differentiation.
        Atherosclerosis. 2009; 202: 557-566
        • Wiernicki I.
        • Millo B.
        • Safranow K.
        • Gorecka-Szyld B.
        • Gutowski P.
        MMP-9, homocysteine and CRP circulating levels are associated with intraluminal thrombus thickness of abdominal aortic aneurysms: new implication of the old biomarkers.
        Dis Markers. 2011; 31: 67-74
        • Xu Y.
        • Tian Y.
        • Wei H.J.
        • Dong J.F.
        • Zhang J.N.
        Methionine diet-induced hyperhomocysteinemia accelerates cerebral aneurysm formation in rats.
        Neurosci Lett. 2011; 494: 139-144
        • Giusti B.
        • Porciani M.C.
        • Brunelli T.
        • et al.
        Phenotypic variability of cardiovascular manifestations in Marfan Syndrome. Possible role of hyperhomocysteinemia and C677T MTHFR gene polymorphism.
        Eur Heart J. 2003; 24: 2038-2045
        • Dayal S.
        • Bottiglieri T.
        • Arning E.
        • et al.
        Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthase-deficient mice.
        Circ Res. 2001; 88: 1203-1209
        • Lee M.E.
        • Wang H.
        Homocysteine and hypomethylation. A novel link to vascular disease.
        Trends Cardiovasc Med. 1999; 9: 49-54
        • Loscalzo J.
        The oxidant stress of hyperhomocyst(e)inemia.
        J Clin Invest. 1996; 98: 5-7
        • Nishio E.
        • Watanabe Y.
        Homocysteine as a modulator of platelet-derived growth factor action in vascular smooth muscle cells: a possible role for hydrogen peroxide.
        Br J Pharmacol. 1997; 122: 269-274
        • Chambers J.C.
        • McGregor A.
        • Jean-Marie J.
        • Kooner J.S.
        Acute hyperhomocysteinaemia and endothelial dysfunction.
        Lancet. 1998; 351: 36-37
        • Zhou J.
        • Austin R.C.
        Contributions of hyperhomocysteinemia to atherosclerosis: causal relationship and potential mechanisms.
        Biofactors. 2009; 35: 120-129
        • Zhang X.
        • Li H.
        • Jin H.
        • Ebin Z.
        • Brodsky S.
        • Goligorsky M.S.
        Effects of homocysteine on endothelial nitric oxide production.
        Am J Physiol Ren Physiol. 2000; 279: F671-F678
        • Upchurch Jr., G.R.
        • Welch G.N.
        • Fabian A.J.
        • et al.
        Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase.
        J Biol Chem. 1997; 272: 17012-17017
        • Hamelahti P.
        • Jarvinen O.
        • Sisto T.
        • et al.
        Methylenetetrahydrofolate reductase gene C677T mutation is related to the defects in the internal elastic lamina of the artery wall.
        Eur J Clin Invest. 2002; 32: 869-873
        • Moat S.J.
        • Lang D.
        • McDowell I.F.
        • et al.
        Folate, homocysteine, endothelial function and cardiovascular disease.
        J Nutr Biochem. 2004; 15: 64-79
        • Jourdheuil-Rahmani D.
        • Rolland P.H.
        • Rosset E.
        • Branchereau A.
        • Garcon D.
        Homocysteine induces synthesis of a serine elastase in arterial smooth muscle cells from multi-organ donors.
        Cardiovasc Res. 1997; 34: 597-602
        • Chaussalet M.
        • Lamy E.
        • Foucault-Bertaud A.
        • et al.
        Homocysteine modulates the proteolytic potential of human vascular endothelial cells.
        Biochem Biophys Res Commun. 2004; 316: 170-176
        • Charpiot P.
        • Bescond A.
        • Augier T.
        • et al.
        Hyperhomocysteinemia induces elastolysis in minipig arteries: structural consequences, arterial site specificity and effect of captopril-hydrochlorothiazide.
        Matrix Biol. 1998; 17: 559-574
        • Neves M.F.
        • Endemann D.
        • Amiri F.
        • et al.
        Small artery mechanics in hyperhomocysteinemic mice: effects of angiotensin II.
        J Hypertens. 2004; 22: 959-966
        • Bortolotto L.A.
        • Safar M.E.
        • Billaud E.
        • et al.
        Plasma homocysteine, aortic stiffness, and renal function in hypertensive patients.
        Hypertension. 1999; 34: 837-842
        • Bescond A.
        • Augier T.
        • Chareyre C.
        • Garcon D.
        • Hornebeck W.
        • Charpiot P.
        Influence of homocysteine on matrix metalloproteinase-2: activation and activity.
        Biochem Biophys Res Commun. 1999; 263: 498-503
        • Ke X.D.
        • Foucault-Bertaud A.
        • Genovesio C.
        • Dignat-George F.
        • Lamy E.
        • Charpiot P.
        Homocysteine modulates the proteolytic potential of human arterial smooth muscle cells through a reactive oxygen species dependant mechanism.
        Mol Cell Biochem. 2010; 335: 203-210
        • Tsarouhas K.
        • Tsitsimpikou C.
        • Apostolakis S.
        • et al.
        Homocysteine and metalloprotease-3 and -9 in patients with ascending aorta aneurysms.
        Thromb Res. 2011 Nov; 128: e95-e99
        • Lentz S.R.
        • Sadler J.E.
        Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine.
        J Clin Invest. 1991; 88: 1906-1914
        • Lentz S.R.
        • Sadler J.E.
        Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum.
        Blood. 1993; 81: 683-689
        • Austin R.C.
        • Lentz S.R.
        • Werstuck G.H.
        Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease.
        Cell Death Differ. 2004; 11: S56-S64
        • Kaufman R.J.
        Orchestrating the unfolded protein response in health and disease.
        J Clin Invest. 2002; 110: 1389-1398
        • Dickhout J.G.
        • Sood S.K.
        • Austin R.C.
        Role of endoplasmic reticulum calcium disequilibria in the mechanism of homocysteine-induced ER stress.
        Antioxid Redox Signal. 2007; 9: 1863-1873
        • Jia F.
        • Wu C.
        • Chen Z.
        • Lu G.
        Atorvastatin inhibits homocysteine-induced endoplasmic reticulum stress through activation of AMP-activated protein kinase.
        Cardiovasc Ther. 2012; 30: 317-325
        • Liu Z.
        • Luo H.
        • Zhang L.
        • et al.
        Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice.
        Circ Res. 2012 Oct 26; 111: 1261-1273
        • Zhang D.
        • Fang P.
        • Jiang X.
        • et al.
        Severe hyperhomocysteinemia promotes bone marrow-derived and resident inflammatory monocyte differentiation and atherosclerosis in LDLr/CBS-deficient mice.
        Circ Res. 2012 Jun 22; 111: 37-49
        • Zhang Q.
        • Zeng X.
        • Guo J.
        • Wang X.
        Oxidant stress mechanism of homocysteine potentiating Con A-induced proliferation in murine splenic T lymphocytes.
        Cardiovasc Res. 2002; 53: 1035-1042
        • Mei W.
        • Rong Y.
        • Jinming L.
        • Yongjun L.
        • Hui Z.
        Effect of homocysteine interventions on the risk of cardio-cerebrovascular events: a meta-analysis of randomised controlled trials.
        Int J Clin Pract. 2010 Jan; 64: 208-215
        • Lentz S.R.
        Mechanisms of homocysteine-induced atherothrombosis.
        J Thromb Haemost. 2005; 3: 1646-1654
        • Ueland P.M.
        • Refsum H.
        • Beresford S.A.
        • Vollset S.E.
        The controversy over homocysteine and cardiovascular risk.
        Am J Clin Nutr. 2000; 72: 324-332
        • Brunelli T.
        • Prisco D.
        • Fedi S.
        • et al.
        High prevalence of mild hyperhomocysteinemia in patients with abdominal aortic aneurysm.
        J Vasc Surg. 2000; 32: 531-536
        • Caldwell S.
        • Burns P.
        • Haggart P.
        • Bradbury A.
        • Mosquera D.
        Association between hyperhomocysteinaemia and abdominal aortic aneurysm.
        Br J Surg. 2001; 88: 609
        • Spark J.
        • Laws P.
        • Fitridge R.
        The incidence of hyperhomocysteinaemia in vascular patients.
        Eur J Vasc Endovasc Surg. 2003; 26: 558-561
        • Warsi A.
        • Davies B.
        • Morris-Stiff G.
        • Hullin D.
        • Lewis M.
        Abdominal aortic aneurysm and its correlation to plasma homocysteine, and vitamins.
        Eur J Endovasc Surg. 2004; 27: 75-79
        • Peeters A.C.
        • van Landeghem B.A.
        • Graafsma S.J.
        • et al.
        Low vitamin B6, and not plasma homocysteine concentration, as risk factor for abdominal aortic aneurysm: a retrospective case-control study.
        J Vasc Surg. 2007; 45: 701-705
        • Sofi F.
        • Marcucci R.
        • Giusti B.
        • et al.
        High levels of homocysteine, lipoprotein (a) and plasminogen activator inhibitor-1 are present in patients with abdominal aortic aneurysm.
        Thromb Haemost. 2005; 94: 1094-1098
        • Moroz P.
        • Le M.T.
        • Norman P.E.
        Homocysteine and abdominal aortic aneurysms.
        ANZ J Surg. 2007; 77: 329-332
        • Halazun K.J.
        • Bofkin K.A.
        • Asthana S.
        • Evans C.
        • Henderson M.
        • Spark J.I.
        Hyperhomocysteinaemia is associated with the rate of abdominal aortic aneurysm expansion.
        Eur J Vasc Endovasc Surg. 2007; 33: 391-394
        • Muskiet F.A.
        The importance of (early) folate status to primary and secondary coronary artery disease prevention.
        Reprod Toxicol. 2005; 20: 403-410
        • Blom H.J.
        Robinson K. Homocysteine and cholesterol, basic and clinical interactions in Hcy and vascular disease. Kluwer Academic Publishers, Dordrecht, The Netherlands2000: 335-348
        • Giusti B.
        • Saracini C.
        • Bolli P.
        • et al.
        Abbate R genetic analysis of 56 polymorphisms in 17 genes involved in methionine metabolism in patients with abdominal aortic aneurysm.
        J Med Genet. 2008 Nov; 45: 721-730
        • Strauss E.
        • Waliszewski K.
        • Gabriel M.
        • Zapalski S.
        • Pawlak A.L.
        Increased risk of the abdominal aortic aneurysm in carriers of the MTHFR 677T allele.
        J Appl Genet. 2003; 44: 85-93
        • Chen Z.
        • Karaplis A.
        • Ackerman S.L.
        • et al.
        Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition.
        Hum Mol Genet. 2001 Mar; 10: 433-443
        • Harrison S.C.
        • Holmes M.V.
        • Agu O.
        • Humphries S.E.
        Genome wide association studies of abdominal aortic aneurysms-biological insights and potential translation applications.
        Atherosclerosis. 2011; 217: 47-56
        • Jones G.T.
        • Harris E.L.
        • Phillips L.
        • van Rij A.M.
        The methylenetetrahydrofolate reductase C677T polymorphism does not associate with susceptibility to abdominal aortic aneurysm.
        Eur J Vasc Endovasc Surg. 2005; 30: 137-142
        • Ferrara F.
        • Novo S.
        • Grimaudo S.
        • et al.
        Methylenetetrahydrofolate reductase mutation in subjects with abdominal aortic aneurysm divided by age.
        Clin Hemorheol Microcirc. 2006; 34: 421-426
        • Sharma P.
        • Senthilkumar R.D.
        • Brahmachari V.
        • et al.
        Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies.
        Review Lipids Health Dis. 2006 Jan 23; 5
        • Dragani A.
        • Falco A.
        • Santilli F.
        • et al.
        Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C>T polymorphism.
        Thromb Haemost. 2012 Sep; 108: 533-542
        • Malinowska J.
        • Olas B.
        Homocysteine and its thiolactone-mediated modification of fibrinogen affect blood platelet adhesion.
        Platelets. 2012; 23: 409-412
        • Rasmussen K.
        • Møller J.
        Total homocysteine measurement in clinical practice.
        Ann Clin Biochem. 2000; 37: 627-648
        • Bellamy M.F.
        • McDowell I.F.
        • Ramsey M.W.
        • et al.
        Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults.
        Circulation. 1998; 98: 1848-1852
        • Dawson H.
        • Collins G.
        • Pyle R.
        • Deep-Dixit V.
        • Taub D.D.
        The immunoregulatory effects of homocysteine and its intermediates on t-lymphocyte function.
        Mech Ageing Dev. 2004; 125: 107-110
        • Ungvari Z.
        • Pacher P.
        • Rischak K.
        • Szollar L.
        • Koller A.
        Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyperhomocysteinemia.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1899-1904
        • Hershfield M.S.
        • Kredich N.M.
        • Koller C.A.
        • et al.
        S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2′-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine.
        Cancer Res. 1983; 43: 3451-3458
        • Caudill M.A.
        • Wang J.C.
        • Melnyk S.
        • et al.
        Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine beta-synthase heterozygous mice.
        J Nutr. 2001; 131: 2811-2818
        • Capdevila A.
        • Decha-Umphai W.
        • Song K.H.
        • Borchardt R.T.
        • Wagner C.
        Pancreatic exocrine secretion is blocked by inhibitors of methylation.
        Arch Biochem Biophys. 1997; 345: 47-55
        • Castro R.
        • Rivera I.
        • Martins C.
        • et al.
        Intracellular S-adenosylhomocysteine increased levels are associated with DNA hypomethylation in HUVEC.
        J Mol Med (Berl). 2005; 83: 831-836
        • Cacciapuoti F.
        Hyper-homocysteinemia: a novel risk factor or a powerful marker for cardiovascular diseases? Pathogenetic and therapeutical uncertainties.
        J Thromb Thrombolysis. 2011; 32: 82-88
        • Kerins D.M.
        • Koury M.J.
        • Capdevila A.
        • Rana S.
        • Wagner C.
        Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine.
        Am J Clin Nutr. 2001; 74: 723-729
        • Wagner C.
        • Koury M.J.
        S-Adenosylhomocysteine: a better indicator of vascular disease than homocysteine?.
        Am J Clin Nutr. 2007; 86: 1581-1585
        • Ingrosso D.
        • Cimmino A.
        • Perna A.F.
        • et al.
        Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia.
        Lancet. 2003; 361: 1693-1699
        • Yi P.
        • Melnyk S.
        • Pogribna M.
        • Pogribny I.P.
        • Hine R.J.
        • James S.J.
        Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation.
        J Biol Chem. 2000; 275: 29318-29323
        • Ikegami K.
        • Ohgane J.
        • Tanaka S.
        • Yagi S.
        • Shiota K.
        Interplay between DNA methylation, histone modification and chromatin remodelling in stem cells and during development.
        Int J Dev Biol. 2009; 53: 203-214
        • James S.J.
        • Melnyk S.
        • Pogribna M.
        • Pogribny I.P.
        • Caudill M.A.
        Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology.
        J Nutr. 2002; 132: 2361S-2366S
        • Bestor T.H.
        The DNA methyltransferases of mammals.
        Hum Mol Genet. 2000; 9: 2395-2402
        • Perna A.F.
        • Ingrosso D.
        • Lombardi C.
        • et al.
        Possible mechanisms of homocysteine toxicity.
        Kidney Int Suppl. 2003; 84: S137-S140
        • Williams K.T.
        • Garrow T.A.
        • Schalinske K.L.
        Type I diabetes leads to tissue-specific DNA hypomethylation in male rats.
        J Nutr. 2008; 138: 2064-2069
        • Zaina S.
        • Lindholm M.W.
        • Lund G.
        Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?.
        J Nutr. 2005; 135: 5-8
        • Pascale R.M.
        • Simile M.M.
        • De Miglio M.R.
        • Feo F.
        Chemoprevention of hepatocarcinogenesis: S-adenosyl-L-methionine.
        Alcohol. 2002; 27: 193-198
        • Szyf M.
        The dynamic epigenome and its implications in toxicology.
        Toxicol Sci. 2007; 100: 7-23
        • Jamaluddin M.D.
        • Chen I.
        • Yang F.
        • et al.
        Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene.
        Blood. 2007; 110: 3648-3655
        • Castro R.
        • Rivera I.
        • Struys E.A.
        • et al.
        Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease.
        Clin Chem. 2003; 49: 1292-1296
        • Perna A.F.
        • Ingrosso D.
        • de Santo N.G.
        • Galletti P.
        • Zappia V.
        Mechanism of erythrocyte accumulation of methylation inhibitor S-adenosylhomocysteine in uremia.
        Kidney Int. 1995; 47: 247-253
        • Perna A.F.
        • Ingrosso D.
        • de Santo N.G.
        • Galletti P.
        • Brunone M.
        • Zappia V.
        Metabolic consequences of folate-induced reduction of hyperhomocysteinemia in uremia.
        J Am Soc Nephrol. 1997; 8: 1899-1905
        • Perna A.F.
        • Ingrosso D.
        • Zappia V.
        • Galletti P.
        • Capasso G.
        • de Santo N.G.
        Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine.
        J Clin Invest. 1993; 91: 2497-2503
        • Jamaluddin M.S.
        • Yang X.
        • Wang H.
        Hyperhomocysteinemia, DNA methylation and vascular disease.
        Clin Chem Lab Med. 2007; 45: 1660-1666
        • Wang H.
        • Yoshizumi M.
        • Lai K.
        • et al.
        Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine.
        J Biol Chem. 1997; 272: 25380-25385
        • Sharma P.
        • Kumar J.
        • Garg G.
        • et al.
        Detection of altered global DNA methylation in coronary artery disease patients.
        DNA Cell Biol. 2008; 27: 357-365
        • Fryer A.A.
        • Emes R.D.
        • Ismail K.M.
        • et al.
        Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans.
        Epigenetics. 2011; 6: 86-94
        • Dong C.
        • Yoon W.
        • Goldschmidt-Clermont P.J.
        DNA methylation and atherosclerosis.
        J Nutr. 2002; 132: 2406S-2409S
        • Lund G.
        • Andersson L.
        • Lauria M.
        • et al.
        DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E.
        J Biol Chem. 2004; 279: 29147-29154
        • Liu C.
        • Wang Q.
        • Guo H.
        • et al.
        Plasma S-adenosylhomocysteine is a better biomarker of atherosclerosis than homocysteine in apolipoprotein E-deficient mice fed high dietary methionine.
        J Nutr. 2008; 138: 311-315
        • Hiltunen M.O.
        • Turunen M.P.
        • Hakkinen T.P.
        • et al.
        DNA hypomethylation and methyltransferase expression in atherosclerotic lesions.
        Vasc Med. 2002; 7: 5-11
        • Li Y.
        • Liu Y.
        • Strickland F.M.
        • Richardson B.
        Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes.
        Exp Gerontol. 2010; 45: 312-322
        • Zhang J.G.
        • Liu J.X.
        • Li Z.H.
        • Wang L.Z.
        • Jiang Y.D.
        • Wang S.R.
        Dysfunction of endothelial NO system originated from homocysteine-induced aberrant methylation pattern in promoter region of DDAH2 gene.
        Chin Med J (Engl). 2007; 120: 2132-2137
        • Bleich S.
        • Lenz B.
        • Ziegenbein M.
        • et al.
        Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence.
        Alcohol Clin Exp Res. 2006; 30: 587-591
        • Lenz B.
        • Bleich S.
        • Beutler S.
        • et al.
        Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites.
        Exp Cell Res. 2006; 312: 4049-4055
        • Huang Y.
        • Peng K.
        • Su J.
        • Xu Y.
        • Wang S.
        Different effects of homocysteine and oxidized low density lipoprotein on methylation status in the promoter region of the estrogen receptor alpha gene.
        Acta Biochim Biophys Sin (Shanghai). 2007; 39: 19-26
        • Kim J.
        • Kim J.Y.
        • Song K.S.
        • et al.
        Epigenetic changes in estrogen receptor beta gene in atherosclerotic cardiovascular tissues and in-vitro vascular senescence.
        Biochim Biophys Acta. 2007; 1772: 72-80
        • Yi-Deng J.
        • Tao S.
        • Hui-Ping Z.
        • et al.
        DNA methylation induced by homocysteine in human monocytes.
        DNA Cell Biol. 2007; 26: 737-744
        • Yideng J.
        • Zhihong L.
        • Jiantuan X.
        • Jun C.
        • Guizhong L.
        • Shuren W.
        Homocysteine-mediated PPARalpha, gamma DNA methylation and its potential pathogenic mechanism in monocytes.
        DNA Cell Biol. 2008; 27: 143-150
        • Li L.
        • Xie J.
        • Zhang M.
        • Wang S.
        Homocysteine harasses the imprinting expression of IGF2 and H19 by demethylation of differentially methylated region between IGF2/H19 genes.
        Acta Biochim Biophys Sin (Shanghai). 2009; 41: 464-471
        • Devlin A.M.
        • Bottiglieri T.
        • Domann F.E.
        • Lentz S.R.
        Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia.
        J Biol Chem. 2005; 280: 25506-25511
        • Jiang Y.
        • Zhang J.
        • Xiong J.
        • Cao J.
        • Li G.
        • Wang S.
        Ligands of peroxisome proliferator-activated receptor inhibit homocysteine-induced DNA methylation of inducible nitric oxide synthase gene.
        Acta Biochim Biophys Sin (Shanghai). 2007; 39: 366-376
        • Bonaldi T.
        • Imhof A.
        • Regula J.T.
        A combination of different mass spectroscopic techniques for the analysis of dynamic changes of histone modifications.
        Proteomics. 2004; 4: 1382-1396
        • Zhang K.
        • Tang H.
        Analysis of core histones by liquid chromatography-mass spectrometry and peptide mapping.
        J Chromatogr B Analyt Technol Biomed Life Sci. 2003; 783: 173-179
        • Jiang Y.
        • Jiang J.
        • Xiong J.
        • et al.
        Homocysteine-induced extracellular superoxide dismutase and its epigenetic mechanisms in monocytes.
        J Exp Biol. 2008; 211: 911-920
        • Choi J.H.
        • Nam K.H.
        • Kim J.
        • et al.
        Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice.
        Arterioscler Thromb Vasc Biol. 2005; 25: 2404-2409
        • Shane B.
        • Stokstad E.L.
        Vitamin B12-folate interrelationships.
        Annu Rev Nutr. 1985; 5: 115-141
        • Friso S.
        • Choi S.W.
        Gene-nutrient interactions and DNA methylation.
        J Nutr. 2002; 132: 2382S-2387S
        • Kruman II,
        • Culmsee C.
        • Chan S.L.
        • et al.
        Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.
        J Neurosci. 2000; 20: 6920-6926
        • Choi S.W.
        • Mason J.B.
        Folate status: effects on pathways of colorectal carcinogenesis.
        J Nutr. 2002; 132: 2413S-2418S
        • Piyathilake C.J.
        • Celedonio J.E.
        • Macaluso M.
        • Bell W.C.
        • Azrad M.
        • Grizzle W.E.
        Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix.
        Nutrition. 2008; 24: 94-99
        • Sauer J.
        • Mason J.B.
        • Choi S.W.
        Too much folate: a risk factor for cancer and cardiovascular disease?.
        Curr Opin Clin Nutr Metab Care. 2009; 12: 30-36
        • Clapin H.F.
        • Fritschi L.
        • Iacopetta B.
        • Heyworth J.S.
        Dietary and supplemental folate and the risk of left- and right-sided colorectal cancer.
        Nutr Cancer. 2012; 64: 937-945
        • Williams E.A.
        Folate, colorectal cancer and the involvement of DNA methylation.
        Proc Nutr Soc. 2012; 71: 592-597
        • Yang Q.
        • Botto L.D.
        • Erickson J.D.
        • et al.
        Improvement in stroke mortality in Canada and the United States, 1990 to 2002.
        Circulation. 2006; 113: 1335-1343
        • Lonn E.
        • Yusuf S.
        • Arnold M.J.
        • et al.
        Homocysteine lowering with folic acid and B vitamins in vascular disease.
        N Engl J Med. 2006; 354: 1567-1577
        • Bonaa K.H.
        • Njolstad I.
        • Ueland P.M.
        • et al.
        Homocysteine lowering and cardiovascular events after acute myocardial infarction.
        N Engl J Med. 2006; 354: 1578-1588
        • Hoffer L.J.
        Testing the homocysteine hypothesis in end-stage renal disease: problems and a possible solution.
        Kidney Int. 2006; 69: 1507-1510
        • Saposnik G.
        • Ray J.G.
        • Sheridan P.
        • McQueen M.
        • Lonn E.
        Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial.
        Stroke. 2009; 40: 1365-1372
        • Hodis H.N.
        • Mack W.J.
        • Dustin L.
        • et al.
        High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial.
        Stroke. 2009; 40: 730-736
        • Maron B.A.
        • Loscalzo J.
        The treatment of hyperhomocysteinemia.
        Annu Rev Med. 2009; 60: 39-54
        • Mager A.
        • Orvin K.
        • Koren-Morag N.
        • et al.
        Impact of homocysteine-lowering vitamin therapy on long-term outcome of patients with coronary artery disease.
        Am J Cardiol. 2009; 104: 745-749
        • Bazzano L.A.
        Folic acid supplementation and cardiovascular disease: the state of the art.
        Am J Med Sci. 2009; 338: 48-49
        • Song Y.
        • Cook N.R.
        • Albert C.M.
        • Van Denburgh M.
        • Manson J.E.
        Effect of homocysteine-lowering treatment with folic Acid and B vitamins on risk of type 2 diabetes in women: a randomized, controlled trial.
        Diabetes. 2009; 58: 1921-1928
        • Ingrosso D.
        • Perna A.F.
        Epigenetics in hyperhomocysteinemic states. A special focus on uremia.
        Biochim Biophys Acta. 2009; 1790: 892-899