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Oxidative Medicine and Cellular Longevity
Volume 2017, Article ID 1670815, 7 pages
https://doi.org/10.1155/2017/1670815
Review Article

DNA Methylation and the Potential Role of Methyl-Containing Nutrients in Cardiovascular Diseases

1Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Center of Healthy Livestock, Hunan Co-Innovation Center of Animal Production Safety, Hunan 410125, China
2University of Chinese Academy of Sciences, Beijing 100049, China
3State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
4College of Packaging and Printing Engineering, Tianjin University of Science and Technology, Tianjin 300222, China
5Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, MSC08 4670, Fitz 258, Albuquerque, NM 87131, USA
6Animal Nutrition and Human Health Laboratory, School of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China
7College of Animal Science, South China Agricultural University, Guangzhou 510642, China

Correspondence should be addressed to Wenkai Ren; moc.621@91iaknewner and Jun Liang; nc.ude.tsut@8111gnailj

Received 27 March 2017; Accepted 31 October 2017; Published 16 November 2017

Academic Editor: Giuseppe Cirillo

Copyright © 2017 Gang Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Patients suffering from cardiovascular diseases (CVDs) experience a low quality of life and increase pressure on healthcare systems both nationally and globally. DNA methylation, which refers to the pathway by which DNA methyltransferase facilitates the addition of a methyl group to DNA, is of critical importance in this respect primarily because the epigenetic modification is implicated in a range of serious conditions including atherosclerosis, CVDs, and cancer. Research findings indicate that the number of epigenetic alterations can be elicited (both in utero and in adults) through the administration of certain nutritional supplements, including folic acid and methionine; this is partly attributable to the effect employed by methyl-containing nutrients in DNA methylation. Thus, for the purpose of illuminating viable therapeutic measures and preventive strategies for CVDs, research should continue to explore the intricate associations that exist between epigenetic regulation and CVD pathogenesis. This review centers on an exposition of the mechanism by which DNA methylation takes place, the impact it has on a range of conditions, and the potential clinical value of nutrition, driven mainly by the observation that nutritional supplements such as folic acid can affect DNA methylation.

1. Introduction

Dietary factors are chief determinants of CVD pathogenesis, and despite the fact that the precise way in which this takes place still remains unclear, Zhu et al. suggest that epigenetic processes may be significant [1]. In view of the centrality of epigenetics to this discussion, it is useful to highlight that epigenetics can generally be described as the modification of gene expression that arises concurrently with no such modification in DNA sequence [2]. Several epigenetic studies have further explained that the term denotes the transmissible modifications that arise in gene expression that is not illuminated by alterations in DNA sequence; rather, the mediation of the modifications takes place by chromatin-based mechanisms [35]. Chromatin modifications, miRNA, and DNA methylation are among the currently identified epigenetic procedures, and it is also important to recognize that epigenetic control is a central regulatory system that informs the phenotypic variance observed with respect to cell types in multicellular organisms [6].

Significant research has been conducted on DNA methylation, with key findings showing that epigenetic alterations in DNA play a prominent part in regulating gene expression. Importantly, epigenetic alteration occurs in gametogenesis with respect to the genetic information translated onto genes, and the expression or transferal of this information then takes place in the direction of the inheritor’s family. Although the importance of DNA methylation and the part it plays in the pathogenesis of a range of diseases and biological procedures is not fully understood, research findings have implicated it in atherosclerosis, CVDs, imprinting conditions, cancer, and the phenomenon of ageing [2]. Nevertheless, a notable finding was reported by Waterland and Jirtle which highlighted epigenomic marks’ responses to environmental variance, as is the case with modifications in nutritional status [7]. Epigenomic marks therefore present opportune diet-based objects on which preventive and therapeutic investigations centering on CVD can be focused on. The reversibility of DNA methylation must also be acknowledged, in addition to the role it plays in CVD pathogenesis and the positive impacts that arise from nutritional supplements. These considerations are further explored in the following section.

2. DNA Methylation

DNA methylation can be described as the process by which a methyl group is added covalently to the C5 position of cytosine residues [8]. To further specify the nature of the process, Law et al. showed that DNA methylation takes place in the cytosine-paired-with-guanine (CpG) dinucleotide sequences [8]. Further research revealed that DNA methylation also takes place at cytosine residues which are not placed adjacently to guanine residues [9] and Law et al. indicated that the process is implicated in the standard cell-based manipulation of gene expression [8]. This study also found that the regulation of DNA methylation occurs dynamically [10]. The long-held perspective that DNA methylation serves as an epigenetic mark characterized by stability has been challenged by the recent identification of active DNA demethylation in postmitotic cells as well as dynamic DNA methylation and demethylation in vivo [11].

The genome-wide demethylation regarding the parental genomes takes place instantaneously following fertilization and continues throughout the preliminary phases of an embryo’s development [12]. Concurrent with this, methylation configurations are reprogrammed and the whole process indicates that a part is being played by available heritable epigenetic memory [12]. This suggest that configurations are transferred over the course of somatic cell division during the lifespan. The observation that susceptibility to external factors that can impact methylation may be a feature of this epigenetic reprogramming process is an important consideration, and it is also worth noting that DNA methylation states do not remain constant throughout a lifespan. Scholarly research has not centered on such modifications with CVDs until relatively recently, with prominent areas of study now focusing on atherosclerosis, hypertension, and diabetes [13]. In addition, the tissue- and cell-specific nature of the epigenetic regulation of gene expression and DNA methylation profiles means that susceptibilities are also tissue- and cell-specific and are also informed by the biological sex and lifespan phase of the organism.

DNA methyltransferases (DNMTs) are responsible for facilitating and regulating DNA methylation, and de novo methylation takes place over the course of embryogenesis as a consequence of the presence of DNMT3a and DNMT3b. In contrast, maintenance methylation takes place over the course of somatic cell division as a consequence of the presence of DNMT1 [14, 15]. Evidence suggests that inducement of epigenetic modifications is facilitated by hydrogen peroxide (H2O2)—a reactive oxygen species (ROS)—and this involves the increasing tightening of DNMT1’s binding to chromatin following hydrogen peroxide treatment. Ultimately, this changes the methylation status of CpG regions [16, 17]. One study demonstrated that mouse DNA that lacks genes to code for methylation enzymes such as DNMTs or methylenetetrahydrofolate reductase (MTHFR) will present with hypomethylation, and it also noted that such mouse DNA displays an increased expression of inflammatory mediators [18]. DNA hypomethylation in mice lacking MTHFR has also been identified as occurring prior to the emergence of aortic fatty streaks [19, 20].

Groups of CpGs, known as “CpG islands,” have been linked to gene promoters, most of which are unmethylated. These CpG islands perform a critical function in the regulation of gene expression, as clearly demonstrated in the context of tissue-specific and developmental-specific configurations [10, 21].

Although CpG islands have been identified as being located in both intragenic and intergenic areas, further study is required to ascertain the functioning of each of these domains. The methylation of DNA at sites inside a promoter region or other sites purposed with regulation is frequently linked with the “silencing” of gene expression, and silencing has a similar capacity to arise when DNA methylation is modified external to a promoter area and not internal to a CpG island [22, 23]. Often referred to as a “CpG island shore,” this occurs in sequences approximately 2 kb upstream [10, 21]. It should also be noted that the potential exists for this to impact the transcriptional activation process, and it is also relevant to emphasize that methylated DNA can counteract the transcriptional activation of chromatic structure, thereby causing it to be in the repressive state [24].

3. DNA Methylation and CVDs

Although the pathogenesis of atherosclerosis is known to involve the propagation of vascular smooth muscles cells (SMCs), the gathering of lipids, the progression of connective tissue, the intrusion of inflammatory cells, and the process of calcification [25], available knowledge regarding the methylation of genes implicated in atherosclerosis is not extensive. Research has, however, demonstrated that a range of atheroprotective genes including ESR1 and ESR2, which encode the oestrogen receptors ERα and ERβ, respectively, are repeatedly subject to hypermethylation in both human coronary atherosclerotic tissues and the plaque areas of the ascending aorta. Kim et al. found evidence suggesting that atherosclerosis can be counteracted by the presence of ERs in the coronary arterial wall regarding SMCs and endothelial cells (ECs) [26]. In addition, tissue samples from individuals subjected to coronary artery bypass grafting indicated the presence of ESR1 hypermethylation in several areas including the aorta, internal mammary artery, and saphenous vein, with higher rates also found to be present in coronary artery atherosclerotic plaques [9].

Evidence linking atherosclerosis with DNA methylation has been found in numerous research studies focusing on both humans and animals [6]. In Lund et al., researchers sought to evaluate DNA methylation in the preliminary phases of atherosclerosis, and it was found that apolipoprotein E-deficient (ApoE−/−) mice displaying vascular lesions are associated with global DNA hypomethylation in aorta and PBMCs [27, 28]. The researchers also identified modifications in the DNA methylation configuration in each tissue category before vascular damage became discernible. In another study, genomic DNA hypomethylation was observed in highly developed atherosclerotic damage in human patients, atherosclerotic damage in ApoE−/− mice, and aortic neointima in balloon-denuded New Zealand white rabbits [29].

It can be concluded from these outcomes that DNA methylation is implicated in the pathogenesis of atherosclerosis. Another group of researchers illuminated methylated CpGs in a differential way, linking them to the occurrence of atherosclerosis and endothelial and smooth muscle operation by formulating a DNA methylation map linked to atherosclerosis in human patients [30]. Zaina et al. identified an increase in atherosclerotic damage relating to DNA methylation, thereby outlining the promise associated with the idea of formulating DNA demethylating measures to facilitate viable clinical outcomes [30]. The Singapore Chinese Health Study also noted that men who have a history of CVD or who are associated with CVD risk factors are characterized by a greater leukocyte global DNA methylation status [31]. In addition, the Samoan Family Study of Overweight and Diabetes found a negative correlation between leukocyte LINE-1 methylation status and plasma LDL in a total sample size of 355 [30]. The study also uncovered a positive correlation between leukocyte LINE-1 methylation status and plasma HDL [32]. The key point to note with regard to these findings is that they reinforce the notion that the global DNA methylation profile of peripheral blood leukocytes has the potential to serve as an appropriate biomarker for heightened risk of CVD.

It is also worthwhile to point out that hyperhomocysteinemia is associated with a reduction in the generation of nitric oxide (NO) and VEGF and is similarly linked to a decrease in global DNA methylation levels and the gene-specific methylation of certain promoters [33, 34]. Research has indicated that DNA methylation is implicated in vascular complications linked to heightened Hcy circulating levels [35]. DNMT1 inhibition, DNA hypomethylation, and chromatin remodeling have been shown to facilitate the inhibition of the expression of certain genes, which further mediate Hcy-induced cyclin A (CCNA2) gene silencing and growth inhibition in regard to ECs [36, 37].

4. Methyl-Containing Nutrients and Potential Roles in CVDs

Nutritional factors are important for a variety of reasons, most notably because they counteract the adverse impacts that result from disease and impact in utero progression [3840]. Evidence has been published to suggest that certain nutritional supplements have the capacity to control DNA methylation. For example, research findings indicate that the administration of certain nutritional supplements, including folic acid and methionine, can lower the number of epigenetic alterations (in utero and in adults), and this is attributable to the part played by methyl-containing nutrients in DNA methylation [41, 42]. The primary donor of methyl group is S-adenosylmethionine (SAM), which is produced from methionine, and the operation of DNA methyltransferase facilitates the methylation reaction. “Methyl nutrients” is the term frequently used to denote the nutritional components needed to facilitate methylation reactions, with vitamins and amino acids being the two major categories of such nutrients [34]. Examples of vitamins include vitamin B12, choline, folate, and riboflavin, while examples of the amino acids include methionine, serine, and glycine.

The majority of studies addressing methyl nutrient disequilibrium and DNA methylation have focused on folate status and hyperhomocysteinemia (HHcys). Many of these studies have documented the way in which a lack of folic acid can result in global DNA hypomethylation, the key implication of which is the connection to cancer and CVD risk [4345]. Research has also noted that folic acid and B vitamins facilitate the development of SAM by providing the one-carbon-metabolism with methionine in a direct manner [46]. Vitamin B substitution therapy involves the usage of folic acid, vitamin B6, and vitamin B12 and is an important process in this context; its chief point of value stems from the way in which it lowers the plasma homocysteine (Hcys) level [47]. The methylation of Hcys to produce methionine is underpinned by the presence of folic acids, and reduced serum levels for folic acid have also been implicated in higher serum levels for Hcys [48]. Supplementing one’s diet each day with folic acid and specific types of vitamin B can therefore lower plasma Hcys levels. Prognosis for those suffering from CHD is improved, while CVD risk is decreased for those with no health impairment [49]. Owing to the impact that folate has with respect to the metabolism of nitric oxide, recent studies have drawn connections between it and endothelial dysfunction. In research examining individuals suffering from coronary artery disease (CAD), authors have identified that people homozygous for the MTHFR 677C>T variant were associated with higher vascular 5-methyl-THF concentrations, while no disparities were observed regarding vascular total Hcys concentrations [50, 51]. These findings were linked to endothelial dysfunction and vascular oxidative stress.

Nevertheless, the available knowledge of the impact that the significant consumption of folic acid has with respect to methyl metabolism and DNA methylation remains limited. Only one study in the extant literature presents results showing that leukocyte global DNA methylation was not impacted by 800 g per day folic acid supplementation [52]. In contrast, increased RBC folate status has been linked to a decrease in leukocyte global DNA methylation for postmenopausal females [53]. It is clear that further research is required to identify the impact that the significant consumption of folic acid has on gene-specific DNA methylation processes and DNA methylation processes for certain blood cell categories.

Several researchers have reported that DNA methylation may be linked to vascular issues and a higher risk of CVD in conjunction with higher Hcys circulation levels [54]. Numerous projects, focusing on both animals and humans, have identified a link between HHcys and vascular endothelial dysfunction (VED)—conceptualized here as damaged vascular endothelium-dependent vasodilation. This is significant because it serves as a preliminary marker for vascular disease as a condition which frequently foreshadows cardiovascular damage [55]. VED was linked to patients displaying severe HHcys after an oral methionine load [56] and a study focusing on older females noted reduced global DNA methylation in leukocytes with reduced serum folate concentrations and increased overall Hcys concentrations on a low-folate 7-week-long diet [57]. In a similar study on metabolic balance carried out by Jacob et al., postmenopausal females were administered with a low-folate diet for a period of 41 days, with the results showing a decrease in lymphocyte global DNA methylation and plasma folate and a corresponding increase in Hcys [58].

One critical consideration for the interpretation of human-based research outcomes is the nature of the tissue specificity of the association between circulating overall Hcys concentrations and intracellular SAH concentrations. This stems from the fact that the assessment of DNA methylation frequently takes place with respect to the heterogeneous cell population of peripheral blood mononuclear cells (PBMCs). Heightened plasma and lymphocyte SAH concentrations were connected to lower global DNA methylation with respect to leukocytes and lymphocytes in two studies using participants linked to HHcys [59, 60]. However, other studies have also found no evidence for this connection [61, 62]. Ingrosso et al. demonstrated gene-specific linkages of HHcys in regard to DNA methylation for humans [63]. Individuals suffering from kidney failure, thereby being connected to haemodialysis and HHcys, were associated with global DNA hypomethylation when considered in relation to control subjects. A subgroup of individuals displaying the greatest level of acute HHcys also displayed biallelic expression of the imprinted H19 gene, and this was attributed to DNA methylation modifications in leukocytes [63].

More research must be conducted regarding the connection between cysteine and CVDs [64]. More specifically, research has found that the cysteine-CVD risk association can be illuminated by the relationship between circulating overall cysteine concentrations and BMI. This supports the widely accepted fact that obese individuals, or those whose BMI is above the recommended upper limit, are more likely to develop CVDs. In the Hordaland Hcys Study, plasma overall cysteine concentrations and BMI and fat mass at baseline were found to be positively correlated [65]. This research suggests that adiposity, a critical determinant of CVD, could be marked by circulating overall cysteine concentrations [64, 65].

Notably, the rapid accumulation of mass was identified when animals consumed large volumes of cysteine or cysteine-rich protein diets [66, 67]. More specifically, after conducting a case-control study for CVD sufferers and healthy controls, a normally distributed correlation for CVD and plasma overall cysteine concentrations was identified (here, the highest level of risk was linked to plasma concentrations of less than 225 mol/L and greater than 300 mol/L) [64]. CVD sufferers were associated with greater plasma overall cysteine concentrations when compared to healthy controls, but it should be noted that the preponderance of results collected suggest that the degree to which the target association is significant is not manifest [68]. As such, it is possible that the primary relationship may be that displayed with respect to adiposity and plasma overall cysteine concentrations.

5. Conclusion

The key preventive role that effective nutrition plays in the context of CVDs has been further emphasized by the wealth of epidemiological and clinical research indicating that properly functioning cardiovascular systems are underpinned by DNA methylation and posttranslational chromatic alterations. DNA methylation facilitates the regulation of gene expression due to the way in which it manipulates the transcription of relevant genes, and the process therefore has the capacity to result in epigenetic alteration. Here, methyl-containing nutrients perform an important function in restricting DNA methylation, and in light of this, subsequent studies should continue to examine the utility of therapeutic measures in mitigating the negative effects arising from DNA methylation.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Acknowledgments

This research was supported by the National Natural Science Foundation of China (nos. 31772642, 31702125, and 31672457), National Key Research and Development Program of China (2016YFD0500504, 2016YFD0501201), International Partnership Program of Chinese Academy of Sciences (161343KYSB20160008), key programs of frontier scientific research of the Chinese Academy of Sciences (QYZDY-SSW-SMC008), and Chinese Academy of Sciences Visiting Professorship for Senior International Scientists Grant no. 2016VBB007.

References

  1. S. Zhu, P. J. Goldschmidt-Clermont, and C. Dong, “Inactivation of monocarboxylate transporter MCT3 by DNA methylation in atherosclerosis,” Circulation, vol. 112, no. 9, pp. 1353–1361, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. D. A. Chistiakov, V. A. Myasoedova, A. N. Orekhov, and Y. V. Bobryshev, “Epigenetically active drugs inhibiting DNA methylation and histone deacetylation,” Current Pharmaceutical Design, vol. 22, no. 37, pp. 5738–5751, 2016. View at Publisher · View at Google Scholar · View at Scopus
  3. C. L. Relton and G. Davey Smith, “Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease,” International Journal of Epidemiology, vol. 41, no. 1, pp. 161–176, 2012. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Sierra, A. Valdes, A. F. Fernandez, R. Torrecillas, and M. F. Fraga, “The effect of exposure to nanoparticles and nanomaterials on the mammalian epigenome,” International Journal of Nanomedicine, vol. 11, pp. 6297–6306, 2016. View at Publisher · View at Google Scholar · View at Scopus
  5. B. E. Bernstein, A. Meissner, and E. S. Lander, “The mammalian epigenome,” Cell, vol. 128, no. 4, pp. 669–681, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. D. A. Chistiakov, A. N. Orekhov, and Y. V. Bobryshev, “Treatment of cardiovascular pathology with epigenetically active agents: focus on natural and synthetic inhibitors of DNA methylation and histone deacetylation,” International Journal of Cardiology, vol. 227, pp. 66–82, 2017. View at Publisher · View at Google Scholar
  7. R. A. Waterland and R. L. Jirtle, “Transposable elements: targets for early nutritional effects on epigenetic gene regulation,” Molecular and Cellular Biology, vol. 23, no. 15, pp. 5293–5300, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. J. A. Law and S. E. Jacobsen, “Establishing, maintaining and modifying DNA methylation patterns in plants and animals,” Nature Reviews Genetics, vol. 11, no. 3, pp. 204–220, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. R. Lister, M. Pelizzola, R. H. Dowen et al., “Human DNA methylomes at base resolution show widespread epigenomic differences,” Nature, vol. 462, no. 7271, pp. 315–322, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. A. M. Deaton and A. Bird, “CpG islands and the regulation of transcription,” Genes & Development, vol. 25, no. 10, pp. 1010–1022, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. M. Klug, S. Heinz, C. Gebhard et al., “Active DNA demethylation in human postmitotic cells correlates with activating histone modifications, but not transcription levels,” Genome Biology, vol. 11, no. 6, p. R63, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. A. V. Probst and G. Almouzni, “Heterochromatin establishment in the context of genome-wide epigenetic reprogramming,” Trends in Genetics, vol. 27, no. 5, pp. 177–185, 2011. View at Publisher · View at Google Scholar · View at Scopus
  13. C. Ling and L. Groop, “Epigenetics: a molecular link between environmental factors and type 2 diabetes,” Diabetes, vol. 58, no. 12, pp. 2718–2725, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. J. Lan, S. Hua, X. N. He, and Y. Zhang, “DNA methyltransferases and methyl-binding proteins of mammals,” Acta Biochimica et Biophysica Sinica, vol. 42, no. 4, pp. 243–252, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. T. H. Bestor, “The DNA methyltransferases of mammals,” Human Molecular Genetics, vol. 9, no. 16, pp. 2395–2402, 2000. View at Publisher · View at Google Scholar
  16. H. M. O'Hagan, W. Wang, S. Sen et al., “Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands,” Cancer Cell, vol. 20, no. 5, pp. 606–619, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. H. M. O'Hagan, W. Wang, S. Sen et al., “Oxidative damage targets complexes containing DNA methyltransferases, SIRT1 and polycomb members to promoter CpG islands,” Cancer Research, vol. 103, no. 44, p. 71, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. K. W. Makar and C. B. Wilson, “DNA methylation is a nonredundant repressor of the Th2 effector program,” Journal of Immunology, vol. 173, no. 7, pp. 4402–4406, 2004. View at Publisher · View at Google Scholar
  19. J. M. Sontag, B. Wasek, G. Taleski et al., “Altered protein phosphatase 2A methylation and tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice,” Frontiers in Aging Neuroscience, vol. 6, 2014. View at Publisher · View at Google Scholar · View at Scopus
  20. Z. T. Chen, A. C. Karaplis, S. L. Ackerman et al., “Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition,” Human Molecular Genetics, vol. 10, no. 5, pp. 433–443, 2001. View at Publisher · View at Google Scholar
  21. Z. Su, G. Liu, X. Song, B. Liang, X. Chang, and D. Huang, “CpG island evolution in the mammalian DHRS4 gene cluster and its role in the regulation of gene transcription,” Genetics and Molecular Research, vol. 15, no. 2, 2016. View at Publisher · View at Google Scholar · View at Scopus
  22. M. H. Kim, M. S. Kim, W. Kim et al., “Suppressor of cytokine signaling (SOCS) genes are silenced by DNA hypermethylation and histone deacetylation and regulate response to radiotherapy in cervical cancer cells,” PLoS One, vol. 10, no. 4, article e0123133, 2015. View at Publisher · View at Google Scholar · View at Scopus
  23. Y. Watanabe, R. Oikawa, H. Yamamoto, and F. Itoh, “The BARHL2 gene is silenced by promoter hypermethylation in early stage of gastric cancer,” Gastroenterology, vol. 148, no. 4, p. S-933, 2015. View at Publisher · View at Google Scholar
  24. K. H. Wood, B. S. Johnson, S. A. Welsh et al., “Tagging methyl-CpG-binding domain proteins reveals different spatiotemporal expression and supports distinct functions,” Epigenomics, vol. 8, no. 4, pp. 455–473, 2016. View at Publisher · View at Google Scholar · View at Scopus
  25. J. C. Wang and M. Bennett, “Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence,” Circulation Research, vol. 111, no. 2, pp. 245–259, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. G. H. Kim, J. J. Ryan, and S. L. Archer, “The role of redox signaling in epigenetics and cardiovascular disease,” Antioxidants & Redox Signaling, vol. 18, no. 15, pp. 1920–1936, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. X. Lin, W. Zhang, Q. Lu et al., “Effect of MTHFR gene polymorphism impact on atherosclerosis via genome-wide methylation,” Medical Science Monitor, vol. 22, pp. 341–345, 2016. View at Publisher · View at Google Scholar · View at Scopus
  28. G. Lund, L. Andersson, M. Lauria et al., “DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E,” Journal of Biological Chemistry, vol. 279, no. 28, pp. 29147–29154, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Hiltunen, M. P. Turunen, T. P. Hakkinen et al., “DNA hypomethylation and methyltransferase expression in atherosclerotic lesions,” Vascular Medicine, vol. 7, no. 1, pp. 5–11, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Zaina, H. Heyn, F. J. Carmona et al., “DNA methylation map of human atherosclerosis,” Circulation. Cardiovascular Genetics, vol. 7, no. 5, pp. 692–700, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Kim, T. I. Long, K. Arakawa, R. W. Wang, M. C. Yu, and P. W. Laird, “DNA methylation as a biomarker for cardiovascular disease risk,” PLoS One, vol. 5, no. 3, article e9692, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. H. L. Cash, S. T. McGarvey, E. A. Houseman et al., “Cardiovascular disease risk factors and DNA methylation at the LINE-1 repeat region in peripheral blood from Samoan islanders,” Epigenetics, vol. 6, no. 10, pp. 1257–1264, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. F. Cacciapuoti, “Hyper-homocysteinemia: a novel risk factor or a powerful marker for cardiovascular diseases? Pathogenetic and therapeutical uncertainties,” Journal of Thrombosis and Thrombolysis, vol. 32, no. 1, pp. 82–88, 2011. View at Publisher · View at Google Scholar · View at Scopus
  34. M. B. Glier, T. J. Green, and A. M. Devlin, “Methyl nutrients, DNA methylation, and cardiovascular disease,” Molecular Nutrition & Food Research, vol. 58, no. 1, pp. 172–182, 2014. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Loscalzo and D. E. Handy, “Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series),” Pulmonary Circulation, vol. 4, no. 2, pp. 169–174, 2014. View at Publisher · View at Google Scholar
  36. F. Paneni, S. Costantino, M. Volpe, T. F. Luscher, and F. Cosentino, “Epigenetic signatures and vascular risk in type 2 diabetes: a clinical perspective,” Atherosclerosis, vol. 230, no. 2, pp. 191–197, 2013. View at Publisher · View at Google Scholar · View at Scopus
  37. M. D. Jamaluddin, I. Chen, F. Yang et al., “Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene,” Blood, vol. 110, no. 10, pp. 3648–3655, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. L. F. Hou, X. Zhang, D. Wang, and A. Baccarelli, “Environmental chemical exposures and human epigenetics,” International Journal of Epidemiology, vol. 41, no. 1, pp. 79–105, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. G. Liu, S. Chen, J. Zhong, K. Teng, and Y. Yin, “Crosstalk between tryptophan metabolism and cardiovascular disease, mechanisms, and therapeutic implications,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 1602074, 5 pages, 2017. View at Publisher · View at Google Scholar
  40. S. Chen, H. Jiang, H. Peng, X. Wu, and J. Fang, “The utility of ovotransferrin and ovotransferrin-derived peptides as possible candidates in the clinical treatment of cardiovascular diseases,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 6504518, 6 pages, 2017. View at Publisher · View at Google Scholar
  41. K. A. Lillycrop and G. C. Burdge, “Environmental challenge, epigenetic plasticity and the induction of altered phenotypes in mammals,” Epigenomics, vol. 6, no. 6, pp. 623–636, 2014. View at Publisher · View at Google Scholar · View at Scopus
  42. C. A. Markunas, A. J. Wilcox, Z. L. Xu et al., “Maternal age at delivery is associated with an epigenetic signature in both newborns and adults,” PLoS One, vol. 11, no. 7, article e0156361, 2016. View at Publisher · View at Google Scholar · View at Scopus
  43. H. McNulty, K. Pentieva, L. Hoey, and M. Ward, “Homocysteine, B-vitamins and CVD,” The Proceedings of the Nutrition Society, vol. 67, no. 02, pp. 232–237, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Zhou, L. Zhu, J. Wu, and S. Fang, “Is folic acid supplementation definitely beneficial to stroke prevention?: comment on: efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials,” European Journal of Internal Medicine, vol. 24, no. 4, p. e55, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. H. T. Yang, M. Lee, K. S. Hong, B. Ovbiagele, and J. L. Saver, “Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials,” European Journal of Internal Medicine, vol. 23, no. 8, pp. 745–754, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. H. Suzuki, T. Tokino, Y. Shinomura, K. Imai, and M. Toyota, “DNA methylation and cancer pathways in gastrointestinal tumors,” Pharmacogenomics, vol. 9, no. 12, pp. 1917–1928, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. B. Debreceni and L. Debreceni, “Why do homocysteine-lowering B vitamin and antioxidant E vitamin supplementations appear to be ineffective in the prevention of cardiovascular diseases?” Cardiovascular Therapeutics, vol. 30, no. 4, pp. 227–233, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. C. Schiano, M. T. Vietri, V. Grimaldi, A. Picascia, M. R. De Pascale, and C. Napoli, “Epigenetic-related therapeutic challenges in cardiovascular disease,” Trends in Pharmacological Sciences, vol. 36, no. 4, pp. 226–235, 2015. View at Publisher · View at Google Scholar · View at Scopus
  49. S. Ziakka, G. Rammos, S. Kountouris et al., “Hyperhomocysteinemia as a risk factor of cardiovascular disease in hemodialysis patients and the beneficial effects of folic acid and vitamin B-6,” Journal of Hypertension, vol. 20, p. S135, 2002. View at Google Scholar
  50. A. Juzeniene, T. T. T. Tam, V. Iani, and J. Moan, “5-Methyltetrahydrofolate can be photodegraded by endogenous photosensitizers,” Free Radical Biology and Medicine, vol. 47, no. 8, pp. 1199–1204, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. Y. Y. Qu, S. X. Zhou, X. Zhang et al., “Functional variants of the 5-methyltetrahydrofolate-homocysteine methyltransferase gene significantly increase susceptibility to prostate cancer: results from an ethnic Han Chinese population,” Scientific Reports, vol. 6, no. 1, 2016. View at Publisher · View at Google Scholar · View at Scopus
  52. A. Y. Jung, Y. Smulders, P. Verhoef et al., “No effect of folic acid supplementation on global DNA methylation in men and women with moderately elevated homocysteine,” PLoS One, vol. 6, no. 9, article e24976, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Bae, C. M. Ulrich, L. B. Bailey et al., “Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women’s Health Initiative Observational Study cohort,” Epigenetics, vol. 9, no. 3, pp. 396–403, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. D. E. Handy, R. Castro, and J. Loscalzo, “Epigenetic modifications basic mechanisms and role in cardiovascular disease,” Circulation, vol. 123, no. 19, pp. 2145–2156, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. C. I. Levene and J. C. Murray, “Etiological role of maternal vitamin-B6 deficiency in development of atherosclerosis,” Lancet, vol. 1, no. 8012, pp. 628–630, 1977. View at Publisher · View at Google Scholar · View at Scopus
  56. M. F. Bellamy, I. F. W. McDowell, M. W. Ramsey et al., “Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults,” Circulation, vol. 98, no. 18, pp. 1848–1852, 1998. View at Publisher · View at Google Scholar
  57. G. C. Rampersaud, G. P. A. Kauwell, A. D. Hutson, J. J. Cerda, and L. B. Bailey, “Genomic DNA methylation decreases in response to moderate folate depletion in elderly women,” American Journal of Clinical Nutrition, vol. 72, no. 4, pp. 998–1003, 2000. View at Google Scholar
  58. R. A. Jacob, D. M. Gretz, P. C. Taylor et al., “Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women,” Journal of Nutrition, vol. 128, no. 7, pp. 1204–1212, 1998. View at Google Scholar
  59. H. C. Lin, H. M. Hsieh, Y. H. Chen, and M. L. Hu, “S-Adenosylhomocysteine increases beta-amyloid formation in BV-2 microglial cells by increased expressions of beta-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters,” Neurotoxicology, vol. 30, no. 4, pp. 622–627, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Melnyk, S. Jernigan, A. Savenka, and S. J. James, “Elevation in S-adenosylhomocysteine and DNA hypomethylation in parents and children with autism,” FASEB Journal, vol. 21, no. 5, p. A348, 2007. View at Google Scholar
  61. H. Yamamoto, Y. Watanabe, R. Oikawa, T. Watanabe, H. Yotsuyanagi, and F. Itoh, “A next-generation sequencing-based G-Navi method revealed that DNA methylation in the integrated HBV genome is related to the methylation status of the integration sites within the human genome,” Gastroenterology, vol. 150, no. 4, p. S921, 2016. View at Publisher · View at Google Scholar
  62. S. Virani, K. M. Rentschler, M. Nishijo et al., “DNA methylation is differentially associated with environmental cadmium exposure based on sex and smoking status,” Chemosphere, vol. 145, pp. 284–290, 2016. View at Publisher · View at Google Scholar · View at Scopus
  63. D. Ingrosso, A. Cimmino, A. F. Perna et al., “Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia,” Lancet, vol. 361, no. 9370, pp. 1693–1699, 2003. View at Publisher · View at Google Scholar · View at Scopus
  64. L. El-Khairy, P. M. Ueland, H. Refsum, I. M. Graham, and S. E. Vollset, “Plasma total cysteine as a risk factor for vascular disease - The European Concerted Action project,” Circulation, vol. 103, no. 21, pp. 2544–2549, 2001. View at Publisher · View at Google Scholar
  65. A. K. Elshorbagy, E. Nurk, C. G. Gjesdal et al., “Homocysteine, cysteine, and body composition in the Hordaland Homocysteine Study: does cysteine link amino acid and lipid metabolism?” American Journal of Clinical Nutrition, vol. 88, no. 3, pp. 738–746, 2008. View at Google Scholar
  66. H. Okawa, T. Morita, and K. Sugiyama, “Cysteine supplementation decreases plasma homocysteine concentration in rats fed on a low-casein diet in rats,” Bioscience Biotechnology and Biochemistry, vol. 71, no. 1, pp. 91–97, 2007. View at Publisher · View at Google Scholar · View at Scopus
  67. A. K. Elshorbagy, C. Church, M. Valdivia-Garcia, A. D. Smith, H. Refsum, and R. Cox, “Dietary cystine level affects metabolic rate and glycaemic control in adult mice,” Journal of Nutritional Biochemistry, vol. 23, no. 4, pp. 332–340, 2012. View at Publisher · View at Google Scholar · View at Scopus
  68. W. E. van den Brandhof, K. Haks, E. G. Schouten, and P. Verhoef, “The relation between plasma cysteine, plasma homocysteine and coronary atherosclerosis,” Atherosclerosis, vol. 157, no. 2, pp. 403–409, 2001. View at Publisher · View at Google Scholar · View at Scopus