DNA Methylation and Hyperhomocysteinemia

doi:10.3969/j.issn.1673－5765.2023.04.005

Abstract

Abstract: DNA methylation is a process catalyzed by DNA methyltransferases (DNMTs) , which is dependent on S-adenosyl-L-homocysteine (SAH) , a substrate related to the metabolism of Hcy. It is an epigenetic mechanism that regulates gene expression, and is critical for maintaining cellular homeostasis. A number of studies have shown that hyperhomocysteinemia (HHcy) may regulate DNA methylation status by regulating the methionine-homocysteine cycle (M-H cycle) , which is involved in multiple pathological process of atherosclerosis formation such as dysfunction of endothelial cells, proliferation and metastasis of damaged smooth muscle cells (SMCs) , and lipid metabolism, then can influence the occurrence and prognosis of cardiovascular diseases.

Key words: DNA; Methylation; Hyperhomocysteinemia; Stroke; Atherosclerosis; Cardiovascular disease

摘要： DNA甲基化是一种调控基因表达的表观遗传机制，由Hcy代谢相关底物S-腺苷同型半胱氨酸（S-adenosyl-L-homocysteine，SAH）依赖性的DNA甲基转移酶（DNA methyltransferases，DNMTs）催化，对维持细胞稳态至关重要。多项研究表明，高同型半胱氨酸血症（hyperhomocysteinemia，HHcy）可能通过调节甲硫氨酸-同型半胱氨酸循环（methionine-homocysteine cycle，M-H cycle）调控DNA甲基化状态，参与动脉粥样硬化形成过程中的血管内皮细胞功能障碍、损伤后平滑肌细胞（smooth muscle cells，SMCs）的增殖和转移、脂质代谢等病理过程，从而影响心血管疾病的发生和预后。

关键词: 脱氧核糖核酸; 甲基化; 高同型半胱氨酸血症; 卒中; 动脉粥样硬化; 心血管疾病

WENG Jiaxu, ZHOU Hongyu, LI Zixiao. DNA Methylation and Hyperhomocysteinemia[J]. Chinese Journal of Stroke, 2023, 18(04): 404-409.

瓮佳旭, 周宏宇, 李子孝. DNA甲基化与高同型半胱氨酸血症[J]. 中国卒中杂志, 2023, 18(04): 404-409.

References

[1] MCCULLY K S. Vascular pathology of homocysteinemia：implications for the pathogenesis of arteriosclerosis[J]. Am J Pathol，1969，56（1）：111-128.
[2] CLARKE R，DALY L，ROBINSON K，et al. Hyperhomocysteinemia：an independent risk factor for vascular disease[J]. N Engl J Med，1991，324（17）：1149-1155.
[3] BOUSHEY C J，BERESFORD S A，OMENN G S，et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes[J]. JAMA，1995，274（13）：1049-1057.
[4] Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke：a meta-analysis[J]. JAMA，2002，288（16）：2015-2022.
[5] AUSTIN R C，LENTZ S R，WERSTUCK G H. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease[J/OL]. Cell Death Differ，2004，11 Suppl 1：S56-64[2022-10-10]. https://doi.org/10.1038/sj.cdd.4401451.
[6] ZHANG X F，FU R G，YU J，et al. DNA demethylation：where genetics meets epigenetics[J]. Curr Pharm Des，2014，20（11）：1625-1631.
[7] YIDENG J，JIANZHONG Z，YING H，et al. Homocysteine-mediated expression of SAHH，DNMTs，MBD2，and DNA hypomethylation potential pathogenic mechanism in VSMCs[J]. DNA Cell Biol，2007，26（8）：603-611.
[8] LI J J，SUN C X，CAI W W，et al. Insights into S-adenosyl-l-methionine（SAM）-dependent methyltransferase related diseases and genetic polymorphisms[J/OL]. Mutat Res Rev Mutat Res，2021，788：108396[2022-10-12]. https://doi.org/10.1016/j.mrrev.2021.108396.
[9] FINKELSTEIN J D，MARTIN J J. Homocysteine[J]. Int J Biochem Cell Biol，2000，32（4）：385-389.
[10] DURAND P，PROST M，LOREAU N，et al. Impaired homocysteine metabolism and atherothrombotic disease[J]. Lab Inves，2001，81（5）：645-672.
[11] SELHUB J，MILLER J W. The pathogenesis of homocysteinemia：interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine[J]. Am J Clin Nutr，1992，55（1）：131-138.
[12] LECLERC D，WILSON A，DUMAS R，et al. Cloning and mapping of a cDNA for methionine synthase reductase，a flavoprotein defective in patients with homocystinuria[J]. Proc Natl Acad Sci U S A，1998，95（6）：3059-3064.
[13] BLOM H J，SMULDERS Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects[J]. J Inherit Metab Dis，2011，34（1）：75-81.
[14] MCKEEVER M P，WEIR D G，MOLLOY A，et al. Betaine-homocysteine methyltransferase：organ distribution in man，pig and rat and subcellular distribution in the rat[J]. Clin Sci（Lond），1991，81（4）：551-556.
[15] MORETTI R，CARUSO P. The controversial role of homocysteine in neurology：from labs to clinical practice[J/OL]. Int J Mol Sci，2019，20（1）：231[2022-10-12]. https://doi.org/10.3390/ijms20010231.
[16] HERRMANN W，HERRMANN M，OBEID R. Hyperhomocysteinaemia：a critical review of old and new aspects[J]. Curr Drug Metab，2007，8（1）：17-31.
[17] ICHINOHE A，KANAUMI T，TAKASHIMA S，et al. Cystathionine beta-synthase is enriched in the brains of Down's patients[J]. Biochem Biophys Res Commun，2005，338（3）：1547-1550.
[18] HANKEY G J，EIKELBOOM J W. Homocysteine and vascular disease[J]. Lancet，1999，354（9176）：407-413.
[19] KIRSCH S H，HERRMANN W，OBEID R. Genetic defects in folate and cobalamin pathways affecting the brain[J]. Clin Chem Lab Med，2013，51（1）：139-155.
[20] KIM J，KIM H，ROH H，et al. Causes of hyperhomocysteinemia and its pathological significance[J]. Arch Pharm Res，2018，41（4）：372-383.
[21] JAKUBOWSKI H. Homocysteine modification in protein structure/function and human disease[J]. Physiol Rev，2019，99（1）：555-604.
[22] YAKUB M，IQBAL M P I，KAKEPOTO G，et al. High prevalence of mild hyperhomocysteinemia and folate，B12 and B6 deficiencies in an urban population in Karachi，Pakistan[J]. Pak J Med Sci，2010，26（4）：923-929.
[23] HANDY D E，CASTRO R，LOSCALZO J. Epigenetic modifications：basic mechanisms and role in cardiovascular disease[J]. Circulation，2011，123（19）：2145-2156.
[24] ZAINA S，LINDHOLM M W，LUND G. Nutrition and aberrant DNA methylation patterns in atherosclerosis：more than just hyperhomocysteinemia? [J]. J Nutr，2005，135（1）：5-8.
[25] CASTRO R，RIVERA I，STRUYS E A，et al. Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease[J]. Clin Chem，2003，49（8）：1292-1296.
[26] CHEN Z，KARAPLIS A C，ACKERMAN S L，et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity，with neuropathology and aortic lipid deposition[J]. Hum Mol Genet，2001，10（5）：433-443.
[27] CHANG S，WANG L，GUAN Y，et al. Long interspersed nucleotide element-1 hypomethylation in folate-deficient mouse embryonic stem cells[J]. J Cell Biochem，2013，114（7）：1549-1558.
[28] POGRIBNY I P，ROSS S A，WISE C，et al. Irreversible global DNA hypomethylation as a key step in hepatocarcinogenesis induced by dietary methyl deficiency[J]. Mutat Res，2006，593（1/2）：80-87.
[29] UNNIKRISHNAN A，FREEMAN W M，JACKSON J，et al. The role of DNA methylation in epigenetics of aging[J/OL]. Pharmacol Ther，2019，195：172-185[2022-10-12]. https://doi.org/10.1016/j.pharmthera.2018.11.001.
[30] SCHALINSKE K L，SMAZAL A L. Homocysteine imbalance：a pathological metabolic marker[J]. Adv Nutr，2012，3（6）：755-762.
[31] HOFFMAN D R，MARION D W，CORNATZER W E，et al. S-adenosylmethionine and S-adenosylhomocystein metabolism in isolated rat liver. Effects of L-methionine，L-homocystein，and adenosine[J]. J Biol Chem，1980，255（22）：10822-10827.
[32] HANDY D E，CASTRO R，LOSCALZO J. Epigenetic modifications[J]. 2011，123（19）：2145-2156.
[33] ESSE R，IMBARD A，FLORINDO C，et al. Protein arginine hypomethylation in a mouse model of cystathionine β-synthase deficiency[J]. Faseb J，2014，28（6）：2686-2695.
[34] LEE H O，WANG L，KUO Y M，et al. Lack of global epigenetic methylation defects in CBS deficient mice[J]. J Inherit Metab Dis，2017，40（1）：113-120.
[35] POGRIBNY I P，BELAND F A. DNA hypomethylation in the origin and pathogenesis of human diseases[J]. Cell Mol Life Sci，2009，66（14）：2249-2261.
[36] GLASS C K，WITZTUM J L. Atherosclerosis. the road ahead[J]. Cell，2001，104（4）：503-516.
[37] LAI W K，KAN M Y. Homocysteine-induced endothelial dysfunction[J]. Ann Nutr Metab，2015，67（1）：1-12.
[38] GIMBRONE M A，GARCíA-CARDEñA G. Endothelial cell dysfunction and the pathobiology of atherosclerosis[J]. Circ Res，2016，118（4）：620-636.
[39] ZHANG D H，SUN X L，LIU J L，et al. Homocysteine accelerates senescence of endothelial cells via DNA hypomethylation of human telomerase reverse transcriptase[J]. Arterioscler Thromb Vasc Biol，2015，35（1）：71-78.
[40] NASEEM K M. The role of nitric oxide in cardiovascular diseases[J]. Mol Aspects Med，2005，26（1/2）：33-65.
[41] JIA S J，LAI Y Q，ZHAO M，et al. Homocysteine-induced hypermethylation of DDAH2 promoter contributes to apoptosis of endothelial cells[J]. Pharmazie，2013，68（4）：282-286.
[42] ZHANG B K，LAI Y Q，NIU P P，et al. Epigallocatechin-3-gallate inhibits homocysteine-induced apoptosis of endothelial cells by demethylation of the DDAH2 gene[J]. Planta Med，2013，79（18）：1715-1719.
[43] BENNETT M R，SINHA S，OWENS G K. Vascular smooth muscle cells in atherosclerosis[J]. Circ Res，2016，118（4）：692-702.
[44] RICCI C，FERRI N. Naturally occurring PDGF receptor inhibitors with potential anti-atherosclerotic properties[J/OL]. Vascul Pharmacol，2015，70：1-7[2022-10-12]. https://doi.org/10.1016/j.vph.2015.02.002.
[45] HAN X B，ZHANG H P，CAO C J，et al. Aberrant DNA methylation of the PDGF gene in homocysteine‑mediated VSMC proliferation and its underlying mechanism[J]. Mol Med Rep，2014，10（2）：947-954.
[46] ADAIKALAKOTESWARI A，FINER S，VOYIAS P D，et al. Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes[J/OL]. Clin Epigenetics，2015，7（1）：14[2022-10-12]. https://doi.org/10.1186/s13148-015-0046-8.
[47] LI H L，WU X，XU A，et al. A-FABP in metabolic diseases and the therapeutic implications：an update[J/OL]. Int J Mol Sci，2021，22（17）：9386[2022-10-12]. https://doi.org/10.3390/ijms22179386.
[48] YANG A N，ZHANG H P，SUN Y，et al. High-methionine diets accelerate atherosclerosis by HHcy-mediated FABP4 gene demethylation pathway via DNMT1 in ApoE（-/-）mice [J/OL]. FEBS Lett，2015，589（24 Pt B）：3998-4009[2022-10-12]. https://doi.org/10.1016/j.febslet.2015.11.010.
[49] YANG X H，CAO R F，YU Y，et al. A study on the correlation between MTHFR promoter methylation and diabetic nephropathy [J]. Am J Transl Res，2016，8（11）：4960-4967.