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Synergy of Homocysteine, MicroRNA, and Epigenetics: A Novel Therapeutic Approach for Stroke

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Abstract

Homocysteine (Hcy) is a thiol-containing amino acid formed during methionine metabolism. Elevated level of Hcy is known as hyperhomocysteinemia (HHcy). HHcy is an independent risk factor for cerebrovascular diseases such as stroke, dementia, Alzheimer’s disease, etc. Stroke, which is caused by interruption of blood supply to the brain, is one of the leading causes of death and disability in a number of people worldwide. The HHcy causes an increased carotid artery plaque that may lead to ischemic stroke but the mechanism is currently not well understood. Though mutations or polymorphisms in the key genes of Hcy metabolism pathway have been well elucidated in stroke, emerging evidences suggested epigenetic mechanisms equally play an important role in stroke development such as DNA methylation, chromatin remodeling, RNA editing, noncoding RNAs (ncRNAs), and microRNAs (miRNAs). However, there is no review available yet that describes the role of genetics and epigenetics during HHcy in stroke. The current review highlights the role of genetics and epigenetics in stroke during HHcy and the role of epigenetics in its therapeutics. The review also highlights possible epigenetic mechanisms, potential therapeutic molecules, putative challenges, and approaches to deal with stroke during HHcy.

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References

  1. Mathers CD, Boerma T, Ma Fat D (2009) Global and regional causes of death. Br Med Bull 92:7–32

    Article  PubMed  Google Scholar 

  2. Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623

    Article  PubMed  CAS  Google Scholar 

  3. Hankey GJ, Eikelboom JW (2005) Homocysteine and stroke. Lancet 365:194–196

    PubMed  Google Scholar 

  4. Harker LA, Ross R, Slichter SJ, Scott CR (1976) Homocysteine induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest 58:731–741

    Article  PubMed  CAS  Google Scholar 

  5. Nishinaga M, Ozawa T, Shimada K (1993) Homocysteine, a thrombogenic agent, suppresses anticoagulant heparin sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 92:1381–1386

    Article  PubMed  CAS  Google Scholar 

  6. Ratnoff OD (1968) Activation of Hageman factor by L-homocystine. Science 162:1007–1009

    Article  PubMed  CAS  Google Scholar 

  7. Wald DS, Law M, Morris JK (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 325:1202–1206

    Article  Google Scholar 

  8. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP (2002) Moderately high homocysteine tied to stroke, Alzheimer’s risk. Science news Oct 4

  9. Biswas A, Ranjan R, Meena A, Akhter MS, Yadav BK et al (2009) Homocystine levels, polymorphisms and the risk of ischemic stroke in young Asian Indians. J Stroke Cerebrovasc Dis 18:103–110

    Article  PubMed  Google Scholar 

  10. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD (2005) Homocysteine and stroke: evidence on a causal link from Mendelian randomisation. Lancet 365:224–232

    PubMed  CAS  Google Scholar 

  11. Fang L, Wu W, Wu YQ (2004) Relationship between polymorphisms of cystathionine beta-synthase gene and stroke. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 16:161–164

    PubMed  CAS  Google Scholar 

  12. Jeyaseelan K, Lim KY, Armugam A (2008) MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke 39:959–966

    Article  PubMed  CAS  Google Scholar 

  13. Thambyrajah J, Townend JN (2000) Homocysteine and atherothrombosis: mechanisms for injury. Eur Heart J 21:967–974

    Article  PubMed  CAS  Google Scholar 

  14. Low H-Q, Chen Christopher PLH, Kasiman K, Thalamathu A, Ng S-S et al (2011) A comprehensive association analysis of homocysteine metabolic pathway genes in Singaporean Chinese with ischemic stroke. PLoS One 6:24757

    Article  Google Scholar 

  15. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113

    Article  PubMed  CAS  Google Scholar 

  16. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6(597):610

    Google Scholar 

  17. Souto JC, Blanco-Vaca F, Soria JM et al (2005) A genome wide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project. Am J Hum Genet 76:925–933

    Article  PubMed  CAS  Google Scholar 

  18. Hu CJ, Chen SD, Yang DI et al (2006) Promoter region methylation and reduced expression of thrombospondin-1 after oxygen-glucose deprivation in murine cerebral endothelial cells. J Cereb Blood Flow Metab 26:1519–1526

    Article  PubMed  CAS  Google Scholar 

  19. Zhou HJ, Zhang HN, Tang T et al (2010) Alteration of thrombospondin-1 and -2 in rat brains following experimental intracerebral hemorrhage. J Neurosurg 113:820–825

    Article  PubMed  CAS  Google Scholar 

  20. Langley B, Brochier C, Rivieccio MA (2009) Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke 40:2899–2905

    Article  PubMed  CAS  Google Scholar 

  21. Ubbink JB (2000) Assay methods for the measurement of total homocyst(e)ine in plasma. Semin Thromb Hemost 26:233–241

    Article  PubMed  CAS  Google Scholar 

  22. Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43:414–421

    PubMed  CAS  Google Scholar 

  23. Zhang W, Sun K, Chen J, Liao Y, Qin Q et al (2010) High plasma homocysteine levels contribute to the risk of stroke recurrence and all-cause mortality in a large prospective stroke population. Clin Sci 118:187–194

    Article  CAS  Google Scholar 

  24. Morita H, Kurihara H, Sugiyama T, Hamada C, Kurihara Y et al (1999) Polymorphism of the methionine synthase gene: association with homocysteine metabolism and late-onset vascular diseases in the Japanese population. Arterioscler Thromb Vasc Biol 19:298–302

    Article  PubMed  CAS  Google Scholar 

  25. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270:2693–2698

    Article  PubMed  CAS  Google Scholar 

  26. Mehler MF (2008) Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog Neurobiol 86:305–341

    Article  PubMed  CAS  Google Scholar 

  27. Mehler MF, Mattick JS (2007) Noncoding RNAs and RNA editing in brain development, functional diversification, and neurological disease. Physiol Rev 87:799–823

    Article  PubMed  CAS  Google Scholar 

  28. Qureshi IA, Mehler MF (2010) Emerging role of epigenetics in stroke: part 1: DNA methylation and chromatin modifications. Arch Neurol 67:1316–1322

    Article  PubMed  Google Scholar 

  29. Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS (2009) Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol 5:401–408

    Article  PubMed  CAS  Google Scholar 

  30. Endres M, Meisel A, Biniszkiewicz D et al (2000) DNA methyltransferase contributes to delayed ischemic brain injury. J Neurosci 20:3175–3181

    PubMed  CAS  Google Scholar 

  31. Endres M, Fan G, Meisel A, Dirnagl U, Jaenisch R (2001) Effects of cerebral ischemia in mice lacking DNA methyltransferase 1 in post-mitotic neurons. Neuroreport 12:3763–3766

    Article  PubMed  CAS  Google Scholar 

  32. Sunday L, Osuna C, Krause DN, Duckles SP (2007) Age alters cerebrovascular inflammation and effects of estrogen. Am J Physiol Heart Circ Physiol 292:2333–2340

    Article  Google Scholar 

  33. Wilson ME, Westberry JM (2009) Regulation of oestrogen receptor gene expression: new insights and novel mechanisms. J Neuroendocrinol 21:238–242

    Article  PubMed  CAS  Google Scholar 

  34. Nicolas FE, Pais H, Schwach F et al (2008) Experimental identification of microRNA-140 targets by silencing and overexpressing miR-140. RNA 14:2513–2520

    Article  PubMed  CAS  Google Scholar 

  35. Chen M, Gavrilova O, Liu J (2005) Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci U S A 102:7386–7391

    Article  PubMed  CAS  Google Scholar 

  36. Dobrovolny R, Dvorakova L, Ledvinova J et al (2005) Relationship between X-inactivation and clinical involvement in Fabry heterozygotes: eleven novel mutations in the alphagalactosidase A gene in the Czech and Slovak population. J Mol Med 83:647–654

    Article  PubMed  CAS  Google Scholar 

  37. Freson K, Izzi B, Labarque V et al (2008) GNAS defects identified by stimulatory G protein alpha-subunit signalling studies in platelets. J Clin Endocrinol Metab 93:4851–4859

    Article  PubMed  CAS  Google Scholar 

  38. Giacomini PS, Shannon PT, Clarke JT, Jaigobin C (2004) Fabry’s disease presenting as stroke in a young female. Can J Neurol Sci 31:112–114

    PubMed  Google Scholar 

  39. Kusuhara T, Ayabe M, Hino H, Shoji H, Neshige R (1996) A case of Prader–Willi syndrome with bilateral middle cerebral artery occlusion and moyamoya phenomenon. Rinsho Shinkeigaku 36:770–773

    PubMed  CAS  Google Scholar 

  40. Cairns BR (2009) The logic of chromatin architecture and remodeling at promoters. Nature 461:193–198

    Article  PubMed  CAS  Google Scholar 

  41. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293(5532):1074–1080

    Article  PubMed  CAS  Google Scholar 

  42. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    Article  PubMed  CAS  Google Scholar 

  43. Fang S, Miao J, Xiang L, Ponugoti B, Treuter E, Kemper JK (2007) Coordinated recruitment of histone methyltransferase G9a and other chromatin-modifying enzymes in SHP-mediated regulation of hepatic bile acid metabolism. Mol Cell Biol 27:1407–1424

    Article  PubMed  CAS  Google Scholar 

  44. Gilardi F, Mitro N, Godio C et al (2007) The pharmacological exploitation of cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis: from binding resins to chromatin remodelling to reduce plasma cholesterol. Pharmacol Ther 116:449–472

    Article  PubMed  CAS  Google Scholar 

  45. Shafaati M, O'Driscoll R, Björkhem I, Meaney S (2009) Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors. Biochem Biophys Res Commun 378:689–694

    Article  PubMed  CAS  Google Scholar 

  46. Finkel T, Deng CX, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460:587–591

    Article  PubMed  CAS  Google Scholar 

  47. Faraco G, Pancani T, Formentini L et al (2006) Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol Pharmacol 70:1876–1884

    Article  PubMed  CAS  Google Scholar 

  48. Soriano FX, Papadia S, Bell KF, Hardingham GE (2009) Role of histone acetylation in the activity-dependent regulation of sulfiredoxin and sestrin 2. Epigenetics 4:152–158

    Article  PubMed  CAS  Google Scholar 

  49. Birney E, Stamatoyannopoulos JA, Dutta A et al (2007) Identification and analysis of functional elements in 1 % of the human genome by the ENCODE pilot project. Nature 447:799–816

    Article  PubMed  CAS  Google Scholar 

  50. Mattick JS, Amaral PP, Dinger ME, Mercer TR, Mehler MF (2009) RNA regulation of epigenetic processes. Bioessays 31:51–59

    Article  PubMed  CAS  Google Scholar 

  51. Schratt G (2009) Fine-tuning neural gene expression with microRNAs. Curr Opin Neurobiol 19:213–219

    Article  PubMed  CAS  Google Scholar 

  52. Dharap A, Bowen K, Place R, Li LC, Vemuganti R (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 29:675–687

    Article  PubMed  CAS  Google Scholar 

  53. Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159

    Article  PubMed  CAS  Google Scholar 

  54. Rashidian J, Iyirhiaro G, Aleyasin H et al (2005) Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Proc Natl Acad Sci U S A 102:14080–14085

    Article  PubMed  CAS  Google Scholar 

  55. Wang X, Arai S, Song X et al (2008) Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454:126–130

    Article  PubMed  CAS  Google Scholar 

  56. Broadbent HM, Peden JF, Lorkowski S et al (2008) Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet 17:806–814

    Article  PubMed  CAS  Google Scholar 

  57. Holdt LM, Beutner F, Scholz M et al (2010) ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler Thromb Vasc Biol 30:620–627

    Article  PubMed  CAS  Google Scholar 

  58. Jarinova O, Stewart AF, Roberts R et al (2009) Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thromb Vasc Biol 29:1671–1677

    Article  PubMed  CAS  Google Scholar 

  59. Liu Y, Sanoff HK, Cho H et al (2009) INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One 4:5027

    Article  Google Scholar 

  60. Pasmant E, Laurendeau I, He'ron D, Vidaud M, Vidaud D, Bièche I (2007) Characterization of a germ-line deletion, including the entire INK4/ARF locus, in amelano-maneural system tumor family. Cancer Res 67:3963–3969

    Article  PubMed  CAS  Google Scholar 

  61. Schaefer AS, Richter GM, Groessner-Schreiber B et al (2009) Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis. PLoS Genet 5:1000378

    Article  Google Scholar 

  62. Visel A, Zhu Y, May D et al (2010) Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464:409–412

    Article  PubMed  CAS  Google Scholar 

  63. Costain WJ, Rasquinha I, Graber T et al (2006) Cerebral ischemia induces neuronal expression of novel VL30 mouse retrotransposons bound to polyribosomes. Brain Res 1094:24–37

    Article  PubMed  CAS  Google Scholar 

  64. Kawahara Y, Megraw M, Kreider E et al (2008) Frequency and fate of microRNA editing in human brain. Nucleic Acids Res 36:5270–5280

    Article  PubMed  CAS  Google Scholar 

  65. Yang W, Chendrimada TP, Wang Q et al (2006) Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol 13:13–21

    Article  PubMed  CAS  Google Scholar 

  66. Kawahara Y, Zinshteyn B, Chendrimada TP, Shiekhattar R, Nishikura K (2007) RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer–TRBP complex. EMBO Rep 8:763–769

    Article  PubMed  CAS  Google Scholar 

  67. Kim JB, Piao CS, Lee KW et al (2004) Delayed genomic responses to transient middle cerebral artery occlusion in the rat. J Neurochem 89:1271–1282

    Article  PubMed  CAS  Google Scholar 

  68. Shani V, Bromberg Y, Sperling O, Zoref-Shani E (2009) Involvement of Src tyrosine kinases (SFKs) and of focal adhesion kinase (FAK) in the injurious mechanism in rat primary neuronal cultures exposed to chemical ischemia. J Mol Neurosci 37:50–59

    Article  PubMed  CAS  Google Scholar 

  69. Shimamura N, Matchett G, Yatsushige H, Calvert JW, Ohkuma H, Zhang J (2006) Inhibition of integrin αvβ3 ameliorates focal cerebral ischemic damage in the rat middle cerebral artery occlusion model. Stroke 37:1902–1909

    Article  PubMed  CAS  Google Scholar 

  70. Kang SK, Lee DH, Bae YC, Kim HK, Baik SY, Jung JS (2003) Improvement of neurological deficits by intracerebral transplantation of human adipose tissue-derived stromal cells after cerebral ischemia in rats. Exp Neurol 183:355–366

    Article  PubMed  CAS  Google Scholar 

  71. Lee TH, Yoon JG (2008) Intracerebral transplantation of human adipose tissue stromal cells after middle cerebral artery occlusion in rats. J Clin Neurosci 15:907–912

    Article  PubMed  Google Scholar 

  72. Plummer R, Vidal L, Griffin M et al (2009) Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors. Clin Cancer Res 5:3177–3183

    Article  Google Scholar 

  73. Csoka AB, Szyf M (2009) Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Med Hypotheses 73:770–780

    Article  PubMed  CAS  Google Scholar 

  74. Milutinovic S, D'Alessio AC, Detich N, Szyf M (2007) Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis 28:560–571

    Article  PubMed  CAS  Google Scholar 

  75. Phiel CJ, Zhang F, Huang EY et al (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741

    Article  PubMed  CAS  Google Scholar 

  76. Szyf M (2010) Epigenetic therapeutics in autoimmune disease. Clin Rev Allergy Immunol 39:62–77

    Article  PubMed  CAS  Google Scholar 

  77. Lu KT, Robin YY, Chen LG et al (2006) Neuroprotective effects of resveratrol on cerebral ischemia-induced neuron loss mediated by free radical scavenging and cerebral blood flow elevation. J Agric Food Chem 54:3126–3131

    Article  PubMed  CAS  Google Scholar 

  78. Ovbiagele B (2008) Potential role of curcumin in stroke prevention. Expert Rev Neurother 8:1175–1176

    Article  PubMed  Google Scholar 

  79. Zhang Z, Yang X, Zhang S, Ma X, Kong J (2007) BNIP3 upregulation and EndoG translocation in delayed neuronal death in stroke and in hypoxia. Stroke 38:1606–1613

    Article  PubMed  CAS  Google Scholar 

  80. Miyawaki T, Ofengeim D, Noh KM et al (2009) The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. Nat Neurosci 12:618–626

    Article  PubMed  CAS  Google Scholar 

  81. Qureshi IA, Mehler MF (2009) Regulation of non-coding RNA networks in the nervous system: what’s the REST of the story? Neurosci Lett 466:73–80

    Article  PubMed  CAS  Google Scholar 

  82. Calderone A, Jover T, Noh KM et al (2003) Ischemic insults derepress the gene silencer REST in neurons destined to die. J Neurosci 23:2112–2121

    PubMed  CAS  Google Scholar 

  83. Formisano L, Noh KM, Miyawaki T, Mashiko T, Bennett MV, Zukin RS (2007) Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons. Proc Natl Acad Sci U S A 104:4170–4175

    Article  PubMed  CAS  Google Scholar 

  84. Li JB, Levanon EY, Yoon JK et al (2009) Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324:1210–1213

    Article  PubMed  CAS  Google Scholar 

  85. Feinberg EH, Hunter CP (2003) Transport of dsRNA into cells by the transmembrane protein SID-1. Science 301:1545–1547

    Article  PubMed  CAS  Google Scholar 

  86. Sproule DM, Kaufmann P (2008) Mitochondrial encephalopathy, lactic acidosis, and stroke like episodes. Ann N Y Acad Sci 1142:133–158

    Article  PubMed  CAS  Google Scholar 

  87. Smalheiser NR (2007) Exosomal transfer of proteins and RNAs at synapses in the nervous system. Biol Direct 2:35

    Article  PubMed  Google Scholar 

  88. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345

    Article  PubMed  CAS  Google Scholar 

  89. Mizrak A, Bolukbasi MF, Ozdener GB et al (2013) Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther 21:101–108

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by NIH grant HL-107640 to NT and NS-51568 to SCT.

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  1. Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, 40202, USA

    Anuradha Kalani, Pradeep K. Kamat, Suresh C. Tyagi & Neetu Tyagi

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  1. Anuradha Kalani
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Kalani, A., Kamat, P.K., Tyagi, S.C. et al. Synergy of Homocysteine, MicroRNA, and Epigenetics: A Novel Therapeutic Approach for Stroke. Mol Neurobiol 48, 157–168 (2013). https://doi.org/10.1007/s12035-013-8421-y

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