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microRNAs in Ischemic Brain: The Fine-Tuning Specialists and Novel Therapeutic Targets

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Translational Stroke Research

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

CNS injuries are associated with extensive spatio-temporal alterations in gene expression that dictate the extent of brain damage and subsequent plasticity. Studies in CNS injury models show that microRNAs (miRNAs) modulate gene expression, which contributes to development of the injury. The expression levels of brain miRNAs show diverse spatio-temporal profiles in the healthy brain and are altered significantly over a sustained period of time in injured states. Apart from the conventional mechanisms of translational inhibition of mRNAs, recent studies have revealed that miRNAs can also target gene promoters to induce or repress their expression, adding another layer to the already complex network of miRNA–gene interactions. The extent of the influence of miRNAs in the CNS is only beginning to be elucidated. miRNAs play a major role in the etiology of neurodegenerative diseases as well as in brain injuries such as traumatic brain injury, spinal cord injury, and ischemia. Studies have shown that they considerably influence the outcome of the ischemic pathophysiology. However, miRNAs have also been observed to play a role in endogenous (preconditioning) and exogenous neuroprotective treatments, indicating their role in inducing ischemic tolerance. Lately, miRNAs have shown promise for serving as clinical biomarkers of stroke and other CNS disorders.

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References

  1. Abarca C, Albrecht U, Spanagel R. Cocaine sensitization and reward are under the influence of circadian genes and rhythm. Proc Natl Acad Sci USA. 2002;99:9026–30.

    Article  PubMed  CAS  Google Scholar 

  2. Adachi T, Nakanishi M, Otsuka Y, Nishimura K, Hirokawa G, Goto Y, Nonogi H, Iwai N. Plasma microRNA 499 as a biomarker of acute myocardial infarction. Clin Chem. 2010;56:1183–5.

    Article  PubMed  CAS  Google Scholar 

  3. Akao Y, Iio A, Itoh T, Noguchi S, Itoh Y, Ohtsuki Y, Naoe T. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther. 2011;19:395–9.

    Article  PubMed  CAS  Google Scholar 

  4. Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, Brownstein MJ, Tuschl T, Margalit H. Clustering and conservation patterns of human microRNAs. Nucl Acid Res. 2005;33:2697–706.

    Article  CAS  Google Scholar 

  5. Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, Matzke M, Ruvkun G, Tuschl T. A uniform system for microRNA annotation. RNA. 2003;9:277–9.

    Article  PubMed  CAS  Google Scholar 

  6. Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–55. Review.

    Article  PubMed  CAS  Google Scholar 

  7. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol. 2010;176:2092–7.

    Article  PubMed  CAS  Google Scholar 

  8. Bahi A, Boyer F, Bussard G, Dreyer JL. Silencing dopamine D3-receptors in the nucleus accumbens shell in vivo induces changes in cocaine-induced hyperlocomotion. Eur J Neurosci. 2005;21:3415–26.

    Article  PubMed  Google Scholar 

  9. Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, Feuerstein GZ. Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke. 1998;29:1937–50.

    Article  PubMed  CAS  Google Scholar 

  10. Bhattacharyya SN, et al. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell. 2006;125:1111–24.

    Article  PubMed  CAS  Google Scholar 

  11. Buller B, Liu X, Wang X, Zhang RL, Zhang L, Hozeska-Solgot A, Chopp M, Zhang ZG. MicroRNA-21 protects neurons from ischemic death. FEBS J. 2010;277:4299–307.

    Article  PubMed  CAS  Google Scholar 

  12. Ceolotto G, Papparella I, Bortoluzzi A, Strapazzon G, Ragazzo F, Bratti P, Fabricio AS, Squarcina E, Gion M, Palatini P, Semplicini A. Interplay between miR-155, AT1R A1166C polymorphism, and AT1R expression in young untreated hypertensives. Am J Hypertens. 2011;24:241–6.

    Article  PubMed  CAS  Google Scholar 

  13. Chandrasekar V, Dreyer JL. MicroRNAs miR-124, let-7d and miR-181a regulate cocaine-induced plasticity. Mol Cell Neurosci. 2009;42:350–62.

    Article  PubMed  CAS  Google Scholar 

  14. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320:1224–9.

    Article  PubMed  CAS  Google Scholar 

  15. Chen J, Yang T, Yu H, Sun K, Shi Y, Song W, Bai Y, Wang X, Lou K, Song Y, Zhang Y, Hui R. A functional variant in the 3′-UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211. Hum Mol Genet. 2010;19:2524–33.

    Article  PubMed  CAS  Google Scholar 

  16. Chen Y, Zhu X, Zhang X, Liu B, Huang L. Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol Ther. 2010;18:1650–6.

    Article  PubMed  CAS  Google Scholar 

  17. Cobb MH. MAP kinase pathways. Prog Biophys Mol Biol. 1999;71:479–500.

    Article  PubMed  CAS  Google Scholar 

  18. Cox LS, Mattison JA. Increasing longevity through caloric restriction or rapamycin feeding in mammals: common mechanisms for common outcomes? Aging Cell. 2009;8:607–13.

    Article  PubMed  CAS  Google Scholar 

  19. Cox MB, Cairns MJ, Gandhi KS, Carroll AP, Moscovis S, Stewart GJ, Broadley S, Scott RJ, Booth DR, Lechner-Scott J. MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One. 2010;5:e12132.

    Article  PubMed  CAS  Google Scholar 

  20. De Oliveira-Sales EB, Nishi EE, Boim MA, Dolnikoff MS, Bergamas-chi CT, Campos RR. Up-regulation of AT1R and iNOS in the rostral ventrolateral medulla (RVLM) is essential for the sympathetic hyperac- tivity and hypertension in the 2 K-1C Wistar rat model. Am J Hypertens. 2010;23:708–15.

    Article  PubMed  CAS  Google Scholar 

  21. Delaloy C, Liu L, Lee JA, Su H, Shen F, Yang GY, Young WL, Ivey KN, Gao FB. MicroRNA-9 coordinates proliferation and migration of human embryonic stem cell-derived neural progenitors. Cell Stem Cell. 2010;6:323–35.

    Article  PubMed  CAS  Google Scholar 

  22. Dempsey RJ, Vemuganti R, Varghese T, Hermann BP. A review of carotid atherosclerosis and vascular cognitive decline: a new understanding of the keys to symptomology. Neurosurgery. 2010;67:484–93.

    Article  PubMed  Google Scholar 

  23. Dharap A, Bowen K, Place R, Li LC, Vemuganti R. Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab. 2009;29:675–87.

    Article  PubMed  CAS  Google Scholar 

  24. Dharap A, Vemuganti R. Ischemic pre-conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways. J Neurochem. 2010;113:1685–91.

    PubMed  CAS  Google Scholar 

  25. Ding YH, Luan XD, Li J, Rafols JA, Guthinkonda M, Diaz FG, Ding Y. Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke. Curr Neurovasc Res. 2004;1:411–20.

    Article  PubMed  CAS  Google Scholar 

  26. Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007;4:721–6.

    Article  PubMed  CAS  Google Scholar 

  27. Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjarn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S. LNA-mediated microRNA silencing in non-human primates. Nature. 2008;452:896–9.

    Article  PubMed  CAS  Google Scholar 

  28. Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, Capogrossi MC, Martelli F. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem. 2008;283:15878–83.

    Article  PubMed  CAS  Google Scholar 

  29. Fasanaro P, Greco S, Lorenzi M, Pescatori M, Brioschi M, Kulshreshtha R, Banfi C, Stubbs A, Calin GA, Ivan M, Capogrossi MC, Martelli F. An integrated approach for experimental target identification of hypoxia-induced miR-210. J Biol Chem. 2009;284:35134–43.

    Article  PubMed  CAS  Google Scholar 

  30. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–11.

    Article  PubMed  CAS  Google Scholar 

  31. Forman JJ, Coller HA. The code within the code: microRNAs target coding regions. Cell Cycle. 2010;9:1533–41.

    Article  PubMed  CAS  Google Scholar 

  32. Gebauer F, Hentze MW. Molecular mechanisms of translational control. Nat Rev Mol Cell Biol. 2004;5:827–35.

    Article  PubMed  CAS  Google Scholar 

  33. Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev Genet. 2009;10:94–108.

    Article  PubMed  CAS  Google Scholar 

  34. Gregory R, Chendrimada T, Shiekhattar R. MicroRNA biogenesis: isolation and characterization of the microprocessor complex. Methods Mol Biol. 2006;342:33–47.

    PubMed  CAS  Google Scholar 

  35. Griffiths-Jones S. The microRNA Registry. Nucl Acid Res. 2004;32:D109–11.

    Article  CAS  Google Scholar 

  36. Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucl Acid Res. 2006;34:D140–4.

    Article  CAS  Google Scholar 

  37. Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA. 2008;105:1516–21.

    Article  PubMed  CAS  Google Scholar 

  38. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.

    PubMed  CAS  Google Scholar 

  39. Haussecker D, Kay MA. MiR-122 continues to blaze the trail for microRNA therapeutics. Mol Ther. 2010;18:240–2.

    Article  PubMed  CAS  Google Scholar 

  40. Huang F, Chotiner JK, Steward O. The mRNA for elongation factor 1alpha is localized in dendrites and translated in response to treatments that induce long-term depression. J Neurosci. 2005;25:7199–209.

    Article  PubMed  CAS  Google Scholar 

  41. Jackson RJ, Standart N. How do microRNAs regulate gene expression? Sci STKE 2007;367:re1.

    Google Scholar 

  42. Jeansson M, Gawlik A, Anderson G, Li C, Kerjaschki D, Henkelman M, Quaggin SE. Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest. 2011;121:2278–89.

    Article  PubMed  CAS  Google Scholar 

  43. Jensen MB, Chacon MR, Sattin JA, Levine RL, Vemuganti R. Potential biomarkers for the diagnosis of stroke. Expert Rev Cardiovasc Ther. 2009;7:389–93.

    Article  PubMed  CAS  Google Scholar 

  44. Jeyaseelan K, Lim KY, Armugam A. MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke. 2008;39:959–66.

    Article  PubMed  CAS  Google Scholar 

  45. Ji R, Cheng Y, Yue J, Yang J, Liu X, Chen H, Dean DB, Zhang C. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res. 2007;100:1579–88.

    Article  PubMed  CAS  Google Scholar 

  46. Kai Z, Pasquinelli A. MicroRNA assassins: factors that regulate the disappearance of miRNAs. Nat Struct Mol Biol. 2010;17:5–10.

    Article  PubMed  CAS  Google Scholar 

  47. Kapsimali M, Kloosterman WP, de Bruijn E, Rosa F, Plasterk RH, Wilson SW. MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol. 2007;8:R173.

    Article  PubMed  CAS  Google Scholar 

  48. Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci. 2008;13:1813–26.

    Article  PubMed  CAS  Google Scholar 

  49. Ketting RF. The many faces of RNAi. Dev Cell. 2011;20:148–61.

    Article  PubMed  CAS  Google Scholar 

  50. Margulies KB. MicroRNAs as novel myocardial biomarkers. Clin Chem. 2009;55: 1897–1899.

    Article  PubMed  Google Scholar 

  51. Kiriakidou M, Tan GS, Lamprinaki S, De Planell-Saguer M, Nelson PT, Mourelatos Z. An mRNA m7G cap binding-like motif within human Ago2 represses translation. Cell. 2007;129:1141–51.

    Article  PubMed  CAS  Google Scholar 

  52. Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA. 2003;9:1274–781.

    Article  PubMed  CAS  Google Scholar 

  53. Krutzfeldt J, Kuwajima S, Braich R, Rajeev KG, Pena J, Tuschl T, Manoharan M, Stoffel M. Specificity, duplex degradation and subcellular localization of antagomirs. Nucl Acid Res. 2007;35:2885–92.

    Article  CAS  Google Scholar 

  54. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685–9.

    Article  PubMed  CAS  Google Scholar 

  55. Kuhn DE, Nuovo GJ, Terry Jr AV, Martin MM, Malana GE, Sansom SE, Pleister AP, Beck WD, Head E, Feldman DS, Elton TS. Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains. J Biol Chem. 2010;285:1529–43.

    Article  PubMed  CAS  Google Scholar 

  56. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294:853–8.

    Article  PubMed  CAS  Google Scholar 

  57. Lau NC, Lim LP, Weinstein EG, Bartel DP. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001;294:858–62.

    Article  PubMed  CAS  Google Scholar 

  58. Lee I, Ajay SS, Yook JI, Kim HS, Hong SH, Kim NH, Dhanasekaran SM, Chinnaiyan AM, Athey BD. New class of microRNA targets containing simultaneous 5’-UTR and 3’-UTR interaction sites. Genome Res. 2009;19:1175–83.

    Article  PubMed  CAS  Google Scholar 

  59. Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001;294:862–4.

    Article  PubMed  CAS  Google Scholar 

  60. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.

    Article  PubMed  CAS  Google Scholar 

  61. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004;23:4051–160.

    Article  PubMed  CAS  Google Scholar 

  62. Lennmyr F, Karlsson S, Gerwins P, Ata KA, Terént A. Activation of mitogen-activated protein kinases in experimental cerebral ischemia. Acta Neurol Scand. 2002;106:333–40.

    Article  PubMed  CAS  Google Scholar 

  63. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.

    Article  PubMed  CAS  Google Scholar 

  64. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769–73.

    Article  PubMed  CAS  Google Scholar 

  65. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79:1431–568.

    PubMed  CAS  Google Scholar 

  66. Liu DZ, Tian Y, Ander BP, Xu H, Stamova BS, Zhan X, Turner RJ, Jickling G, Sharp FR. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab. 2010;30:92–101.

    Article  PubMed  CAS  Google Scholar 

  67. Lusardi TA, Farr CD, Faulkner CL, Pignataro G, Yang T, Lan J, Simon RP, Saugstad JA. Ischemic preconditioning regulates expression of microRNAs and a predicted target, MeCP2, in mouse cortex. J Cereb Blood Flow Metab. 2010;30:744–56.

    Article  PubMed  CAS  Google Scholar 

  68. Magill ST, Cambronne XA, Luikart BW, Lioy DT, Leighton BH, Westbrook GL, Mandel G, Goodman RH. microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc Natl Acad Sci USA. 2010;107:20382–7.

    Article  PubMed  CAS  Google Scholar 

  69. Mansfield JH, Harfe BD, Nissen R, Obenauer J, Srineel J, Chaudhuri A, Farzan-Kashani R, Zuker M, Pasquinelli AE, Ruvkun G, Sharp PA, Tabin CJ, McManus MT. MicroRNA-responsive ‘sensor’ transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nat Genet. 2004;36:1079–83.

    Article  PubMed  CAS  Google Scholar 

  70. Marais E, Genade S, Huisamen B, Strijdom JG, Moolman JA, Lochner A. Activation of p38 MAPK induced by a multi-cycle ischaemic preconditioning protocol is associated with attenuated p38 MAPK activity during sustained ischaemia and reperfusion. J Mol Cell Cardiol. 2001;33:769–78.

    Article  PubMed  CAS  Google Scholar 

  71. Margulies KB. MicroRNAs as novel myocardial biomarkers. Clin Chem. 2009;55:1897–99.

    Article  PubMed  CAS  Google Scholar 

  72. Martin MM, Buckenberger JA, Jiang J, Malana GE, Nuovo GJ, Chotani M, Feldman DS, Schmittgen TD, Elton TS. The human angiotensin II type 1 receptor 1166 A/C polymorphism attenuates microrna-155 binding. J Biol Chem. 2007;282:24262–9.

    Article  PubMed  CAS  Google Scholar 

  73. Mathonnet G, Fabian MR, Svitkin YV, Parsyan A, Huck L, Murata T, Biffo S, Merrick WC, Darzynkiewicz E, Pillai RS, Filipowicz W, Duchaine TF, Sonenberg N. MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F. Science. 2007;317:1764–7.

    Article  PubMed  CAS  Google Scholar 

  74. Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev. 2007;54:34–66.

    Article  PubMed  CAS  Google Scholar 

  75. Mettimano M, Romano-Spica V, Ianni A, Specchia M, Migneco A, Savi L. AGT and AT1R gene polymorphism in hypertensive heart disease. Int J Clin Pract. 2002;56:574–7.

    PubMed  CAS  Google Scholar 

  76. Meyuhas O. Synthesis of the translational apparatus is regulated at the translational level. Eur J Biochem. 2000;267:6321–30.

    Article  PubMed  CAS  Google Scholar 

  77. Mishima T, Mizuguchi Y, Kawahigashi Y, Takizawa T, Takizawa T. RT-PCR-based analysis of microRNA (miR-1 and −124) expression in mouse CNS. Brain Res. 2007;1131:37–43.

    Article  PubMed  CAS  Google Scholar 

  78. Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol. 2004;5:R68.

    Article  PubMed  Google Scholar 

  79. Moolman JA, Hartley S, van Wyk J, Marais E, Lochner A. Inhibition of myocardial apoptosis by ischaemic and beta-adrenergic preconditioning is dependent on p38 MAPK. Cardiovasc Drugs Ther. 2006;20:13–25.

    Article  PubMed  CAS  Google Scholar 

  80. Moretti F, Thermann R, Hentze MW. Mechanism of translational regulation by miR-2 from sites in the 5′ untranslated region or the open reading frame. RNA. 2010;16:2493–502.

    Article  PubMed  CAS  Google Scholar 

  81. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–36.

    Article  PubMed  CAS  Google Scholar 

  82. Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol. 1998;18:842–51.

    Article  PubMed  CAS  Google Scholar 

  83. Nakazawa T, Kuriu T, Tezuka T, Umemori H, Okabe S, Yamamoto T. Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP. J Neurochem. 2008;105:1384–93.

    Article  PubMed  CAS  Google Scholar 

  84. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393:386–9.

    Article  PubMed  CAS  Google Scholar 

  85. Napoli C, Lemieux C, Jorgensen R. Introduction of a chimeric chalcone synthase gene into Petunia results in reversible co-suppression of homologous genes in trans. Plant Cell. 1990;2:279–89.

    PubMed  CAS  Google Scholar 

  86. Nozaki K, Nishimura M, Hashimoto N. Mitogen-activated protein kinases and cerebral ischemia. Mol Neurobiol. 2001;23:1–19.

    Article  PubMed  CAS  Google Scholar 

  87. O’Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest. 1993;92:945–51.

    Article  PubMed  Google Scholar 

  88. Onteniente B, Rasika S, Benchoua A, Guégan C. Molecular pathways in cerebral ischemia: cues to novel therapeutic strategies. Mol Neurobiol. 2003;27:33–72.

    Article  PubMed  CAS  Google Scholar 

  89. Orom UA, Nielsen FC, Lund AH. MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell. 2008;30:460–71.

    Article  PubMed  CAS  Google Scholar 

  90. Ostroff LE, Fiala JC, Allwardt B, Harris KM. Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron. 2002;35:535–45.

    Article  PubMed  CAS  Google Scholar 

  91. Parker R, Sheth U. P bodies and the control of mRNA translation and degradation. Mol Cell. 2007;25:635–46.

    Article  PubMed  CAS  Google Scholar 

  92. Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, MĂ¼ller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408:86–9.

    Article  PubMed  CAS  Google Scholar 

  93. Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM, Siegelmann HT, Treistman SN. Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron. 2008;59:274–87.

    Article  PubMed  CAS  Google Scholar 

  94. Pillai RS, Bhattacharyya SN, Artus CG, Zoller T, Cougot N, Basyuk E, Bertrand E, Filipowicz W. Inhibition of translational initiation by let-7 microRNA in human cells. Science. 2005;309:1573–6.

    Article  PubMed  CAS  Google Scholar 

  95. Pillai RS, Bhattacharyya SN, Filipowicz W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol. 2007;17:118–26.

    Article  PubMed  CAS  Google Scholar 

  96. Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA. 2008;105:1608–13.

    Article  PubMed  CAS  Google Scholar 

  97. Potter WB, O’Riordan KJ, Barnett D, Osting SM, Wagoner M, Burger C, Roopra A. Metabolic regulation of neuronal plasticity by the energy sensor AMPK. PLoS One. 2010;5:e8996.

    Article  PubMed  CAS  Google Scholar 

  98. Pratt A, MacRae I. The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 2009;284:17897–901.

    Article  PubMed  CAS  Google Scholar 

  99. Rahbek UL, Nielsen AF, Dong M, You Y, Chauchereau A, Oupicky D, Besenbacher F, Kjems J, Howard KA. Bioresponsive hyperbranched polymers for siRNA and miRNA delivery. J Drug Target. 2010;18:812–20.

    Article  PubMed  CAS  Google Scholar 

  100. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403:901–6.

    Article  PubMed  CAS  Google Scholar 

  101. Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature. 2005;433:477–80.

    Article  PubMed  CAS  Google Scholar 

  102. Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 2004;14:1902–10.

    Article  PubMed  CAS  Google Scholar 

  103. Rogaev EI. Small RNAs in human brain development and disorders. Biochemistry. 2005;70:1404–7.

    PubMed  CAS  Google Scholar 

  104. Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev. 2010;90:1507–46.

    Article  PubMed  CAS  Google Scholar 

  105. Schnall-Levin M, Zhao Y, Perrimon N, Berger B. Conserved microRNA targeting in Drosophila is as widespread in coding regions as in 3′UTRs. Proc Natl Acad Sci USA. 2010;107:15751–6.

    Article  PubMed  CAS  Google Scholar 

  106. Scholer N, Langer C, Döhner H, Buske C, Kuchenbauer F. Serum microRNAs as a novel class of biomarkers: a comprehensive review of the literature. Exp Hematol. 2010;38:1126–30.

    Article  PubMed  CAS  Google Scholar 

  107. Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439:283–9.

    Article  PubMed  CAS  Google Scholar 

  108. Schwarz D, Zamore P. Why do miRNAs live in the miRNP? Genes Dev. 2002;16:1025–31.

    Article  PubMed  CAS  Google Scholar 

  109. Sharp FR, Jickling GC, Stamova B, Tian Y, Zhan X, Liu D, Kuczynski B, Cox CD, Ander BP. Molecular markers and mechanisms of stroke: RNA studies of blood in animals and humans. J Cereb Blood Flow Metab. 2011;31:1513–31.

    Article  PubMed  CAS  Google Scholar 

  110. Si LM, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26:2799–803.

    Article  PubMed  CAS  Google Scholar 

  111. Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. Regulation of miRNA expression during neural cell specification. Eur J Neurosci. 2005;21:1469–77.

    Article  PubMed  Google Scholar 

  112. Stenzel-Poore MP, Stevens SL, Xiong Z, Lessov NS, Harrington CA, Mori M, Meller R, Rosenzweig HL, Tobar E, Shaw TE, Chu X, Simon RP. Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet. 2003;362:1028–37.

    Article  PubMed  CAS  Google Scholar 

  113. Steward O, Worley P. Local synthesis of proteins at synaptic sites on dendrites: role in synaptic plasticity and memory consolidation? Neurobiol Learn Mem. 2002;78:508–27.

    Article  PubMed  CAS  Google Scholar 

  114. Strauss WM, Chen C, Lee CT, Ridzon D. Nonrestrictive developmental regulation of microRNA gene expression. Mamm Genome. 2006;17:833–40.

    Article  PubMed  CAS  Google Scholar 

  115. Subramaniam S, Unsicker K. ERK and cell death: ERK1/2 in neuronal death. FEBS J. 2010;277:22–9.

    Article  PubMed  CAS  Google Scholar 

  116. Tan KS, Armugam A, Sepramaniam S, Lim KY, Setyowati KD, Wang CW, Jeyaseelan K. Expression profile of MicroRNAs in young stroke patients. PLoS One. 2009;4:e7689.

    Article  PubMed  CAS  Google Scholar 

  117. Tang F, Hajkova P, O’Carroll D, Lee C, Tarakhovsky A, Lao K, Surani MA. MicroRNAs are tightly associated with RNA-induced gene silencing complexes in vivo. Biochem Biophys Res Commun. 2008;372:24–9.

    Article  PubMed  CAS  Google Scholar 

  118. Van den Berg A, Mols J, Han J. RISC-target interaction: cleavage and translational suppression. Biochim Biophys Acta. 2008;1779:668–77.

    Article  PubMed  CAS  Google Scholar 

  119. Van der Krol AR, Mur LA, de Lange P, Mol JN, Stuitje AR. Inhibition of flower pigmentation by antisense CHS genes: promoter and minimal sequence requirements for the antisense effect. Plant Mol Biol. 1990;14:457–66.

    Article  PubMed  Google Scholar 

  120. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931–4.

    Article  PubMed  CAS  Google Scholar 

  121. Vasudevan S, Tong Y, Steitz JA. Cell-cycle control of microRNA-mediated translation regulation. Cell Cycle. 2008;7:1545–9.

    Article  PubMed  CAS  Google Scholar 

  122. Veldhuis WB, Derksen JW, Floris S, Van Der Meide PH, De Vries HE, Schepers J, Vos IM, Dijkstra CD, Kappelle LJ, Nicolay K, Bar PR. Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat. J Cereb Blood Flow Metab. 2003;23:1029–39.

    Article  PubMed  CAS  Google Scholar 

  123. Vemuganti R, Dempsey RJ. Carotid atherosclerotic plaques from symptomatic stroke patients share the molecular fingerprints to develop in a neoplastic fashion: a microarray analysis study. Neuroscience. 2005;131:359–74.

    Article  PubMed  CAS  Google Scholar 

  124. Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15:261–71.

    Article  PubMed  CAS  Google Scholar 

  125. Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, Qin YW, Jing Q. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010;31:659–66.

    Article  PubMed  CAS  Google Scholar 

  126. Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, Marks D, Obrietan K, Soderling TR, Goodman RH, Impey S. An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci USA. 2008;105:9093–8.

    Article  PubMed  CAS  Google Scholar 

  127. Weber M, Baker MB, Moore JP, Searles CD. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity. Biochem Biophys Res Commun. 2010;393:643–8.

    Article  PubMed  CAS  Google Scholar 

  128. Witwer KW, Sisk JM, Gama L, Clements JE. MicroRNA regulation of IFN-beta protein expression: rapid and sensitive modulation of the innate immune response. J Immunol. 2010; 184:2369–76.

    Article  PubMed  CAS  Google Scholar 

  129. Wright MW, Bruford EA. Naming ‘junk’: human non-protein coding RNA (ncRNA) gene nomenclature. Hum Genomics. 2011;5:90–8.

    PubMed  CAS  Google Scholar 

  130. Wu J, Xie X. Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol. 2006;7:R85.

    Article  PubMed  CAS  Google Scholar 

  131. Xu CC, Han WQ, Xiao B, Li NN, Zhu DL, Gao PJ. Differential expression of microRNAs in the aorta of spontaneously hypertensive rats. Sheng Li Xue Bao. 2008;60:553–60.

    PubMed  CAS  Google Scholar 

  132. Yi JH, Park SW, Kapadia R, Vemuganti R. Role of transcription factors in mediating post­ischemic cerebral inflammation and brain damage. Neurochem Int. 2007;50:1014–27.

    PubMed  CAS  Google Scholar 

  133. Yin KJ, Deng Z, Hamblin M, Xiang Y, Huang H, Zhang J, Jiang X, Wang Y, Chen YE. Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J Neurosci. 2010;30:6398–408.

    Article  PubMed  CAS  Google Scholar 

  134. Yin KJ, Deng Z, Huang H, Hamblin M, Xie C, Zhang J, Chen YE. miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia. Neurobiol Dis. 2010;38:17–26.

    Article  PubMed  CAS  Google Scholar 

  135. Younger ST, Corey DR. Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucl Acid Res. 2011;39:5682–91.

    Article  CAS  Google Scholar 

  136. Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, Shah A, Willeit J, Mayr M. Plasma microRNA profiling reveals loss of endothelial MiR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107:810–7.

    Article  PubMed  CAS  Google Scholar 

  137. Zhou X, Ruan J, Wang G, Zhang W. Characterization and identification of microRNA core promoters in four model species. PLoS Comput Biol. 2007;3:e37.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by NIH grant 061071 and NIH grant 074444.

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Authors and Affiliations

  1. Department of Neurological Surgery and Neuroscience Training Program, University of Wisconsin, 600 Highland Ave, Madison, WI, 53792, USA

    Ashutosh Dharap, Venkata P. Nakka & Raghu Vemuganti PhD

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  1. Ashutosh Dharap
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  2. Venkata P. Nakka
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  3. Raghu Vemuganti PhD
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Correspondence to Raghu Vemuganti PhD .

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  1. , Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Paul A. Lapchak

  2. Loma Linda University, 11234 Anderson Street, Room 2562B, Loma Linda, 92354, California, USA

    John H. Zhang

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Dharap, A., Nakka, V.P., Vemuganti, R. (2012). microRNAs in Ischemic Brain: The Fine-Tuning Specialists and Novel Therapeutic Targets. In: Lapchak, P., Zhang, J. (eds) Translational Stroke Research. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9530-8_17

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