The risk of ischemic stroke increases substantially with age, making it the third leading cause of death and the leading cause of long-term disability in the world. Numerous studies demonstrated that genes, RNAs, and proteins are involved in the occurrence and development of stroke. Current studies found that microRNAs (miRNAs or miRs) are also closely related to the pathological process of stroke. miRNAs are a group of short, noncoding RNA molecules playing important role in posttranscriptional regulation of gene expression and they have emerged as regulators of ischemic preconditioning and ischemic postconditioning. Here we give an overview of the expression and function of miRNAs in the brain, miRNAs as biomarkers during cerebral ischemia, and clinical applications and limitations of miRNAs. Future prospects of miRNAs are also discussed. 1. Introduction miRNAs are approximately 20-nucleotide, single-stranded RNA molecules that target mRNA through partial complementarity and they can regulate gene expression through inhibition of translation or transcript degradation [1]. It is now predicted that 40% to 50% of mammalian mRNAs could be regulated at the translational level by miRNAs [2]. In mammals, specific miRNAs are known to control processes including development, neuronal cell fate, apoptosis, proliferation, adipocyte differentiation, hematopoiesis, and exocytosis as well as in diseases [3–5] and possibly neuronal disorders [6]. miRNA expression has been detected in stroke [2, 7], Alzheimer’s disease [8], Parkinson’s disease [9], Down’s syndrome [10], and schizophrenia [11]. These miRNAs expression profiles may be as diagnostically useful as mRNA expression profiles [12]. In the nucleus, miRNAs are transcribed as hairpin clusters of primary miRNAs (pri-miRNAs; 5′-capped polyadenylated transcripts), which is converted to 70-nt stem loop structures (pre-miRNAs) by Drosha (a type-III RNase) in association with a cofactor Pasha (aka DiGeorge syndrome critical region gene 8) [13]. pre-miRNAs are transported from nucleus to cytosol by exportin-5 and acted on by another type-III RNase known as Dicer that deletes the terminal loop of pre-miRNAs to form mature miRNAs [14]. 2. miRNA Expression and Its Functions in the Brain miRNAs serve important roles in the development and function of the brain [15–19]. Studies support that tissue-specific miRNAs contribute to establish and maintain protein expression profiles underlying distinct cellular phenotypes. The discovery of seven brain-specific miRNAs (miR-9, miR-124a, miR-124b, miR-135, miR-153, miR-183, and
References
[1]
C. Zhang, “Micrornomics: a newly emerging approach for disease biology,” Physiological Genomics, vol. 33, no. 2, pp. 139–147, 2008.
[2]
K. Jeyaseelan, K. Y. Lim, and A. Armugam, “MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion,” Stroke, vol. 39, no. 3, pp. 959–966, 2008.
[3]
W. P. Kloosterman and R. H. A. Plasterk, “The diverse functions of MicroRNAs in animal development and disease,” Developmental Cell, vol. 11, no. 4, pp. 441–450, 2006.
[4]
G. A. Calin and C. M. Croce, “MicroRNA signatures in human cancers,” Nature Reviews Cancer, vol. 6, no. 11, pp. 857–866, 2006.
[5]
E. Hernando, “microRNAs and cancer: role in tumorigenesis, patient classification and therapy,” Clinical and Translational Oncology, vol. 9, no. 3, pp. 155–160, 2007.
[6]
K. S. Kosik, “The neuronal microRNA system,” Nature Reviews Neuroscience, vol. 7, no. 12, pp. 911–920, 2006.
[7]
A. Dharap, K. Bowen, R. Place, L. C. Li, and R. Vemuganti, “Transient focal ischemia induces extensive temporal changes in rat cerebral MicroRNAome,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 4, pp. 675–687, 2009.
[8]
S. S. Hébert, K. Horré, L. Nicola？ et al., “Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 17, pp. 6415–6420, 2008.
[9]
J. Kim, K. Inoue, J. Ishii et al., “A microRNA feedback circuit in midbrain dopamine neurons,” Science, vol. 317, no. 5842, pp. 1220–1224, 2007.
[10]
D. E. Kuhn, G. J. Nuovo, M. M. Martin et al., “Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts,” Biochemical and Biophysical Research Communications, vol. 370, no. 3, pp. 473–477, 2008.
[11]
N. J. Beveridge, P. A. Tooney, A. P. Carroll et al., “Dysregulation of miRNA 181b in the temporal cortex in schizophrenia,” Human Molecular Genetics, vol. 17, no. 8, pp. 1156–1168, 2008.
[12]
D. J. Guarnieri and R. J. Dileone, “MicroRNAs: a new class of gene regulators,” Annals of Medicine, vol. 40, no. 3, pp. 197–208, 2008.
[13]
Y. Lee, C. Ahn, J. Han et al., “The nuclear RNase III Drosha initiates microRNA processing,” Nature, vol. 425, no. 6956, pp. 415–419, 2003.
[14]
S. D. Boyd, “Everything you wanted to know about small RNA but were afraid to ask,” Laboratory Investigation, vol. 88, no. 6, pp. 569–578, 2008.
[15]
S. Bicker and G. Schratt, “microRNAs: tiny regulators of synapse function in development and disease,” Journal of Cellular and Molecular Medicine, vol. 12, no. 5A, pp. 1466–1476, 2008.
[16]
R. Fiore, G. Siegel, and G. Schratt, “MicroRNA function in neuronal development, plasticity and disease,” Biochimica et Biophysica Acta, vol. 1779, no. 8, pp. 471–478, 2008.
[17]
M. Christensen and G. M. Schratt, “microRNA involvement in developmental and functional aspects of the nervous system and in neurological diseases,” Neuroscience Letters, vol. 466, no. 2, pp. 55–62, 2009.
[18]
G. Schratt, “Fine-tuning neural gene expression with microRNAs,” Current Opinion in Neurobiology, vol. 19, no. 2, pp. 213–219, 2009.
[19]
Y. Zeng, “Regulation of the mammalian nervous system by MicroRNAs,” Molecular Pharmacology, vol. 75, no. 2, pp. 259–264, 2009.
[20]
L. F. Sempere, S. Freemantle, I. Pitha-Rowe, E. Moss, E. Dmitrovsky, and V. Ambros, “Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation,” Genome biology, vol. 5, no. 3, article R13, 2004.
[21]
T. Mishima, Y. Mizuguchi, Y. Kawahigashi, T. Takizawa, and T. Takizawa, “RT-PCR-based analysis of microRNA (miR-1 and -124) expression in mouse CNS,” Brain Research, vol. 1131, no. 1, pp. 37–43, 2007.
[22]
L. P. Lim, N. C. Lau, P. Garrett-Engele et al., “Microarray analysis shows that some microRNAs downregulate large numbers of-target mRNAs,” Nature, vol. 433, no. 7027, pp. 769–773, 2005.
[23]
D.-Z. Liu, B. P. Ander, Y. Tian et al., “Integrated analysis of mRNA and microRNA expression in mature neurons, neural progenitor cells and neuroblastoma cells,” Gene, vol. 495, no. 2, pp. 120–127, 2012.
[24]
G. M. Schratt, F. Tuebing, E. A. Nigh et al., “A brain-specific microRNA regulates dendritic spine development,” Nature, vol. 439, no. 7074, pp. 283–289, 2006.
[25]
C. Rink and S. Khanna, “MicroRNA in ischemic stroke etiology and pathology,” Physiological Genomics, vol. 43, no. 10, pp. 521–528, 2011.
[26]
C. Liu, Z. Peng, N. Zhang et al., “Identification of differentially expressed microRNAs and their PKC-isoform specific gene network prediction during hypoxic pre-conditioning and focal cerebral ischemia of mice,” Journal of Neurochemistry, vol. 120, no. 5, pp. 830–841, 2012.
[27]
S. Sepramaniam, A. Armugam, K. Y. Lim et al., “MicroRNA 320a functions as a novel endogenous modulator of aquaporins 1 and 4 as well as a potential therapeutic target in cerebral ischemia,” Journal of Biological Chemistry, vol. 285, no. 38, pp. 29223–29230, 2010.
[28]
K. S. Tan, A. Armugam, S. Sepramaniam et al., “Expression profile of microRNAs in young stroke patients,” PLoS One, vol. 4, no. 11, Article ID e7689, 2009.
[29]
K. J. Yin, Z. Deng, H. Huang et al., “miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia,” Neurobiology of Disease, vol. 38, no. 1, pp. 17–26, 2010.
[30]
X. Cao, S. L. Pfaff, and F. H. Gage, “A functional study of miR-124 in the developing neural tube,” Genes and Development, vol. 21, no. 5, pp. 531–536, 2007.
[31]
A. Selvamani, P. Sathyan, R. C. Miranda, and F. Sohrabji, “An antagomir to microRNA let7f promotes neuroprotection in an ischemic stroke model,” PLoS One, vol. 7, no. 2, Article ID e32662, 2012.
[32]
K. Hu, Y.-Y. Xie, C. Zhang et al., “MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus,” BMC Neuroscience, vol. 13, no. 1, article 115, 2012.
[33]
Y.-B. Ouyang, Y. Lu, S. Yue, and R. G. Giffard, “MiR-181 targets multiple Bcl-2 family members and influences apoptosis and mitochondrial function in astrocytes,” Mitochondrion, vol. 12, no. 2, pp. 213–219, 2012.
[34]
Y.-B. Ouyang, Y. Lu, S. Yue et al., “MiR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo,” Neurobiology of Disease, vol. 45, no. 1, pp. 555–563, 2012.
[35]
A. Caporali and C. Emanueli, “MicroRNAs in postischemic vascular repair,” Cardiology Research and Practice, vol. 1, no. 1, Article ID Article number486702, 2012.
[36]
T. Würdinger, B. A. Tannous, O. Saydam et al., “miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells,” Cancer Cell, vol. 14, no. 5, pp. 382–393, 2008.
[37]
P. Fasanaro, Y. D'Alessandra, V. Di Stefano et al., “MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand ephrin-A3,” Journal of Biological Chemistry, vol. 283, no. 23, pp. 15878–15883, 2008.
[38]
L. Zeng, J. Liu, Y. Wang et al., “MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia,” Frontiers in Bioscience, vol. 3, pp. 1265–1272, 2011.
[39]
G. Ghosh, I. V. Subramanian, N. Adhikari et al., “Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-α isoforms and promotes angiogenesis,” Journal of Clinical Investigation, vol. 120, no. 11, pp. 4141–4154, 2010.
[40]
Q. Zhou, R. Gallagher, R. Ufret-Vincenty, X. Li, E. N. Olson, and S. Wang, “Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23~27~24 clusters,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 20, pp. 8287–8292, 2011.
[41]
D. Y. Lee, Z. Deng, C. H. Wang, and B. B. Yang, “MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 51, pp. 20350–20355, 2007.
[42]
J.-S. Li and Z.-X. Yao, “MicroRNAs: novel regulators of oligodendrocyte differentiation and potential therapeutic targets in demyelination-related diseases,” Molecular Neurobiology, vol. 45, no. 1, pp. 200–212, 2012.
[43]
H. Budde, S. Schmitt, D. Fitzner, L. Opitz, G. Salinas-Riester, and M. Simons, “Control of oligodendroglial cell number by the miR-17-92 cluster,” Development, vol. 137, no. 13, pp. 2127–2132, 2010.
[44]
V. Olive, M. J. Bennett, J. C. Walker et al., “miR-19 is a key oncogenic component of mir-17-92,” Genes and Development, vol. 23, no. 24, pp. 2839–2849, 2009.
[45]
A. Dharap and R. Vemuganti, “Ischemic pre-conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways,” Journal of Neurochemistry, vol. 113, no. 6, pp. 1685–1691, 2010.
[46]
X. Chen, Y. Ba, L. Ma et al., “Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases,” Cell Research, vol. 18, no. 10, pp. 997–1006, 2008.
[47]
C. Chen, Q. Hu, J. Yan et al., “Early inhibition of HIF-1α with small interfering RNA reduces ischemic-reperfused brain injury in rats,” Neurobiology of Disease, vol. 33, no. 3, pp. 509–517, 2009.
[48]
S. T. Lee, K. Chu, K. H. Jung et al., “MicroRNAs induced during ischemic preconditioning,” Stroke, vol. 41, no. 8, pp. 1646–1651, 2010.
[49]
S. Rane, M. He, D. Sayed et al., “Downregulation of MiR-199a derepresses hypoxia-inducible factor-1α and sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes,” Circulation Research, vol. 104, no. 7, pp. 879–886, 2009.
[50]
J. Chen, T. Yang, H. Yu et al., “A functional variant in the 3′-UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211,” Human Molecular Genetics, vol. 19, no. 12, Article ID ddq131, pp. 2524–2533, 2010.
[51]
J. B. Weiss, S. U. Eisenhardt, G. B. Stark, C. Bode, M. Moser, and S. Grundmann, “Micrornas in ischemia-reperfusion injury,” American Journal of Cardiovascular Disease, vol. 2, no. 3, pp. 237–247, 2012.
[52]
J. G. Godwin, X. Ge, K. Stephan, A. Jurisch, S. G. Tullius, and J. Iacomini, “Identification of a microRNA signature of renal ischemia reperfusion injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 32, pp. 14339–14344, 2010.
[53]
J. Krützfeldt, N. Rajewsky, R. Braich et al., “Silencing of microRNAs in vivo with “antagomirs”,” Nature, vol. 438, no. 7068, pp. 685–689, 2005.
[54]
A. Collison, C. Herbert, J. S. Siegle, J. Mattes, P. S. Foster, and R. K. Kumar, “Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target,” BMC Pulmonary Medicine, vol. 11, article 29, 2011.
[55]
K. McArthur, B. Feng, Y. Wu, S. Chen, and S. Chakrabarti, “MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy,” Diabetes, vol. 60, no. 4, pp. 1314–1323, 2011.
[56]
A. Kumar, “MicroRNA in HCV infection and liver cancer,” Biochimica et Biophysica Acta, vol. 1809, no. 11-12, pp. 694–699, 2011.
[57]
G. Nunnari and M. J. Schnell, “MicroRNA-122: a therapeutic target for hepatitis c virus (hcv) infection,” Frontiers in Bioscience, vol. 3, pp. 1032–1037, 2011.
[58]
T. Thum, “Microrna therapeutics in cardiovascular medicine,” EMBO Molecular Medicine, vol. 4, no. 1, pp. 3–14, 2012.
[59]
S. Hu, M. Huang, Z. Li et al., “MicroRNA-210 as a novel therapy for treatment of ischemic heart disease,” Circulation, vol. 122, no. 11, pp. S124–S131, 2010.
