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Pathogenic and Therapeutic Role of MicroRNA in Pulmonary Arterial Hypertension

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Book cover Diagnosis and Treatment of Pulmonary Hypertension

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that play an integral role in regulating gene expression. Increasing evidence supports the important role of miRNAs in the development and progression of pulmonary arterial hypertension (PAH). The function of miRNAs can also be efficiently and specifically regulated using a number of therapeutic strategies, supporting their potential as targets for the treatment of PAH. In this chapter we briefly describe the biogenesis of miRNAs, summarize our current knowledge of the role of various miRNAs in the pathogenic mechanisms of PAH, introduce strategies of targeting miRNAs to treat the disease, review the preclinical results and potential for using miRNAs for treatment of PAH in in vivo models, and finally discuss the current challenges facing the field to deliver miRNA-targeting therapeutics specifically and efficiently to patients.

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References

  1. Hoeper MM, Simon RGJ. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respir Rev. 2014;23(134):450–7. doi:10.1183/09059180.00007814.

    Article  PubMed  Google Scholar 

  2. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J. 2009;34(4):888–94. doi:10.1183/09031936.00145608.

    Article  CAS  PubMed  Google Scholar 

  3. Thum T, Batkai S. MicroRNAs in right ventricular (dys)function (2013 Grover Conference series). Pulm Circ. 2014;4(2):185–90. doi:10.1086/675981 PC2013103 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kim GH, Ryan JJ, Marsboom G, Archer SL. Epigenetic mechanisms of pulmonary hypertension. Pulm Circ. 2011;1(3):347–56. doi:10.4103/2045-8932.87300 PC-1-347 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Frumkin LR. The pharmacological treatment of pulmonary arterial hypertension. Pharmacol Rev. 2012;64(3):583–620. doi:10.1124/pr.111.005587.

    Article  CAS  PubMed  Google Scholar 

  6. Joshi SR, McLendon JM, Comer BS, Gerthoffer WT. MicroRNAs-control of essential genes: implications for pulmonary vascular disease. Pulm Circ. 2011;1(3):357–64. doi:10.4103/2045-8932.87301 PC-1-357 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. White K, Loscalzo J, Chan SY. Holding our breath: the emerging and anticipated roles of microRNA in pulmonary hypertension. Pulm Circ. 2012;2(3):278–90. doi:10.4103/2045-8932.101395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11(3):228–34. doi:10.1038/ncb0309-228.

    Article  CAS  PubMed  Google Scholar 

  9. Geraci MW. Integrating molecular genetics and systems approaches to pulmonary vascular diseases. Pulm Circ. 2013;3(1):171–5. doi:10.4103/2045-8932.109959 PC-3-171 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sessa R, Hata A. Role of microRNAs in lung development and pulmonary diseases. Pulm Circ. 2013;3(2):315–28. doi:10.4103/2045-8932.114758 PC-3-315 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Da Sacco L, Masotti A. Recent insights and novel bioinformatics tools to understand the role of microRNAs binding to 5′ untranslated region. Int J Mol Sci. 2012;14(1):480–95. doi:10.3390/ijms14010480 ijms14010480 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  12. Towler BP, Jones CI, Newbury SF. Mechanisms of regulation of mature miRNAs. Biochem Soc Trans. 2015;43(6):1208–14. doi:10.1042/BST20150157. BST20150157 [pii]

    Article  CAS  PubMed  Google Scholar 

  13. Barrett LW, Fletcher S, Wilton SD. Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cell Mol Life Sci. 2012;69(21):3613–34. doi:10.1007/s00018-012-0990-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Albinsson S, Suarez Y, Skoura A, Offermanns S, Miano JM, Sessa WC. MicroRNAs are necessary for vascular smooth muscle growth, differentiation, and function. Arterioscler Thromb Vasc Biol. 2010;30(6):1118–26. doi:10.1161/ATVBAHA.109.200873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716–23. doi:10.1161/ATVBAHA.109.202028.

    Article  CAS  PubMed  Google Scholar 

  16. Rupaimoole R, Wu SY, Pradeep S, Ivan C, Pecot CV, Gharpure KM, et al. Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nat Commun. 2014;5:5202. doi:10.1038/ncomms6202 ncomms6202 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bandara V, Michael MZ, Gleadle JM. Hypoxia represses microRNA biogenesis proteins in breast cancer cells. BMC Cancer. 2014;14:533. doi:10.1186/1471-2407-14-533. 1471-2407-14-533 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  18. Klinge CM. miRNAs regulated by estrogens, tamoxifen, and endocrine disruptors and their downstream gene targets. Mol Cell Endocrinol. 2015; doi:10.1016/j.mce.2015.01.035.

    PubMed Central  Google Scholar 

  19. Grant JS, Morecroft I, Dempsie Y, van Rooij E, MacLean MR, Baker AH. Transient but not genetic loss of miR-451 is protective in the development of pulmonary arterial hypertension. Pulm Circ. 2013;3(4):840–50. doi:10.1086/674751. PC2013009 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wang L, Guo LJ, Liu J, Wang W, Yuan JX, Zhao L, et al. MicroRNA expression profile of pulmonary artery smooth muscle cells and the effect of let-7d in chronic thromboembolic pulmonary hypertension. Pulm Circ. 2013;3(3):654–64. doi:10.1086/674310.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Parikh VN, Jin RC, Rabello S, Gulbahce N, White K, Hale A, et al. MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation. 2012;125(12):1520–32. doi:10.1161/CIRCULATIONAHA.111.060269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Green DE, Murphy TC, Kang BY, Searles CD, Hart CM. PPARgamma ligands attenuate hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of microRNA-21. PLoS One 2015;10(7):e0133391. doi:10.1371/journal.pone.0133391 PONE-D-15-13472 [pii].

  23. Drake KM, Zygmunt D, Mavrakis L, Harbor P, Wang L, Comhair SA, et al. Altered microRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med. 2011;184(12):1400–8. doi:10.1164/rccm.201106-1130OC. 201106-1130OC [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takahashi H, Goto N, Kojima Y, Tsuda Y, Morio Y, Muramatsu M et al. Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Phys Lung Cell Mol Phys 2006;290(3):L450–L458. doi:00206.2005 [pii] 10.1152/ajplung.00206.2005.

  25. Morty RE, Nejman B, Kwapiszewska G, Hecker M, Zakrzewicz A, Kouri FM et al. Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2007;27(5):1072–1078. doi:ATVBAHA.107.141200 [pii] 10.1161/ATVBAHA.107.141200.

  26. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105(14):1672–8.

    Article  CAS  PubMed  Google Scholar 

  27. Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008;454(7200):56–61. doi:10.1038/nature07086. nature07086 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sarkar J, Gou D, Turaka P, Viktorova E, Ramchandran R, Raj JU. MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration. Am J Phys Lung Cell Mol Phys. 2010;299(6):L861–71. doi:10.1152/ajplung.00201.2010.

    CAS  Google Scholar 

  29. Polytarchou C, Iliopoulos D, Hatziapostolou M, Kottakis F, Maroulakou I, Struhl K et al. Akt2 regulates all Akt isoforms and promotes resistance to hypoxia through induction of miR-21 upon oxygen deprivation. Cancer Res 2011;71(13):4720–4731. doi:10.1158/0008-5472.CAN-11-0365 0008-5472.CAN-11-0365 [pii].

  30. Iannone L, Zhao L, Dubois O, Duluc L, Rhodes CJ, Wharton J, et al. miR-21/DDAH1 pathway regulates pulmonary vascular responses to hypoxia. Biochem J. 2014;462(1):103–12. doi:10.1042/BJ20140486. BJ20140486 [pii]

    Article  CAS  PubMed  Google Scholar 

  31. Yang S, Banerjee S, Freitas A, Cui H, Xie N, Abraham E et al. miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Phys Lung Cell Mol Phys 2012;302(6):L521–L529. doi:10.1152/ajplung.00316.2011 ajplung.00316.2011 [pii].

  32. Lin Y, Liu X, Cheng Y, Yang J, Huo Y, Zhang C. Involvement of microRNAs in hydrogen peroxide-mediated gene regulation and cellular injury response in vascular smooth muscle cells. J Biol Chem 2009;284(12):7903–7913. doi:10.1074/jbc.M806920200 M806920200 [pii].

  33. White K, Dempsie Y, Caruso P, Wallace E, McDonald RA, Stevens H, et al. Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis. Hypertension. 2014;64(1):185–94. doi:10.1161/HYPERTENSIONAHA.113.03037 HYPERTENSIONAHA.113.03037 [pii]

    Article  CAS  PubMed  Google Scholar 

  34. Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res. 2003;92(10):1162–9. doi:10.1161/01.RES.0000073585.50092.14 01.RES.0000073585.50092.14 [pii]

    Article  CAS  PubMed  Google Scholar 

  35. Falcetti E, Hall SM, Phillips PG, Patel J, Morrell NW, Haworth SG, et al. Smooth muscle proliferation and role of the prostacyclin (IP) receptor in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182(9):1161–70. doi:10.1164/rccm.201001-0011OC 201001-0011OC [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wojciak-Stothard B, Zhao L, Oliver E, Dubois O, Wu Y, Kardassis D, et al. Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia. Circ Res. 2012;110(11):1423–34. doi:10.1161/CIRCRESAHA.112.264473 CIRCRESAHA.112.264473 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ghatnekar A, Chrobak I, Reese C, Stawski L, Seta F, Wirrig E, et al. Endothelial GATA-6 deficiency promotes pulmonary arterial hypertension. Am J Pathol. 2013;182(6):2391–406. doi:10.1016/j.ajpath.2013.02.039 S0002-9440(13)00218-6 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chan YC, Banerjee J, Choi SY, Sen CK. miR-210: the master hypoxamir. Microcirculation. 2012;19(3):215–23. doi:10.1111/j.1549-8719.2011.00154.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chan SY, Loscalzo J. MicroRNA-210: a unique and pleiotropic hypoxamir. Cell Cycle. 2010;9(6):1072–83. doi:11006 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gou D, Ramchandran R, Peng X, Yao L, Kang K, Sarkar J, et al. miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia. Am J Phys Lung Cell Mol Phys. 2012;303(8):L682–91. doi:10.1152/ajplung.00344.2011.

    CAS  Google Scholar 

  41. White K, Lu Y, Annis S, Hale AE, Chau BN, Dahlman JE, et al. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol Med. 2015;7(6):695–713. doi:10.15252/emmm.201404511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009;10(4):273–84. doi:10.1016/j.cmet.2009.08.015 S1550-4131(09)00265-4 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hong S, Paulson QX, Johnson DG. E2F1 and E2F3 activate ATM through distinct mechanisms to promote E1A-induced apoptosis. Cell Cycle. 2008;7(3):391–400.

    Article  CAS  PubMed  Google Scholar 

  44. Martinez LA, Goluszko E, Chen HZ, Leone G, Post S, Lozano G, et al. E2F3 is a mediator of DNA damage-induced apoptosis. Mol Cell Biol. 2010;30(2):524–36. doi:10.1128/MCB.00938-09.

    Article  CAS  PubMed  Google Scholar 

  45. Jin Y, Pang T, Nelin LD, Wang W, Wang Y, Yan J, et al. MKP-1 is a target of miR-210 and mediate the negative regulation of miR-210 inhibitor on hypoxic hPASMC proliferation. Cell Biol Int. 2015;39(1):113–20. doi:10.1002/cbin.10339.

    Article  CAS  PubMed  Google Scholar 

  46. Caruso P, Dempsie Y, Stevens HC, McDonald RA, Long L, Lu R, et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res. 2012;111(3):290–300. doi:10.1161/CIRCRESAHA.112.267591 CIRCRESAHA.112.267591 [pii]

    Article  CAS  PubMed  Google Scholar 

  47. Shatat MA, Tian H, Zhang R, Tandon G, Hale A, Fritz JS, et al. Endothelial Kruppel-like factor 4 modulates pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2014;50(3):647–53. doi:10.1165/rcmb.2013-0135OC.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Atkins GB, Jain MK. Role of Kruppel-like transcription factors in endothelial biology. Circ Res. 2007;100(12):1686–95. doi:100/12/1686 [pii] 10.1161/01.RES.0000267856.00713.0a

    Article  CAS  PubMed  Google Scholar 

  49. Davis-Dusenbery BN, Chan MC, Reno KE, Weisman AS, Layne MD, Lagna G, et al. down-regulation of Kruppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-beta and bone morphogenetic protein 4. J Biol Chem. 2011;286(32):28097–110. doi:10.1074/jbc.M111.236950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460(7256):705–10. doi:10.1038/nature08195.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Cheng Y, Liu X, Yang J, Lin Y, Xu DZ, Lu Q, et al. MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res. 2009;105(2):158–66. doi:10.1161/CIRCRESAHA.109.197517 CIRCRESAHA.109.197517 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, et al. Kruppel-like factor 4 regulates endothelial inflammation. J Biol Chem. 2007;282(18):13769–79. doi:M700078200 [pii] 10.1074/jbc.M700078200

    Article  CAS  PubMed  Google Scholar 

  53. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9. doi:10.1016/j.jacc.2009.04.006 S0735-1097(09)01208-X [pii]

    Article  CAS  PubMed  Google Scholar 

  54. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A. 2007;104(27):11418–23. doi:0610467104 [pii] 10.1073/pnas.0610467104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bierer R, Nitta CH, Friedman J, Codianni S, de Frutos S, Dominguez-Bautista JA, et al. NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice. Am J Phys Lung Cell Mol Phys. 2011;301(6):L872–80. doi:10.1152/ajplung.00405.2010 ajplung.00405.2010 [pii]

    CAS  Google Scholar 

  56. Kang K, Peng X, Zhang X, Wang Y, Zhang L, Gao L, et al. MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells. J Biol Chem. 2013;288(35):25414–27. doi:10.1074/jbc.M113.460287 M113.460287 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang D, Zhang H, Li M, Frid MG, Flockton AR, McKeon BA, et al. MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res. 2014;114(1):67–78. doi:10.1161/CIRCRESAHA.114.301633.

    Article  CAS  PubMed  Google Scholar 

  58. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11(4):335–47. doi:S1535-6108(07)00059-1 [pii] 10.1016/j.ccr.2007.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Itoh T, Nagaya N, Ishibashi-Ueda H, Kyotani S, Oya H, Sakamaki F, et al. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology. 2006;11(2):158–63. doi:RES [pii] 10.1111/j.1440-1843.2006.00821.x.

    Article  PubMed  Google Scholar 

  60. Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest. 2014;124(8):3514–28. doi:10.1172/JCI74773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bertero T, Cottrill K, Krauszman A, Lu Y, Annis S, Hale A, et al. The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. J Biol Chem. 2015;290(4):2069–85. doi:10.1074/jbc.M114.617845 M114.617845 [pii]

    Article  CAS  PubMed  Google Scholar 

  62. Masri FA, Xu W, Comhair SA, Asosingh K, Koo M, Vasanji A, et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Phys Lung Cell Mol Phys. 2007;293(3):L548–54. doi:00428.2006 [pii] 10.1152/ajplung.00428.2006

    CAS  Google Scholar 

  63. Potus F, Graydon C, Provencher S, Bonnet S. Vascular remodeling process in pulmonary arterial hypertension, with focus on miR-204 and miR-126 (2013 Grover Conference series). Pulm Circ. 2014;4(2):175–84. doi:10.1086/675980 PC2013105 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  64. Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208(3):535–48. doi:10.1084/jem.20101812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014;129(7):786–97. doi:10.1161/CIRCULATIONAHA.113.006167 CIRCULATIONAHA.113.006167 [pii]

    Article  CAS  PubMed  Google Scholar 

  66. Cui RR, Li SJ, Liu LJ, Yi L, Liang QH, Zhu X, et al. MicroRNA-204 regulates vascular smooth muscle cell calcification in vitro and in vivo. Cardiovasc Res. 2012;96(2):320–9. doi:10.1093/cvr/cvs258 cvs258 [pii]

    Article  CAS  PubMed  Google Scholar 

  67. Kuhr FK, Smith KA, Song MY, Levitan I, Yuan JX. New mechanisms of pulmonary arterial hypertension: role of Ca(2)(+) signaling. Am J Physiol Heart Circ Physiol. 2012;302(8):H1546–62. doi:10.1152/ajpheart.00944.2011 ajpheart.00944.2011 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. He L, Xu J, Chen L, Li L. Apelin/APJ signaling in hypoxia-related diseases. Clin Chim Acta. 2015;451(Pt B):191–8. doi:10.1016/j.cca.2015.09.029 S0009-8981(15)00438-6 [pii]

    Article  CAS  PubMed  Google Scholar 

  69. Chandra SM, Razavi H, Kim J, Agrawal R, Kundu RK, de Jesus PV, et al. Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2011;31(4):814–20. doi:10.1161/ATVBAHA.110.219980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013;19(1):74–82. doi:10.1038/nm.3040.

    Article  CAS  PubMed  Google Scholar 

  71. Chen T, Zhou G, Zhou Q, Tang H, Ibe JC, Cheng H, et al. Loss of microRNA-17 approximately 92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. Am J Respir Crit Care Med. 2015;191(6):678–92. doi:10.1164/rccm.201405-0941OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M, et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res. 2009;104(10):1184–91. doi:10.1161/CIRCRESAHA.109.197491.

    Article  CAS  PubMed  Google Scholar 

  73. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;104(2):236–44. 28p following 44. doi:10.1161/CIRCRESAHA.108.182014 CIRCRESAHA.108.182014 [pii]

    Article  CAS  PubMed  Google Scholar 

  74. Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med. 2012;185(4):409–19. doi:10.1164/rccm.201106-1093OC.

    Article  CAS  PubMed  Google Scholar 

  75. Brock M, Samillan VJ, Trenkmann M, Schwarzwald C, Ulrich S, Gay RE, et al. AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur Heart J. 2014;35(45):3203–11. doi:10.1093/eurheartj/ehs060 ehs060 [pii]

    Article  CAS  PubMed  Google Scholar 

  76. Brock M, Haider TJ, Vogel J, Gassmann M, Speich R, Trenkmann M, et al. The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A. Int J Biochem Cell Biol. 2015;61:129–37. doi:10.1016/j.biocel.2015.02.002 S1357-2725(15)00045-X [pii]

    Article  CAS  PubMed  Google Scholar 

  77. Li XJ, Ren ZJ, Tang JH. MicroRNA-34a: a potential therapeutic target in human cancer. Cell Death Dis. 2014;5:e1327.doi:10.1038/cddis.2014.270 cddis2014270 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Diaz MR, Vivas-Mejia PE. Nanoparticles as drug delivery systems in cancer medicine: emphasis on RNAi-containing nanoliposomes. Pharmaceuticals (Basel). 2013;6(11):1361–80. doi:10.3390/ph6111361 ph6111361 [pii]

    Article  Google Scholar 

  79. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685–94. doi:10.1056/NEJMoa1209026.

    Article  CAS  PubMed  Google Scholar 

  80. Kao SC, Fulham M, Wong K, Cooper W, Brahmbhatt H, MacDiarmid J, et al. A significant metabolic and radiological response after a novel targeted microRNA-based treatment approach in malignant pleural mesothelioma. Am J Respir Crit Care Med. 2015;191(12):1467–9. doi:10.1164/rccm.201503-0461LE.

    Article  PubMed  Google Scholar 

  81. Hydbring P, Badalian-Very G. Clinical applications of microRNAs. F1000Res. 2013;2:136. doi:10.12688/f1000research.2–136.v3

    Google Scholar 

  82. Wang H, Jiang Y, Peng H, Chen Y, Zhu P, Huang Y. Recent progress in microRNA delivery for cancer therapy by non-viral synthetic vectors. Adv Drug Deliv Rev. 2015;81:142–60. doi:10.1016/j.addr.2014.10.031 S0169-409X(14)00239-7 [pii]

    Article  CAS  PubMed  Google Scholar 

  83. Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D, et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 2010;70(14):5923–30. doi:10.1158/0008-5472.CAN-10-0655 0008-5472.CAN-10-0655 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bader AG, Brown D, Stoudemire J, Lammers P. Developing therapeutic microRNAs for cancer. Gene Ther. 2011;18(12):1121–6. doi:10.1038/gt.2011.79 gt201179 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Peng B, Chen Y, Leong KW. MicroRNA delivery for regenerative medicine. Adv Drug Deliv Rev. 2015;88:108–22. doi:10.1016/j.addr.2015.05.014 S0169-409X(15)00109-X [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007;4(9):721–6. doi:nmeth1079 [pii] 10.1038/nmeth1079

    Article  CAS  PubMed  Google Scholar 

  87. Ebert MS, Sharp PA. MicroRNA sponges: progress and possibilities. RNA. 2010;16(11):2043–50. doi:10.1261/rna.2414110 rna.2414110 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Montgomery RL, Hullinger TG, Semus HM, Dickinson BA, Seto AG, Lynch JM, et al. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation. 2011;124(14):1537–47. doi:10.1161/CIRCULATIONAHA.111.030932 CIRCULATIONAHA.111.030932 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li Z, Rana TM. Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov. 2014;13(8):622–38. doi:10.1038/nrd4359 nrd4359 [pii]

    Article  CAS  PubMed  Google Scholar 

  90. Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, et al. Disruption of PPARgamma/beta-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest. 2011;121(9):3735–46. doi:10.1172/JCI43382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sarrion I, Milian L, Juan G, Ramon M, Furest I, Carda C, et al. Role of circulating miRNAs as biomarkers in idiopathic pulmonary arterial hypertension: possible relevance of miR-23a. Oxidative Med Cell Longev. 2015;2015:792846. doi:10.1155/2015/792846.

    Article  Google Scholar 

  92. Newman MA, Hammond SM. Emerging paradigms of regulated microRNA processing. Genes Dev. 2010;24(11):1086–92. doi:10.1101/gad.1919710 24/11/1086 [pii].

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lal A, Navarro F, Maher CA, Maliszewski LE, Yan N, O'Day E, et al. miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements. Mol Cell. 2009;35(5):610–25. doi:10.1016/j.molcel.2009.08.020 S1097-2765(09)00600-5 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Arechavala-Gomeza V, Graham IR, Popplewell LJ, Adams AM, Aartsma-Rus A, Kinali M, et al. Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Hum Gene Ther. 2007;18(9):798–810. doi:10.1089/hum.2006.061.

    Article  CAS  PubMed  Google Scholar 

  95. Kerkmann M, Costa LT, Richter C, Rothenfusser S, Battiany J, Hornung V, et al. Spontaneous formation of nucleic acid-based nanoparticles is responsible for high interferon-alpha induction by CpG-A in plasmacytoid dendritic cells. J Biol Chem. 2005;280(9):8086–93. doi:M410868200 [pii] 10.1074/jbc.M410868200.

    Article  CAS  PubMed  Google Scholar 

  96. Rivera RM, Bennett LB. Epigenetics in humans: an overview. Curr Opin Endocrinol Diabetes Obes. 2010;17(6):493–9. doi:10.1097/MED.0b013e3283404f4b.

    Article  PubMed  Google Scholar 

  97. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132(5):875–86. doi:10.1016/j.cell.2008.02.019 S0092-8674(08)00267-5 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dakhlallah D, Batte K, Wang Y, Cantemir-Stone CZ, Yan P, Nuovo G, et al. Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;187(4):397–405. doi:10.1164/rccm.201205-0888OC rccm.201205-0888OC [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ji R, Cheng Y, Yue J, Yang J, Liu X, Chen H, et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation. Circ Res. 2007;100(11):1579–88. doi:CIRCRESAHA.106.141986 [pii] 10.1161/CIRCRESAHA.106.141986.

    Article  CAS  PubMed  Google Scholar 

  100. Li Y, Yan L, Zhang W, Hu N, Chen W, Wang H, et al. MicroRNA-21 inhibits platelet-derived growth factor-induced human aortic vascular smooth muscle cell proliferation and migration through targeting activator protein-1. Am J Transl Res. 2014;6(5):507–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Kang BY, Park KK, Green DE, Bijli KM, Searles CD, Sutliff RL, et al. Hypoxia mediates mutual repression between microRNA-27a and PPARgamma in the pulmonary vasculature. PLoS One. 2013;8(11):e79503.doi:10.1371/journal.pone.0079503 PONE-D-13-24907 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  102. Bi R, Bao C, Jiang L, Liu H, Yang Y, Mei J, et al. MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor gamma dependent Hsp90-eNOS signaling and nitric oxide production. Biochem Biophys Res Commun. 2015;460(2):469–75. doi:10.1016/j.bbrc.2015.03.057 S0006-291X(15)00492-1 [pii]

    Article  CAS  PubMed  Google Scholar 

  103. Elia L, Quintavalle M, Zhang J, Contu R, Cossu L, Latronico MV, et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ. 2009;16(12):1590–8. doi:10.1038/cdd.2009.153 cdd2009153 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Deng L, Blanco FJ, Stevens H, Lu R, Caudrillier A, McBride M, et al. MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circ Res. 2015;117(10):870–83. doi:10.1161/CIRCRESAHA.115.306806 CIRCRESAHA.115.306806 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Horita HN, Simpson PA, Ostriker A, Furgeson S, Van Putten V, Weiser-Evans MC, et al. Serum response factor regulates expression of phosphatase and tensin homolog through a microRNA network in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2011;31(12):2909–19. doi:10.1161/ATVBAHA.111.233585 ATVBAHA.111.233585 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, et al. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest. 2010;120(11):4141–54. doi:10.1172/JCI42980 42980 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

This work was supported by the grants obtained from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL115014, HL066012, and HL098053). The authors would like to thank Nikita Babichev for assistance with graphic layout of the figures.

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  1. Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, AZ, 85721, USA

    Aleksandra Babicheva, Kimberly M. McDermott, Samuel C. Williams, Allison M. Yee, Swetaleena Dash, Marisela Rodriquez, Nadia Ingabire & Jason X. -J. Yuan

  2. Department of Physiology, The University of Arizona College of Medicine, Tucson, AZ, 85721, USA

    Ayako Makino & Jason X. -J. Yuan

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  1. Aleksandra Babicheva
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Correspondence to Jason X. -J. Yuan .

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  1. Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan

    Yoshihiro Fukumoto

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Babicheva, A. et al. (2017). Pathogenic and Therapeutic Role of MicroRNA in Pulmonary Arterial Hypertension. In: Fukumoto, Y. (eds) Diagnosis and Treatment of Pulmonary Hypertension. Springer, Singapore. https://doi.org/10.1007/978-981-287-840-3_3

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  • DOI: https://doi.org/10.1007/978-981-287-840-3_3

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