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Critical effects of epigenetic regulation in pulmonary arterial hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is characterized by persistent pulmonary vasoconstriction and pulmonary vascular remodeling. The pathogenic mechanisms of PAH remain to be fully clarified and measures of effective prevention are lacking. Recent studies; however, have indicated that epigenetic processes may exert pivotal influences on PAH pathogenesis. In this review, we summarize the latest research findings regarding epigenetic regulation in PAH, focusing on the roles of non-coding RNAs, histone modifications, ATP-dependent chromatin remodeling and DNA methylation, and discuss the potential of epigenetic-based therapies for PAH.

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References

  1. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62(25 Suppl):D34–D41. doi:10.1016/j.jacc.2013.10.029

    Article  PubMed  Google Scholar 

  2. Rabinovitch M (2012) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Investig 122(12):4306–4313. doi:10.1172/JCI60658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F (2011) Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 8(8):443–455. doi:10.1038/nrcardio.2011.87

    Article  CAS  PubMed  Google Scholar 

  4. Aaronson PI, Robertson TP, Ward JP (2002) Endothelium-derived mediators and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol 132(1):107–120

    Article  CAS  PubMed  Google Scholar 

  5. Vaillancourt M, Ruffenach G, Meloche J, Bonnet S (2015) Adaptation and remodelling of the pulmonary circulation in pulmonary hypertension. Can J Cardiol 31(4):407–415. doi:10.1016/j.cjca.2014.10.023

    Article  PubMed  Google Scholar 

  6. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M (2009) Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54(1 Suppl):S10–S19. doi:10.1016/j.jacc.2009.04.006

    Article  CAS  PubMed  Google Scholar 

  7. Stenmark KR, Fagan KA, Frid MG (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99(7):675–691. doi:10.1161/01.RES.0000243584.45145.3f

    Article  CAS  PubMed  Google Scholar 

  8. Mishra A, Mohammad G, Norboo T, Newman JH, Pasha MA (2015) Lungs at high-altitude: genomic insights into hypoxic responses. J Appl Physiol 119(1):1–15. doi:10.1152/japplphysiol.00513.2014

    Article  CAS  PubMed  Google Scholar 

  9. Bird A (2007) Perceptions of epigenetics. Nature 447(7143):396–398. doi:10.1038/nature05913

    Article  CAS  PubMed  Google Scholar 

  10. Gamen E, Seeger W, Pullamsetti SS (2016) The emerging role of epigenetics in pulmonary hypertension. Eur Respir J 48(3):903–917. doi:10.1183/13993003.01714-2015

    Article  PubMed  Google Scholar 

  11. Chelladurai P, Seeger W, Pullamsetti SS (2016) Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives. Eur Respir Rev 25(140):135–140. doi:10.1183/16000617.0036-2016

    Article  PubMed  Google Scholar 

  12. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigo R, Gingeras TR (2012) Landscape of transcription in human cells. Nature 489(7414):101–108. doi:10.1038/nature11233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cech TR, Steitz JA (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157(1):77–94. doi:10.1016/j.cell.2014.03.008

    Article  CAS  PubMed  Google Scholar 

  14. St Laurent G, Wahlestedt C, Kapranov P (2015) The Landscape of long noncoding RNA classification. Trends Genet 31(5):239–251. doi:10.1016/j.tig.2015.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang Z, Yao H, Lin S, Zhu X, Shen Z, Lu G, Poon WS, Xie D, Lin MC, Kung HF (2013) Transcriptional and epigenetic regulation of human microRNAs. Cancer Lett 331(1):1–10. doi:10.1016/j.canlet.2012.12.006

    Article  CAS  PubMed  Google Scholar 

  16. Ambros V (2001) microRNAs: tiny regulators with great potential. Cell 107(7):823–826

    Article  CAS  PubMed  Google Scholar 

  17. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433(7027):769–773. doi:10.1038/nature03315

    Article  CAS  PubMed  Google Scholar 

  18. Meloche J, Pflieger A, Vaillancourt M, Graydon C, Provencher S, Bonnet S (2014) miRNAs in PAH: biomarker, therapeutic target or both? Drug Discov Today 19(8):1264–1269. doi:10.1016/j.drudis.2014.05.015

    Article  CAS  PubMed  Google Scholar 

  19. Rothman AM, Chico TJ, Lawrie A (2014) MicroRNA in pulmonary vascular disease. Progr Mol Biol Transl Sci 124:43–63. doi:10.1016/B978-0-12-386930-2.00003-3

    Article  CAS  Google Scholar 

  20. Grant JS, White K, MacLean MR, Baker AH (2013) MicroRNAs in pulmonary arterial remodeling. Cell Mol Life Sci 70(23):4479–4494. doi:10.1007/s00018-013-1382-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, MacDonald RA, Greig JA, Robertson KE, Masson R, Denby L, Dempsie Y, Long L, Morrell NW, Baker AH (2010) Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol 30(4):716–723. doi:10.1161/ATVBAHA.109.202028

    Article  CAS  PubMed  Google Scholar 

  22. Potus F, Graydon C, Provencher S, Bonnet S (2014) Vascular remodeling process in pulmonary arterial hypertension, with focus on miR-204 and miR-126 (2013 Grover Conference series). Pulm Circ 4(2):175–184. doi:10.1086/675980

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Rhodes CJ, Wharton J, Boon RA, Roexe T, Tsang H, Wojciak-Stothard B, Chakrabarti A, Howard LS, Gibbs JS, Lawrie A, Condliffe R, Elliot CA, Kiely DG, Huson L, Ghofrani HA, Tiede H, Schermuly R, Zeiher AM, Dimmeler S, Wilkins MR (2013) Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 187(3):294–302. doi:10.1164/rccm.201205-0839OC

    Article  CAS  PubMed  Google Scholar 

  24. Morrell NW (2006) Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 3(8):680–686. doi:10.1513/pats.200605-118SF

    Article  CAS  PubMed  Google Scholar 

  25. Diebold I, Hennigs JK, Miyagawa K, Li CG, Nickel NP, Kaschwich M, Cao A, Wang L, Reddy S, Chen PI, Nakahira K, Alcazar MA, Hopper RK, Ji L, Feldman BJ, Rabinovitch M (2015) BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metab 21(4):596–608. doi:10.1016/j.cmet.2015.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li M, Vattulainen S, Aho J, Orcholski M, Rojas V, Yuan K, Helenius M, Taimen P, Myllykangas S, De Jesus Perez V, Koskenvuo JW, Alastalo TP (2014) Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 50(6):1118–1128. doi:10.1165/rcmb.2013-0349OC

    Article  PubMed  CAS  Google Scholar 

  27. Hopper RK, Moonen JR, Diebold I, Cao A, Rhodes CJ, Tojais NF, Hennigs JK, Gu M, Wang L, Rabinovitch M (2016) In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug. Circulation 133(18):1783–1794. doi:10.1161/CIRCULATIONAHA.115.020617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Orriols M, Gomez-Puerto MC, Ten Dijke P (2017) BMP type II receptor as a therapeutic target in pulmonary arterial hypertension. CMLS, Cell Mol Life Sci. doi:10.1007/s00018-017-2510-4

    Google Scholar 

  29. Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M, Ulrich S, Speich R, Huber LC (2009) Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res 104(10):1184–1191. doi:10.1161/CIRCRESAHA.109.197491

    Article  CAS  PubMed  Google Scholar 

  30. Parikh VN, Jin RC, Rabello S, Gulbahce N, White K, Hale A, Cottrill KA, Shaik RS, Waxman AB, Zhang YY, Maron BA, Hartner JC, Fujiwara Y, Orkin SH, Haley KJ, Barabasi AL, Loscalzo J, Chan SY (2012) MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation 125(12):1520–1532. doi:10.1161/CIRCULATIONAHA.111.060269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu Y, Liu G, Zhang H, Wang J (2016) MiRNA-199a-5p influences pulmonary artery hypertension via downregulating Smad3. Biochem Biophys Res Commun 473(4):859–866. doi:10.1016/j.bbrc.2016.03.140

    Article  CAS  PubMed  Google Scholar 

  32. Wilkins SE, Abboud MI, Hancock RL, Schofield CJ (2016) Targeting protein–protein interactions in the HIF system. Chem Med Chem 11(8):773–786. doi:10.1002/cmdc.201600012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lei W, He Y, Shui X, Li G, Yan G, Zhang Y, Huang S, Chen C, Ding Y (2016) Expression and analyses of the HIF-1 pathway in the lungs of humans with pulmonary arterial hypertension. Mol Med Rep 14(5):4383–4390. doi:10.3892/mmr.2016.5752

    Article  CAS  PubMed  Google Scholar 

  34. Dunham-Snary KJ, Wu D, Sykes EA, Thakrar A, Parlow LR, Mewburn JD, Parlow JL, Archer SL (2017) Hypoxic pulmonary vasoconstriction: from molecular mechanisms to medicine. Chest 151(1):181–192. doi:10.1016/j.chest.2016.09.001

    Article  PubMed  Google Scholar 

  35. Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC, Tuder RM (2010) Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 176(3):1130–1138. doi:10.2353/ajpath.2010.090832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sen A, Ren S, Lerchenmuller C, Sun J, Weiss N, Most P, Peppel K (2013) MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1. PLoS One 8(11):e78684. doi:10.1371/journal.pone.0078684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sen A, Most P, Peppel K (2014) Induction of microRNA-138 by pro-inflammatory cytokines causes endothelial cell dysfunction. FEBS Lett 588(6):906–914. doi:10.1016/j.febslet.2014.01.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou W, Zhou W, Zeng Q, Xiong J (2017) MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1alpha-mediated MAPK and AKT signaling. Exp Ther Med 13(3):1017–1024. doi:10.3892/etm.2017.4091

    Article  PubMed  PubMed Central  Google Scholar 

  39. Rabinovitch M (2010) PPARgamma and the pathobiology of pulmonary arterial hypertension. Adv Exp Med Biol 661:447–458. doi:10.1007/978-1-60761-500-2_29

    Article  CAS  PubMed  Google Scholar 

  40. Kang BY, Park KK, Green DE, Bijli KM, Searles CD, Sutliff RL, Hart CM (2013) Hypoxia mediates mutual repression between microRNA-27a and PPARgamma in the pulmonary vasculature. PLoS One 8(11):e79503. doi:10.1371/journal.pone.0079503

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Bi R, Bao C, Jiang L, Liu H, Yang Y, Mei J, Ding F (2015) 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 460(2):469–475. doi:10.1016/j.bbrc.2015.03.057

    Article  CAS  PubMed  Google Scholar 

  42. Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, Graham BB, Kumar R, Black SM, Fratz S, Fineman JR, West JD, Haley KJ, Waxman AB, Chau BN, Cottrill KA, Chan SY (2014) Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Investig 124(8):3514–3528. doi:10.1172/JCI74773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN (2008) The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 15(2):261–271. doi:10.1016/j.devcel.2008.07.002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bockmeyer CL, Maegel L, Janciauskiene S, Rische J, Lehmann U, Maus UA, Nickel N, Haverich A, Hoeper MM, Golpon HA, Kreipe H, Laenger F, Jonigk D (2012) Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression. J Heart Lung Transpl 31(7):764–772. doi:10.1016/j.healun.2012.03.010

    Article  Google Scholar 

  45. Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, McLean DL, Park H, Comhair SA, Greif DM, Erzurum SC, Chun HJ (2013) An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med 19(1):74–82. doi:10.1038/nm.3040

    Article  CAS  PubMed  Google Scholar 

  46. Bertero T, Cottrill K, Krauszman A, Lu Y, Annis S, Hale A, Bhat B, Waxman AB, Chau BN, Kuebler WM, Chan SY (2015) The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. J Biol Chem 290(4):2069–2085. doi:10.1074/jbc.M114.617845

    Article  CAS  PubMed  Google Scholar 

  47. Owens GK (1995) Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 75(3):487–517

    CAS  PubMed  Google Scholar 

  48. Owens GK (2007) Molecular control of vascular smooth muscle cell differentiation and phenotypic plasticity. Novartis Found Symp 283:174–191 (discussion 191–173, 238–141)

    Article  CAS  PubMed  Google Scholar 

  49. Brock M, Samillan VJ, Trenkmann M, Schwarzwald C, Ulrich S, Gay RE, Gassmann M, Ostergaard L, Gay S, Speich R, Huber LC (2014) AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur Heart J 35(45):3203–3211. doi:10.1093/eurheartj/ehs060

    Article  CAS  PubMed  Google Scholar 

  50. Zeng Y, Pan Y, Liu H, Kang K, Wu Y, Hui G, Peng W, Ramchandran R, Raj JU, Gou D (2014) MiR-20a regulates the PRKG1 gene by targeting its coding region in pulmonary arterial smooth muscle cells. FEBS Lett 588(24):4677–4685. doi:10.1016/j.febslet.2014.10.040

    Article  CAS  PubMed  Google Scholar 

  51. Zhou W, Negash S, Liu J, Raj JU (2009) Modulation of pulmonary vascular smooth muscle cell phenotype in hypoxia: role of cGMP-dependent protein kinase and myocardin. Am J Physiol Lung Cell Mol Physiol 296(5):L780–L789. doi:10.1152/ajplung.90295.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sarkar J, Gou D, Turaka P, Viktorova E, Ramchandran R, Raj JU (2010) MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration. Am J Physiol Lung Cell Mol Physiol 299(6):L861–L871. doi:10.1152/ajplung.00201.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang S, Banerjee S, Freitas A, Cui H, Xie N, Abraham E, Liu G (2012) miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 302(6):L521–L529. doi:10.1152/ajplung.00316.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen X, Talati M, Fessel JP, Hemnes AR, Gladson S, French J, Shay S, Trammell A, Phillips JA, Hamid R, Cogan JD, Dawson EP, Womble KE, Hedges LK, Martinez EG, Wheeler LA, Loyd JE, Majka SJ, West J, Austin ED (2016) Estrogen metabolite 16alpha-hydroxyestrone exacerbates bone morphogenetic protein receptor type II-associated pulmonary arterial hypertension through microRNA-29-mediated modulation of cellular metabolism. Circulation 133(1):82–97. doi:10.1161/CIRCULATIONAHA.115.016133

    Article  CAS  PubMed  Google Scholar 

  55. Lee HW, Park SH (2017) Elevated microRNA-135a is associated with pulmonary arterial hypertension in experimental mouse model. Oncotarget. doi:10.18632/oncotarget.16011

    Google Scholar 

  56. Rothman AM, Arnold ND, Pickworth JA, Iremonger J, Ciuclan L, Allen RM, Guth-Gundel S, Southwood M, Morrell NW, Thomas M, Francis SE, Rowlands DJ, Lawrie A (2016) MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J Clin Investig 126(7):2495–2508. doi:10.1172/JCI83361

    Article  PubMed  PubMed Central  Google Scholar 

  57. Caruso P, Dempsie Y, Stevens HC, McDonald RA, Long L, Lu R, White K, Mair KM, McClure JD, Southwood M, Upton P, Xin M, van Rooij E, Olson EN, Morrell NW, MacLean MR, Baker AH (2012) A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res 111(3):290–300. doi:10.1161/CIRCRESAHA.112.267591

    Article  CAS  PubMed  Google Scholar 

  58. Deng L, Blanco FJ, Stevens H, Lu R, Caudrillier A, McBride M, McClure JD, Grant J, Thomas M, Frid M, Stenmark K, White K, Seto AG, Morrell NW, Bradshaw AC, MacLean MR, Baker AH (2015) MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circ Res 117(10):870–883. doi:10.1161/CIRCRESAHA.115.306806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, Ivey KN, Srivastava D (2009) miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460(7256):705–710. doi:10.1038/nature08195

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Cheng Y, Liu X, Yang J, Lin Y, Xu DZ, Lu Q, Deitch EA, Huo Y, Delphin ES, Zhang C (2009) MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res 105(2):158–166. doi:10.1161/CIRCRESAHA.109.197517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shan F, Li J, Huang QY (2014) HIF-1 alpha-induced up-regulation of miR-9 contributes to phenotypic modulation in pulmonary artery smooth muscle cells during hypoxia. J Cell Physiol 229(10):1511–1520. doi:10.1002/jcp.24593

    Article  CAS  PubMed  Google Scholar 

  62. Yan L, Gao H, Li C, Han X, Qi X (2017) Effect of miR-23a on anoxia-induced phenotypic transformation of smooth muscle cells of rat pulmonary arteries and regulatory mechanism. Oncol Lett 13(1):89–98. doi:10.3892/ol.2016.5440

    PubMed  Google Scholar 

  63. Li S, Ran Y, Zhang D, Chen J, Li S, Zhu D (2013) MicroRNA-138 plays a role in hypoxic pulmonary vascular remodelling by targeting Mst1. Biochem J 452(2):281–291. doi:10.1042/BJ20120680

    Article  CAS  PubMed  Google Scholar 

  64. Gou D, Ramchandran R, Peng X, Yao L, Kang K, Sarkar J, Wang Z, Zhou G, Raj JU (2012) miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia. Am J Physiol Lung Cell Mol Physiol 303(8):L682–L691. doi:10.1152/ajplung.00344.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. White K, Lu Y, Annis S, Hale AE, Chau BN, Dahlman JE, Hemann C, Opotowsky AR, Vargas SO, Rosas I, Perrella MA, Osorio JC, Haley KJ, Graham BB, Kumar R, Saggar R, Saggar R, Wallace WD, Ross DJ, Khan OF, Bader A, Gochuico BR, Matar M, Polach K, Johannessen NM, Prosser HM, Anderson DG, Langer R, Zweier JL, Bindoff LA, Systrom D, Waxman AB, Jin RC, Chan SY (2015) Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol Med 7(6):695–713. doi:10.15252/emmm.201404511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zeng Y, Liu H, Kang K, Wang Z, Hui G, Zhang X, Zhong J, Peng W, Ramchandran R, Raj JU, Gou D (2015) Hypoxia inducible factor-1 mediates expression of miR-322: potential role in proliferation and migration of pulmonary arterial smooth muscle cells. Sci Rep 5:12098. doi:10.1038/srep12098

    Article  PubMed  PubMed Central  Google Scholar 

  67. Chen TJ, Zhou QY, Tang HY, Bozkanat M, Yuan JXJ, Raj JU, Zhou GF (2016) miR-17/20 controls prolyl hydroxylase 2 (PHD2)/hypoxia-inducible factor 1 (HIF1) to regulate pulmonary artery smooth muscle cell proliferation. J Am Heart Assoc. doi:10.1161/JAHA.116.004510

    Google Scholar 

  68. Jalali S, Ramanathan GK, Parthasarathy PT, Aljubran S, Galam L, Yunus A, Garcia S, Cox RR Jr, Lockey RF, Kolliputi N (2012) Mir-206 regulates pulmonary artery smooth muscle cell proliferation and differentiation. PLoS One 7(10):e46808. doi:10.1371/journal.pone.0046808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yue J, Guan J, Wang X, Zhang L, Yang Z, Ao Q, Deng Y, Zhu P, Wang G (2013) MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1alpha/Fhl-1 pathway. Lab Investig J Tech Methods Pathol 93(7):748–759. doi:10.1038/labinvest.2013.63

    Article  CAS  Google Scholar 

  70. Deng B, Du J, Hu R, Wang AP, Wu WH, Hu CP, Li YJ, Li XH (2016) MicroRNA-103/107 is involved in hypoxia-induced proliferation of pulmonary arterial smooth muscle cells by targeting HIF-1 beta. Life Sci 147:117–124. doi:10.1016/j.lfs.2016.01.043

    Article  CAS  PubMed  Google Scholar 

  71. Brock M, Haider TJ, Vogel J, Gassmann M, Speich R, Trenkmann M, Ulrich S, Kohler M, Huber LC (2015) The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A. Int J Biochem Cell Biol 61:129–137. doi:10.1016/j.biocel.2015.02.002

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Wang P, Xu J, Hou Z, Wang F, Song Y, Wang J, Zhu H, Jin H (2016) miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA. Cell Prolif 49(4):484–493. doi:10.1111/cpr.12265

    Article  CAS  PubMed  Google Scholar 

  74. Sharma S, Umar S, Potus F, Iorga A, Wong G, Meriwether D, Breuils-Bonnet S, Mai D, Navab K, Ross D, Navab M, Provencher S, Fogelman AM, Bonnet S, Reddy ST, Eghbali M (2014) Apolipoprotein A–I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p. Circulation 130(9):776–785. doi:10.1161/CIRCULATIONAHA.114.007405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shi L, Kojonazarov B, Elgheznawy A, Popp R, Dahal BK, Bohm M, Pullamsetti SS, Ghofrani HA, Godecke A, Jungmann A, Katus HA, Muller OJ, Schermuly RT, Fisslthaler B, Seeger W, Fleming I (2016) miR-223-IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach. Cardiovasc Res 111(3):184–193. doi:10.1093/cvr/cvw065

    Article  CAS  PubMed  Google Scholar 

  76. Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F, Provencher S, Bonnet S (2015) miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol 309(6):C363–C372. doi:10.1152/ajpcell.00149.2015

    Article  CAS  PubMed  Google Scholar 

  77. Zeng Y, Zhang X, Kang K, Chen J, Wu Z, Huang J, Lu W, Chen Y, Zhang J, Wang Z, Zhai Y, Qu J, Ramchandran R, Raj JU, Wang J, Gou D (2016) MicroRNA-223 attenuates hypoxia-induced vascular remodeling by targeting RhoB/MLC2 in pulmonary arterial smooth muscle cells. Sci Rep 6:24900. doi:10.1038/srep24900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Guo L, Qiu Z, Wei L, Yu X, Gao X, Jiang S, Tian H, Jiang C, Zhu D (2012) The microRNA-328 regulates hypoxic pulmonary hypertension by targeting at insulin growth factor 1 receptor and L-type calcium channel-alpha1C. Hypertension 59(5):1006–1013. doi:10.1161/HYPERTENSIONAHA.111.185413

    Article  CAS  PubMed  Google Scholar 

  79. Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17(18):2205–2232. doi:10.1101/gad.1102703

    Article  CAS  PubMed  Google Scholar 

  80. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, Hashimoto K, Bonnet SN, Michelakis ED (2007) The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 104(27):11418–11423. doi:10.1073/pnas.0610467104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chen R, Yan J, Liu P, Wang Z, Wang C, Zhong W, Xu L (2017) The role of nuclear factor of activated T cells in pulmonary arterial hypertension. Cell Cycle 16(6):508–514. doi:10.1080/15384101.2017.1281485

    Article  CAS  PubMed  Google Scholar 

  82. Kang K, Peng X, Zhang X, Wang Y, Zhang L, Gao L, Weng T, Zhang H, Ramchandran R, Raj JU, Gou D, Liu L (2013) 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 288(35):25414–25427. doi:10.1074/jbc.M113.460287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Cote J, Simard MJ, Bonnet S (2011) Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 208(3):535–548. doi:10.1084/jem.20101812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, Graydon C, Courboulin A, Breuils-Bonnet S, Tremblay E, Couture C, Michelakis ED, Provencher S, Bonnet S (2014) Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 129(7):786–797. doi:10.1161/CIRCULATIONAHA.113.006167

    Article  CAS  PubMed  Google Scholar 

  85. Ruffenach G, Chabot S, Tanguay VF, Courboulin A, Boucherat O, Potus F, Meloche J, Pflieger A, Breuils-Bonnet S, Nadeau V, Paradis R, Tremblay E, Girerd B, Hautefort A, Montani D, Fadel E, Dorfmuller P, Humbert M, Perros F, Paulin R, Provencher S, Bonnet S (2016) Role for runt-related transcription factor 2 in proliferative and calcified vascular lesions in pulmonary arterial hypertension. Am J Respir Crit Care Med 194(10):1273–1285. doi:10.1164/rccm.201512-2380OC

    Article  PubMed  Google Scholar 

  86. Li SS, Ran YJ, Zhang DD, Li SZ, Zhu D (2014) MicroRNA-190 regulates hypoxic pulmonary vasoconstriction by targeting a voltage-gated K(+) channel in arterial smooth muscle cells. J Cell Biochem 115(6):1196–1205. doi:10.1002/jcb.24771

    Article  CAS  PubMed  Google Scholar 

  87. Zhang WF, Xiong YW, Zhu TT, Xiong AZ, Bao HH, Cheng XS (2017) MicroRNA let-7g inhibited hypoxia-induced proliferation of PASMCs via G0/G1 cell cycle arrest by targeting c-myc. Life Sci 170:9–15. doi:10.1016/j.lfs.2016.11.020

    Article  CAS  PubMed  Google Scholar 

  88. Wang R, Ding X, Zhou S, Li M, Sun L, Xu X, Fei G (2016) Microrna-26b attenuates monocrotaline-induced pulmonary vascular remodeling via targeting connective tissue growth factor (CTGF) and cyclin D1 (CCND1). Oncotarget 7(45):72746–72757. doi:10.18632/oncotarget.10125

    PubMed  PubMed Central  Google Scholar 

  89. Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, Ghofrani HA, Weissmann N, Grimminger F, Bonauer A, Seeger W, Zeiher AM, Dimmeler S, Schermuly RT (2012) Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med 185(4):409–419. doi:10.1164/rccm.201106-1093OC

    Article  CAS  PubMed  Google Scholar 

  90. Lu Z, Li S, Zhao S, Fa X (2016) Upregulated miR-17 regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation and apoptosis by targeting mitofusin 2. Med Sci Monit Int Med J Exp Clin Res 22:3301–3308

    Google Scholar 

  91. Stenmark KR, Yeager ME, El Kasmi KC, Nozik-Grayck E, Gerasimovskaya EV, Li M, Riddle SR, Frid MG (2013) The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol 75:23–47. doi:10.1146/annurev-physiol-030212-183802

    Article  CAS  PubMed  Google Scholar 

  92. Short M, Nemenoff RA, Zawada WM, Stenmark KR, Das M (2004) Hypoxia induces differentiation of pulmonary artery adventitial fibroblasts into myofibroblasts. Am J Physiol Cell Physiol 286(2):C416–C425. doi:10.1152/ajpcell.00169.2003

    Article  CAS  PubMed  Google Scholar 

  93. Wang D, Zhang H, Li M, Frid MG, Flockton AR, McKeon BA, Yeager ME, Fini MA, Morrell NW, Pullamsetti SS, Velegala S, Seeger W, McKinsey TA, Sucharov CC, Stenmark KR (2014) MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res 114(1):67–78. doi:10.1161/CIRCRESAHA.114.301633

    Article  CAS  PubMed  Google Scholar 

  94. Marques AC, Ponting CP (2014) Intergenic lncRNAs and the evolution of gene expression. Curr Opin Genet Dev 27:48–53. doi:10.1016/j.gde.2014.03.009

    Article  CAS  PubMed  Google Scholar 

  95. Gaiti F, Fernandez-Valverde SL, Nakanishi N, Calcino AD, Yanai I, Tanurdzic M, Degnan BM (2015) Dynamic and widespread lncRNA expression in a sponge and the origin of animal complexity. Mol Biol Evol 32(9):2367–2382. doi:10.1093/molbev/msv117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10(3):155–159. doi:10.1038/nrg2521

    Article  CAS  PubMed  Google Scholar 

  97. Li L, Song X (2014) In vivo functions of long non-coding RNAs. Hereditas 36(3):228–236

    CAS  PubMed  Google Scholar 

  98. Fang Y, Fullwood MJ (2016) Roles, functions, and mechanisms of long non-coding RNAs in cancer. Genom Proteom Bioinf 14(1):42–54. doi:10.1016/j.gpb.2015.09.006

    Article  Google Scholar 

  99. Wang X, Yan C, Xu X, Dong L, Su H, Hu Y, Zhang R, Ying K (2016) Long noncoding RNA expression profiles of hypoxic pulmonary hypertension rat model. Gene 579(1):23–28. doi:10.1016/j.gene.2015.12.044

    Article  CAS  PubMed  Google Scholar 

  100. Michalik KM, You X, Manavski Y, Doddaballapur A, Zornig M, Braun T, John D, Ponomareva Y, Chen W, Uchida S, Boon RA, Dimmeler S (2014) Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res 114(9):1389–1397. doi:10.1161/CIRCRESAHA.114.303265

    Article  CAS  PubMed  Google Scholar 

  101. Zhuo Y, Zeng Q, Zhang P, Li G, Xie Q, Cheng Y (2017) Functional polymorphism of lncRNA MALAT1 contributes to pulmonary arterial hypertension susceptibility in Chinese people. Clin Chem Lab Med 55(1):38–46. doi:10.1515/cclm-2016-0056

    Article  CAS  PubMed  Google Scholar 

  102. Leisegang MS, Fork C, Josipovic I, Richter F, Preussner J, Hu J, Miller MJ, Epah JN, Hofmann P, Gunther S, Moll F, Valasarajan C, Heidler J, Ponomareva Y, Freiman TM, Maegdefessel L, Plate KH, Mittelbronn M, Uchida S, Kunne C, Stellos K, Schermuly RT, Weissmann N, Devraj K, Wittig I, Boon RA, Dimmeler S, Pullamsetti SS, Looso M, Miller FJ, Brandes RP (2017) Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation. doi:10.1161/CIRCULATIONAHA.116.026991

    PubMed  PubMed Central  Google Scholar 

  103. Wu G, Cai J, Han Y, Chen J, Huang ZP, Chen C, Cai Y, Huang H, Yang Y, Liu Y, Xu Z, He D, Zhang X, Hu X, Pinello L, Zhong D, He F, Yuan GC, Wang DZ, Zeng C (2014) LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation 130(17):1452–1465. doi:10.1161/CIRCULATIONAHA.114.011675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhou WQ, Wang P, Shao QP, Wang J (2016) Lipopolysaccharide promotes pulmonary fibrosis in acute respiratory distress syndrome (ARDS) via lincRNA-p21 induced inhibition of Thy-1 expression. Mol Cell Biochem 419(1–2):19–28. doi:10.1007/s11010-016-2745-7

    Article  CAS  PubMed  Google Scholar 

  105. Taguchi A, Yanagisawa K, Tanaka M, Cao K, Matsuyama Y, Goto H, Takahashi T (2008) Identification of hypoxia-inducible factor-1 alpha as a novel target for miR-17-92 microRNA cluster. Can Res 68(14):5540–5545. doi:10.1158/0008-5472.CAN-07-6460

    Article  CAS  Google Scholar 

  106. Stevens HC, Deng L, Grant JS, Pinel K, Thomas M, Morrell NW, MacLean MR, Baker AH, Denby L (2016) Regulation and function of miR-214 in pulmonary arterial hypertension. Pulm Circ 6(1):109–117. doi:10.1086/685079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kim J, Hwangbo C, Hu X, Kang Y, Papangeli I, Mehrotra D, Park H, Ju H, McLean DL, Comhair SA, Erzurum SC, Chun HJ (2015) Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation 131(2):190–199. doi:10.1161/CIRCULATIONAHA.114.013339

    Article  PubMed  Google Scholar 

  108. Teif VB, Rippe K (2009) Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities. Nucleic Acids Res 37(17):5641–5655. doi:10.1093/nar/gkp610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Marino-Ramirez L, Kann MG, Shoemaker BA, Landsman D (2005) Histone structure and nucleosome stability. Expert Rev Proteom 2(5):719–729. doi:10.1586/14789450.2.5.719

    Article  CAS  Google Scholar 

  110. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765):41–45. doi:10.1038/47412

    Article  CAS  PubMed  Google Scholar 

  111. Gregoretti IV, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 338(1):17–31. doi:10.1016/j.jmb.2004.02.006

    Article  CAS  PubMed  Google Scholar 

  112. Krogan NJ, Dover J, Khorrami S, Greenblatt JF, Schneider J, Johnston M, Shilatifard A (2002) COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of gene expression. J Biol Chem 277(13):10753–10755. doi:10.1074/jbc.C200023200

    Article  CAS  PubMed  Google Scholar 

  113. Strahl BD, Grant PA, Briggs SD, Sun ZW, Bone JR, Caldwell JA, Mollah S, Cook RG, Shabanowitz J, Hunt DF, Allis CD (2002) Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol Cell Biol 22(5):1298–1306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 16(22):2893–2905. doi:10.1101/gad.1035902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406(6796):593–599. doi:10.1038/35020506

    Article  CAS  PubMed  Google Scholar 

  116. Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenuwein T (2004) A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 18(11):1251–1262. doi:10.1101/gad.300704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Song N, Liu J, An S, Nishino T, Hishikawa Y, Koji T (2011) Immunohistochemical analysis of histone H3 modifications in germ cells during mouse spermatogenesis. Acta Histochem Cytochem 44(4):183–190. doi:10.1267/ahc.11027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Xu XF, Lv Y, Gu WZ, Tang LL, Wei JK, Zhang LY, Du LZ (2013) Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR. Respir Res 14:20. doi:10.1186/1465-9921-14-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Jordan SD, Quiros PM, Steffen KK, Williams EG, Mouchiroud L, Tronnes SU, Murillo V, Wolff SC, Shaw RJ, Auwerx J, Dillin A (2016) Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165(5):1209–1223. doi:10.1016/j.cell.2016.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tian Y, Garcia G, Bian Q, Steffen KK, Joe L, Wolff S, Meyer BJ, Dillin A (2016) Mitochondrial stress induces chromatin reorganization to promote longevity and UPR(mt). Cell 165(5):1197–1208. doi:10.1016/j.cell.2016.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cavasin MA, Demos-Davies K, Horn TR, Walker LA, Lemon DD, Birdsey N, Weiser-Evans MC, Harral J, Irwin DC, Anwar A, Yeager ME, Li M, Watson PA, Nemenoff RA, Buttrick PM, Stenmark KR, McKinsey TA (2012) Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. Circ Res 110(5):739–748. doi:10.1161/CIRCRESAHA.111.258426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Galletti M, Cantoni S, Zambelli F, Valente S, Palazzini M, Manes A, Pasquinelli G, Mai A, Galie N, Ventura C (2014) Dissecting histone deacetylase role in pulmonary arterial smooth muscle cell proliferation and migration. Biochem Pharmacol 91(2):181–190. doi:10.1016/j.bcp.2014.07.011

    Article  CAS  PubMed  Google Scholar 

  123. Zhao L, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, Wang D, Li M, McKinsey TA, Stenmark KR, Wilkins MR (2012) Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation 126(4):455–467. doi:10.1161/CIRCULATIONAHA.112.103176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Li M, Riddle SR, Frid MG, El Kasmi KC, McKinsey TA, Sokol RJ, Strassheim D, Meyrick B, Yeager ME, Flockton AR, McKeon BA, Lemon DD, Horn TR, Anwar A, Barajas C, Stenmark KR (2011) Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. Journal of immunology 187(5):2711–2722. doi:10.4049/jimmunol.1100479

    Article  CAS  Google Scholar 

  125. Yang Q, Sun M, Ramchandran R, Raj JU (2015) IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: role of epigenetic regulation. Vascul Pharmacol 73:20–31. doi:10.1016/j.vph.2015.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Chen F, Li X, Aquadro E, Haigh S, Zhou J, Stepp DW, Weintraub NL, Barman SA, Fulton DJ (2016) Inhibition of histone deacetylase reduces transcription of NADPH oxidases and ROS production and ameliorates pulmonary arterial hypertension. Free Radical Biol Med 99:167–178. doi:10.1016/j.freeradbiomed.2016.08.003

    Article  CAS  Google Scholar 

  127. Nozik-Grayck E, Woods C, Stearman RS, Venkataraman S, Ferguson BS, Swain K, Bowler RP, Geraci MW, Ihida-Stansbury K, Stenmark KR, McKinsey TA, Domann FE (2016) Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 311(1):L124–L134. doi:10.1152/ajplung.00263.2015

    Article  PubMed  PubMed Central  Google Scholar 

  128. Yang Q, Lu Z, Singh D, Raj JU (2012) BIX-01294 treatment blocks cell proliferation, migration and contractility in ovine foetal pulmonary arterial smooth muscle cells. Cell Prolif 45(4):335–344. doi:10.1111/j.1365-2184.2012.00828.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Chen D, Yang Y, Cheng X, Fang F, Xu G, Yuan Z, Xia J, Kong H, Xie W, Wang H, Fang M, Gao Y, Xu Y (2015) Megakaryocytic leukemia 1 directs a histone H3 lysine 4 methyltransferase complex to regulate hypoxic pulmonary hypertension. Hypertension 65(4):821–833. doi:10.1161/HYPERTENSIONAHA.114.04585

    Article  CAS  PubMed  Google Scholar 

  130. Yang Y, Cheng X, Tian W, Zhou B, Wu X, Xu H, Fang F, Fang M, Xu Y (2014) MRTF-A steers an epigenetic complex to activate endothelin-induced pro-inflammatory transcription in vascular smooth muscle cells. Nucleic Acids Res 42(16):10460–10472. doi:10.1093/nar/gku776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Weng X, Yu L, Liang P, Li L, Dai X, Zhou B, Wu X, Xu H, Fang M, Chen Q, Xu Y (2015) A crosstalk between chromatin remodeling and histone H3K4 methyltransferase complexes in endothelial cells regulates angiotensin II-induced cardiac hypertrophy. J Mol Cell Cardiol 82:48–58. doi:10.1016/j.yjmcc.2015.02.010

    Article  CAS  PubMed  Google Scholar 

  132. Lan B, Hayama E, Kawaguchi N, Furutani Y, Nakanishi T (2015) Therapeutic efficacy of valproic acid in a combined monocrotaline and chronic hypoxia rat model of severe pulmonary hypertension. PLoS One 10(1):e0117211. doi:10.1371/journal.pone.0117211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Saha A, Wittmeyer J, Cairns BR (2006) Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 7(6):437–447. doi:10.1038/nrm1945

    Article  CAS  PubMed  Google Scholar 

  134. Chen D, Fang F, Yang Y, Chen J, Xu G, Xu Y, Gao Y (2013) Brahma-related gene 1 (Brg1) epigenetically regulates CAM activation during hypoxic pulmonary hypertension. Cardiovasc Res 100(3):363–373. doi:10.1093/cvr/cvt214

    Article  CAS  PubMed  Google Scholar 

  135. Yang Y, Chen D, Yuan Z, Fang F, Cheng X, Xia J, Fang M, Xu Y, Gao Y (2013) Megakaryocytic leukemia 1 (MKL1) ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1. Nucleic Acids Res 41(12):6005–6017. doi:10.1093/nar/gkt311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Strobl JS (1990) A role for DNA methylation in vertebrate gene expression? Mol Endocrinol 4(2):181–183. doi:10.1210/mend-4-2-181

    Article  CAS  PubMed  Google Scholar 

  137. Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA, Gehrke C (1982) Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res 10(8):2709–2721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN, Cipriani N, Rehman J (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121(24):2661–2671. doi:10.1161/CIRCULATIONAHA.109.916098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ryan J, Dasgupta A, Huston J, Chen KH, Archer SL (2015) Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med 93(3):229–242. doi:10.1007/s00109-015-1263-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Archer SL (2016) Acquired mitochondrial abnormalities, including epigenetic inhibition of superoxide dismutase 2, in pulmonary hypertension and cancer: therapeutic implications. Adv Exp Med Biol 903:29–53. doi:10.1007/978-1-4899-7678-9_3

    Article  PubMed  Google Scholar 

  141. Jiang JX, Aitken KJ, Sotiropoulos C, Kirwan T, Panchal T, Zhang N, Pu S, Wodak S, Tolg C, Bagli DJ (2013) Phenotypic switching induced by damaged matrix is associated with DNA methyltransferase 3A (DNMT3A) activity and nuclear localization in smooth muscle cells (SMC). PLoS One 8(8):e69089. doi:10.1371/journal.pone.0069089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhang L, Tang L, Wei J, Lao L, Gu W, Hu Q, Lv Y, Fu L, Du L (2014) Extrauterine growth restriction on pulmonary vascular endothelial dysfunction in adult male rats: the role of epigenetic mechanisms. J Hypertens 32(11):2188–2198. doi:10.1097/HJH.0000000000000309 (discussion 2198)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Pousada G, Baloira A, Valverde D (2016) Methylation analysis of the BMPR2 gene promoter region in patients with pulmonary arterial hypertension. Arch Bronconeumol 52(6):293–298. doi:10.1016/j.arbres.2015.10.006

    Article  PubMed  Google Scholar 

  144. Thompson AA, Lawrie A (2017) Targeting vascular remodeling to treat pulmonary arterial hypertension. Trends Mol Med 23(1):31–45. doi:10.1016/j.molmed.2016.11.005

    Article  CAS  PubMed  Google Scholar 

  145. Barrier M, Meloche J, Jacob MH, Courboulin A, Provencher S, Bonnet S (2012) Today’s and tomorrow’s imaging and circulating biomarkers for pulmonary arterial hypertension. Cell Mol Life Sci 69(17):2805–2831. doi:10.1007/s00018-012-0950-4

    Article  CAS  PubMed  Google Scholar 

  146. Perri F, Longo F, Giuliano M, Sabbatino F, Favia G, Ionna F, Addeo R, Scarpati GDV, Di Lorenzo G, Pisconti S (2017) Epigenetic control of gene expression: potential implications for cancer treatment. Crit Rev Oncol Hemat 111:166–172. doi:10.1016/j.critrevonc.2017.01.020

    Article  CAS  Google Scholar 

  147. Zhou WQ, Feng XY, Han H, Guo SC, Wang GD (2016) Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells. Sci Rep. doi:10.1038/Srep28004

    Google Scholar 

  148. Kim SM, Park KC, Jeon JY, Kim BW, Kim HK, Chang HJ, Choi SH, Park CS, Chang HS (2015) Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer. BMC Cancer. doi:10.1186/S12885-015-1982-6

    Google Scholar 

  149. Wang J, Saren G, Jiang H (2015) HDAC inhibition: a novel therapeutic target for attenuating pulmonary hypertension by regulating Tregs. Int J Cardiol 198:176–177. doi:10.1016/j.ijcard.2015.06.172

    Article  PubMed  Google Scholar 

  150. Gaowa S, Zhou W, Yu L, Zhou X, Liao K, Yang K, Lu Z, Jiang H, Chen X (2014) Effect of Th17 and Treg axis disorder on outcomes of pulmonary arterial hypertension in connective tissue diseases. Mediators Inflamm 2014:247372. doi:10.1155/2014/247372

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Tamosiuniene R, Tian W, Dhillon G, Wang L, Sung YK, Gera L, Patterson AJ, Agrawal R, Rabinovitch M, Ambler K, Long CS, Voelkel NF, Nicolls MR (2011) Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res 109(8):867–879. doi:10.1161/CIRCRESAHA.110.236927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chu Y, Xiangli X, Xiao W (2015) Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice. Mol Med Rep 11(4):3181–3187. doi:10.3892/mmr.2014.3106

    Article  CAS  PubMed  Google Scholar 

  153. Bogaard HJ, Mizuno S, Hussaini AA, Toldo S, Abbate A, Kraskauskas D, Kasper M, Natarajan R, Voelkel NF (2011) Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. Am J Respir Crit Care Med 183(10):1402–1410. doi:10.1164/rccm.201007-1106OC

    Article  CAS  PubMed  Google Scholar 

  154. Bouchie A (2013) First microRNA mimic enters clinic. Nat Biotechnol 31(7):577. doi:10.1038/nbt0713-577

    Article  CAS  PubMed  Google Scholar 

  155. Kamo Y, Ichikawa T, Miyaaki H, Uchida S, Yamaguchi T, Shibata H, Honda T, Taura N, Isomoto H, Takeshima F, Nakao K (2015) Significance of miRNA-122 in chronic hepatitis C patients with serotype 1 on interferon therapy. Hepatol Res 45(1):88–96. doi:10.1111/hepr.12317

    Article  CAS  PubMed  Google Scholar 

  156. Bienertova-Vasku J, Novak J, Vasku A (2015) MicroRNAs in pulmonary arterial hypertension: pathogenesis, diagnosis and treatment. J Am Soc Hypertens 9(3):221–234. doi:10.1016/j.jash.2014.12.011

    Article  CAS  PubMed  Google Scholar 

  157. Meloche J, Paulin R, Provencher S, Bonnet S (2015) Therapeutic potential of microRNA modulation in pulmonary arterial hypertension. Curr Vasc Pharmacol 13(3):331–340

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Natural Science Foundation of China (Nos. 81501626, 81471814, J1310001).

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  1. Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, People’s Republic of China

    Dewei Chen, Wenxiang Gao, Shouxian Wang & Bing Ni

  2. Institute of Medicine and Hygienic Equipment for High Altitude Region, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, People’s Republic of China

    Yuqi Gao

  3. Key Laboratory of High Altitude Medicine of PLA, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Dewei Chen, Wenxiang Gao, Shouxian Wang, Bing Ni & Yuqi Gao

Authors
  1. Dewei Chen
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  2. Wenxiang Gao
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  3. Shouxian Wang
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  4. Bing Ni
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  5. Yuqi Gao
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Corresponding authors

Correspondence to Bing Ni or Yuqi Gao.

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Chen, D., Gao, W., Wang, S. et al. Critical effects of epigenetic regulation in pulmonary arterial hypertension. Cell. Mol. Life Sci. 74, 3789–3808 (2017). https://doi.org/10.1007/s00018-017-2551-8

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  • DOI: https://doi.org/10.1007/s00018-017-2551-8

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