Skip to main content

Noncoding RNA as regulators of cardiac fibrosis: current insight and the road ahead

Pflügers Archiv - European Journal of Physiology volume 468, pages 1103–1111 (2016)Cite this article

Abstract

Cardiac fibrosis is an important pathological feature of cardiac remodeling in heart diseases. The molecular mechanisms of cardiac fibrosis are unknown. Genomic analyses estimated that many noncoding DNA regions generate noncoding RNAs (ncRNAs). ncRNAs have emerged as key molecular players in the regulation of gene expression in different biological processes. Recent studies have started to reveal the importance of ncRNAs in heart development and suggest also an involvement in cardiac fibrosis. These molecules are emerging as important regulators of cellular process. Here, we review particularly focuses on the involvement of two large families of ncRNAs, namely microRNAs (miRNAs) and long noncoding RNAs (LncRNAs) in the regulation of cardiac fibrosis. Furthermore, we review the functions and role of ncRNAs in cardiac biology and discuss these reports and the therapeutic potential of ncRNAs for cardiac fibrosis associated with fibroblast activation and proliferation.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

MiRNAs:

MicroRNAs

LncRNA:

Long noncoding RNA

RNAPII:

RNA polymerase II

ICRs:

Imprinting control regions

α-SMA:

α-smooth muscle actin

rRNAs:

Ribosomal RNAs

tRNA:

Transfer RNA

snRNAs:

Small nuclear RNAs

snoRNAs:

Small nucleolar RNAs

RNAi:

RNA interference

piRNAs:

Piwi-interacting RNAs

CHRF:

Cardiac hypertrophy related factor

pri-miRNA:

Primary miRNA

pre-miRNA:

Precursor miRNA

RISC:

RNA-induced silencing complex

References

  1. Abonnenc M, Nabeebaccus AA, Mayr U, Barallobre-Barreiro J, Dong X, Cuello F, Sur S, Drozdov I, Langley SR, Lu R, Stathopoulou K, Didangelos A, Yin X, Zimmermann WH, Shah AM, Zampetaki A, Mayr M (2013) Extracellular matrix secretion by cardiac fibroblasts: role of microRNA-29b and microRNA-30c. Circ Res 113:1138–47. doi:10.1161/CIRCRESAHA.113.302400

    CAS  PubMed  Article  Google Scholar 

  2. Alshalalfa M (2014) miRNA regulation in the context of functional protein networks: principles and applications. Wiley Interdiscip Rev Syst Biol Med 6:189–99. doi:10.1002/wsbm.1251

    CAS  PubMed  Article  Google Scholar 

  3. Beaumont J, Lopez B, Hermida N, Schroen B, San Jose G, Heymans S, Valencia F, Gomez-Doblas JJ, De Teresa E, Diez J, Gonzalez A (2014) microRNA-122 down-regulation may play a role in severe myocardial fibrosis in human aortic stenosis through TGF-beta1 up-regulation. Clin Sci (Lond) 126:497–506. doi:10.1042/CS20130538

    CAS  Article  Google Scholar 

  4. Bennasser Y, Chable-Bessia C, Triboulet R, Gibbings D, Gwizdek C, Dargemont C, Kremer EJ, Voinnet O, Benkirane M (2011) Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels. Nat Struct Mol Biol 18:323–7. doi:10.1038/nsmb.1987

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, Gregorevic P, Obad S, Kauppinen S, Du XJ, Lin RC, McMullen JR (2012) Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci U S A 109:17615–20. doi:10.1073/pnas.1206432109

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Bhatia H, Verma G, Datta M (2014) miR-107 orchestrates ER stress induction and lipid accumulation by post-transcriptional regulation of fatty acid synthase in hepatocytes. Biochim Biophys Acta 1839:334–43. doi:10.1016/j.bbagrm.2014.02.009

    CAS  PubMed  Article  Google Scholar 

  7. Bierhoff H, Postepska-Igielska A, Grummt I (2013) Noisy silence: non-coding RNA and heterochromatin formation at repetitive elements. Epigenetics 9:53–61

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Bogerd HP, Whisnant AW, Kennedy EM, Flores O, Cullen BR (2014) Derivation and characterization of Dicer- and microRNA-deficient human cells. RNA 20:923–37. doi:10.1261/rna.044545.114

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Braitsch CM, Kanisicak O, van Berlo JH, Molkentin JD, Yutzey KE (2013) Differential expression of embryonic epicardial progenitor markers and localization of cardiac fibrosis in adult ischemic injury and hypertensive heart disease. J Mol Cell Cardiol 65:108–19. doi:10.1016/j.yjmcc.2013.10.005

    CAS  PubMed  Article  Google Scholar 

  10. Bratkovic T, Rogelj B (2014) The many faces of small nucleolar RNAs. Biochim Biophys Acta 1839:438–43. doi:10.1016/j.bbagrm.2014.04.009

    CAS  PubMed  Article  Google Scholar 

  11. Broadbent KM, Park D, Wolf AR, Van Tyne D, Sims JS, Ribacke U, Volkman S, Duraisingh M, Wirth D, Sabeti PC, Rinn JL (2011) A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs. Genome Biol 12:R56. doi:10.1186/gb-2011-12-6-r56

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Bronnum H, Andersen DC, Schneider M, Sandberg MB, Eskildsen T, Nielsen SB, Kalluri R, Sheikh SP (2013) miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving programmed cell death 4 and sprouty-1. PLoS One 8:e56280. doi:10.1371/journal.pone.0056280

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Castoldi G, Di Gioia CR, Bombardi C, Catalucci D, Corradi B, Gualazzi MG, Leopizzi M, Mancini M, Zerbini G, Condorelli G, Stella A (2012) MiR-133a regulates collagen 1A1: potential role of miR-133a in myocardial fibrosis in angiotensin II-dependent hypertension. J Cell Physiol 227:850–6. doi:10.1002/jcp.22939

    CAS  PubMed  Article  Google Scholar 

  14. Cavin S, Maric D, Diviani D (2014) A-kinase anchoring protein-Lbc promotes pro-fibrotic signaling in cardiac fibroblasts. Biochim Biophys Acta 1843:335–45. doi:10.1016/j.bbamcr.2013.11.008

    CAS  PubMed  Article  Google Scholar 

  15. Chatterjee A, Chattopadhyay D, Chakrabarti G (2014) miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression. PLoS One 9:e95716. doi:10.1371/journal.pone.0095716

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Chen J, Zhang Y, Liu J, Xia M, Wang W, Shen F (2014) Genome-wide analysis of the RNA helicase gene family in Gossypium raimondii. Int J Mol Sci 15:4635–56. doi:10.3390/ijms15034635

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. Chen S, Puthanveetil P, Feng B, Matkovich SJ, Dorn GW 2nd, Chakrabarti S (2014) Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes. J Cell Mol Med 18:415–21. doi:10.1111/jcmm.12218

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. de Haas HJ, Arbustini E, Fuster V, Kramer CM, Narula J (2014) Molecular imaging of the cardiac extracellular matrix. Circ Res 114:903–15. doi:10.1161/CIRCRESAHA.113.302680

    PubMed  Article  CAS  Google Scholar 

  19. Duisters RF, Tijsen AJ, Schroen B, Leenders JJ, Lentink V, van der Made I, Herias V, van Leeuwen RE, Schellings MW, Barenbrug P, Maessen JG, Heymans S, Pinto YM, Creemers EE (2009) miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res 104:170–8. doi:10.1161/CIRCRESAHA.108.182535, 6p following 178

    CAS  PubMed  Article  Google Scholar 

  20. Erson-Bensan AE (2014) Introduction to microRNAs in biological systems. Methods Mol Biol 1107:1–14. doi:10.1007/978-1-62703-748-8_1

    CAS  PubMed  Article  Google Scholar 

  21. Fachel AA, Tahira AC, Vilella-Arias SA, Maracaja-Coutinho V, Gimba ER, Vignal GM, Campos FS, Reis EM, Verjovski-Almeida S (2013) Expression analysis and in silico characterization of intronic long noncoding RNAs in renal cell carcinoma: emerging functional associations. Mol Cancer 12:140. doi:10.1186/1476-4598-12-140

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Falaleeva M, Stamm S (2013) Processing of snoRNAs as a new source of regulatory non-coding RNAs: snoRNA fragments form a new class of functional RNAs. Bioessays 35:46–54. doi:10.1002/bies.201200117

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Flores O, Kennedy EM, Skalsky RL, Cullen BR (2014) Differential RISC association of endogenous human microRNAs predicts their inhibitory potential. Nucleic Acids Res 42:4629–39. doi:10.1093/nar/gkt1393

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Gaspard GJ, Maclean J, Rioux D, Pasumarthi KB (2014) A novel beta-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts. Am J Physiol Cell Physiol 306:C540–50. doi:10.1152/ajpcell.00206.2013

    CAS  PubMed  Article  Google Scholar 

  25. Ghosal S, Das S, Chakrabarti J (2013) Long noncoding RNAs: new players in the molecular mechanism for maintenance and differentiation of pluripotent stem cells. Stem Cells Dev 22:2240–53. doi:10.1089/scd.2013.0014

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Ghosh AK, Nagpal V, Covington JW, Michaels MA, Vaughan DE (2012) Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT. Cell Signal 24:1031–6. doi:10.1016/j.cellsig.2011.12.024

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Gvozdeva OV, Dovydenko IS, Venyaminova AG, Zenkova MA, Vlassov VV, Chernolovskaya EL (2014) 42- and 63-bp anti-MDR1-siRNAs bearing 2'-OMe modifications in nuclease-sensitive sites induce specific and potent gene silencing. FEBS Lett 588:1037–43. doi:10.1016/j.febslet.2014.02.015

    CAS  PubMed  Article  Google Scholar 

  28. Hacisuleyman E, Goff LA, Trapnell C, Williams A, Henao-Mejia J, Sun L, McClanahan P, Hendrickson DG, Sauvageau M, Kelley DR, Morse M, Engreitz J, Lander ES, Guttman M, Lodish HF, Flavell R, Raj A, Rinn JL (2014) Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol 21:198–206. doi:10.1038/nsmb.2764

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Hasegawa Y, Nakagawa S (2011) Revisiting the function of nuclear scaffold/matrix binding proteins in X chromosome inactivation. RNA Biol 8:735–9. doi:10.4161/rna.8.5.16367

    CAS  PubMed  Article  Google Scholar 

  30. Haussecker D, Huang Y, Lau A, Parameswaran P, Fire AZ, Kay MA (2010) Human tRNA-derived small RNAs in the global regulation of RNA silencing. RNA 16:673–95. doi:10.1261/rna.2000810

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. He Y, Huang C, Lin X, Li J (2013) MicroRNA-29 family, a crucial therapeutic target for fibrosis diseases. Biochimie 95:1355–9. doi:10.1016/j.biochi.2013.03.010

    CAS  PubMed  Article  Google Scholar 

  32. Hsieh WJ, Lin FM, Huang HD, Wang H (2014) Investigating microRNA-target interaction-supported tissues in human cancer tissues based on miRNA and target gene expression profiling. PLoS One 9:e95697. doi:10.1371/journal.pone.0095697

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Hsu WL, Chen CL, Huang SW, Wu CC, Chen IH, Nadar M, Su YP, Tsai CH (2014) The untranslated regions of classic swine fever virus RNA trigger apoptosis. PLoS One 9:e88863. doi:10.1371/journal.pone.0088863

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Huang F, Zhu X, Hu XQ, Fang ZF, Tang L, Lu XL, Zhou SH (2013) Mesenchymal stem cells modified with miR-126 release angiogenic factors and activate Notch ligand Delta-like-4, enhancing ischemic angiogenesis and cell survival. Int J Mol Med 31:484–92. doi:10.3892/ijmm.2012.1200

    CAS  PubMed  Google Scholar 

  35. Huang Y, Xu T, Li J (2014) Role of miR-208 in cardiac fibrosis: prevention or promotion? Arch Med Res 45:356. doi:10.1016/j.arcmed.2014.03.010

    CAS  PubMed  Article  Google Scholar 

  36. Hussain M, O'Neill SL, Asgari S (2013) Wolbachia interferes with the intracellular distribution of Argonaute 1 in the dengue vector Aedes aegypti by manipulating the host microRNAs. RNA Biol 10:1868–75. doi:10.4161/rna.27392

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Iyengar BR, Choudhary A, Sarangdhar MA, Venkatesh KV, Gadgil CJ, Pillai B (2014) Non-coding RNA interact to regulate neuronal development and function. Front Cell Neurosci 8:47. doi:10.3389/fncel.2014.00047

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. Jazbutyte V, Fiedler J, Kneitz S, Galuppo P, Just A, Holzmann A, Bauersachs J, Thum T (2013) MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr) 35:747–62. doi:10.1007/s11357-012-9407-9

    CAS  Article  Google Scholar 

  39. Jia W, Chen W, Kang J (2013) The functions of microRNAs and long non-coding RNAs in embryonic and induced pluripotent stem cells. Genomics Proteomics Bioinformatics 11:275–83. doi:10.1016/j.gpb.2013.09.004

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Jiang X, Ning Q, Wang J (2013) Angiotensin II induced differentially expressed microRNAs in adult rat cardiac fibroblasts. J Physiol Sci 63:31–8. doi:10.1007/s12576-012-0230-y

    CAS  PubMed  Article  Google Scholar 

  41. Kalsotra A, Singh RK, Gurha P, Ward AJ, Creighton CJ, Cooper TA (2014) The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue, dramatically altering miRNA and mRNA expression. Cell Rep 6:336–45. doi:10.1016/j.celrep.2013.12.025

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Karakikes I, Chaanine AH, Kang S, Mukete BN, Jeong D, Zhang S, Hajjar RJ, Lebeche D (2013) Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling. J Am Heart Assoc 2:e000078. doi:10.1161/JAHA.113.000078

    PubMed  PubMed Central  Article  Google Scholar 

  43. Karginov FV, Hannon GJ (2013) Remodeling of Ago2-mRNA interactions upon cellular stress reflects miRNA complementarity and correlates with altered translation rates. Genes Dev 27:1624–32. doi:10.1101/gad.215939.113

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Khan IS, Taniguchi RT, Fasano KJ, Anderson MS, Jeker LT (2014) Canonical microRNAs in thymic epithelial cells promote central tolerance. Eur J Immunol 44:1313–9. doi:10.1002/eji.201344079

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. King I, Yartseva V, Salas D, Kumar A, Heidersbach A, Ando DM, Stallings NR, Elliott JL, Srivastava D, Ivey KN (2014) The RNA binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex. J Biol Chem 289:14263–71. doi:10.1074/jbc.M114.561902

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Kinoshita T, Ishikawa Y, Arita M, Akishima-Fukasawa Y, Fujita K, Inomata N, Suzuki T, Namiki A, Mikami T, Ikeda T, Yamazaki J, Ishii T, Akasaka Y (2014) Antifibrotic response of cardiac fibroblasts in hypertensive hearts through enhanced TIMP-1 expression by basic fibroblast growth factor. Cardiovasc Pathol 23:92–100. doi:10.1016/j.carpath.2013.11.001

    CAS  PubMed  Article  Google Scholar 

  47. Kraus P, Sivakamasundari V, Lim SL, Xing X, Lipovich L, Lufkin T (2013) Making sense of Dlx1 antisense RNA. Dev Biol 376:224–35. doi:10.1016/j.ydbio.2013.01.035

    CAS  PubMed  Article  Google Scholar 

  48. Kuo CH, Hsieh CC, Lee MS, Chang KT, Kuo HF, Hung CH (2014) Epigenetic regulation in allergic diseases and related studies. Asia Pac Allergy 4:14–18. doi:10.5415/apallergy.2014.4.1.14

    PubMed  PubMed Central  Article  Google Scholar 

  49. Lai CH, Han CK, Shibu MA, Pai PY, Ho TJ, Day CH, Tsai FJ, Tsai CH, Yao CH, Huang CY (2014) Lumbrokinase from earthworm extract ameliorates second-hand smoke-induced cardiac fibrosis. Environ Toxicol 30:1216–25. doi:10.1002/tox.21993

    PubMed  Article  CAS  Google Scholar 

  50. Lepoivre C, Belhocine M, Bergon A, Griffon A, Yammine M, Vanhille L, Zacarias-Cabeza J, Garibal MA, Koch F, Maqbool MA, Fenouil R, Loriod B, Holota H, Gut M, Gut I, Imbert J, Andrau JC, Puthier D, Spicuglia S (2013) Divergent transcription is associated with promoters of transcriptional regulators. BMC Genomics 14:914. doi:10.1186/1471-2164-14-914

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20. doi:10.1016/j.cell.2004.12.035

    CAS  PubMed  Article  Google Scholar 

  52. Li Q, Song XW, Zou J, Wang GK, Kremneva E, Li XQ, Zhu N, Sun T, Lappalainen P, Yuan WJ, Qin YW, Jing Q (2010) Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy. J Cell Sci 123:2444–52. doi:10.1242/jcs.067165

    CAS  PubMed  Article  Google Scholar 

  53. Li K, Du Y, Jiang BL, He JF (2014) Increased microRNA-155 and decreased microRNA-146a may promote ocular inflammation and proliferation in Graves’ ophthalmopathy. Med Sci Monit 20:639–43. doi:10.12659/MSM.890686

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Liang H, Zhang C, Ban T, Liu Y, Mei L, Piao X, Zhao D, Lu Y, Chu W, Yang B (2012) A novel reciprocal loop between microRNA-21 and TGFbetaRIII is involved in cardiac fibrosis. Int J Biochem Cell Biol 44:2152–60. doi:10.1016/j.biocel.2012.08.019

    CAS  PubMed  Article  Google Scholar 

  55. Lu D, Aroonsakool N, Yokoyama U, Patel HH, Insel PA (2013) Increase in cellular cyclic AMP concentrations reverses the profibrogenic phenotype of cardiac myofibroblasts: a novel therapeutic approach for cardiac fibrosis. Mol Pharmacol 84:787–93. doi:10.1124/mol.113.087742

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Lu KH, Li W, Liu XH, Sun M, Zhang ML, Wu WQ, Xie WP, Hou YY (2013) Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer 13:461. doi:10.1186/1471-2407-13-461

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. Luteijn MJ, Ketting RF (2013) PIWI-interacting RNAs: from generation to transgenerational epigenetics. Nat Rev Genet 14:523–34. doi:10.1038/nrg3495

    CAS  PubMed  Article  Google Scholar 

  58. Maruyama R, Suzuki H (2012) Long noncoding RNA involvement in cancer. BMB Rep 45:604–11

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Matkovich SJ, Wang W, Tu Y, Eschenbacher WH, Dorn LE, Condorelli G, Diwan A, Nerbonne JM, Dorn GW 2nd (2010) MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res 106:166–75. doi:10.1161/CIRCRESAHA.109.202176

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Morceau F, Chateauvieux S, Gaigneaux A, Dicato M, Diederich M (2013) Long and short non-coding RNAs as regulators of hematopoietic differentiation. Int J Mol Sci 14:14744–70. doi:10.3390/ijms140714744

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. Morlando M, Ballarino M, Fatica A, Bozzoni I (2014) The role of long noncoding RNAs in the epigenetic control of gene expression. ChemMedChem 9:505–10. doi:10.1002/cmdc.201300569

    CAS  PubMed  Article  Google Scholar 

  62. Nazer E, Lei EP (2014) Modulation of chromatin modifying complexes by noncoding RNAs in trans. Curr Opin Genet Dev 25C:68–73. doi:10.1016/j.gde.2013.11.019

    Article  CAS  Google Scholar 

  63. Ojala M, Rajala K, Pekkanen-Mattila M, Miettinen M, Huhtala H, Aalto-Setala K (2012) Culture conditions affect cardiac differentiation potential of human pluripotent stem cells. PLoS One 7:e48659. doi:10.1371/journal.pone.0048659

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Oka T, Akazawa H, Naito AT, Komuro I (2014) Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. Circ Res 114:565–71. doi:10.1161/CIRCRESAHA.114.300507

    CAS  PubMed  Article  Google Scholar 

  65. Orom UA, Shiekhattar R (2011) Long non-coding RNAs and enhancers. Curr Opin Genet Dev 21:194–8. doi:10.1016/j.gde.2011.01.020

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Pan Z, Sun X, Shan H, Wang N, Wang J, Ren J, Feng S, Xie L, Lu C, Yuan Y, Zhang Y, Wang Y, Lu Y, Yang B (2012) MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-beta1 pathway. Circulation 126:840–50. doi:10.1161/CIRCULATIONAHA.112.094524

    CAS  PubMed  Article  Google Scholar 

  67. Perez-Pinera P, Jones MF, Lal A, Lu TK (2015) Putting non-coding RNA on display with CRISPR. Mol Cell 59:146–8. doi:10.1016/j.molcel.2015.07.002

    CAS  PubMed  Article  Google Scholar 

  68. Ponicsan SL, Houel S, Old WM, Ahn NG, Goodrich JA, Kugel JF (2013) The non-coding B2 RNA binds to the DNA cleft and active-site region of RNA polymerase II. J Mol Biol 425:3625–38. doi:10.1016/j.jmb.2013.01.035

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Putko BN, Yogasundaram H, Oudit GY (2014) The harbinger of mortality in heart failure with preserved ejection fraction: do GDF-15 levels reflect tandem, deterministic effects of fibrosis and inflammation? Can J Cardiol 30:264–6. doi:10.1016/j.cjca.2013.12.021

    PubMed  Article  Google Scholar 

  70. Richter H, Mohr S, Randau L (2013) C/D box sRNA, CRISPR RNA and tRNA processing in an archaeon with a minimal fragmented genome. Biochem Soc Trans 41:411–5. doi:10.1042/BST20120276

    CAS  PubMed  Article  Google Scholar 

  71. Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–66. doi:10.1146/annurev-biochem-051410-092902

    CAS  PubMed  Article  Google Scholar 

  72. Romero R, Tarca AL, Chaemsaithong P, Miranda J, Chaiworapongsa T, Jia H, Hassan SS, Kalita CA, Cai J, Yeo L, Lipovich L (2014) Transcriptome interrogation of human myometrium identifies differentially expressed sense-antisense pairs of protein-coding and long non-coding RNA genes in spontaneous labor at term. J Matern Fetal Neonatal Med 27:1397–408. doi:10.3109/14767058.2013.860963

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Roncarati R, Anselmi CV, Losi MA, Papa L, Cavarretta E, Costa Martins PD, Jotti GS, Franzone A, Galastri L, Latronico MV, Imbriaco M, Esposito G, De Windt L, Betocchi S, Condorelli G (2013) Circulating miR-29a, among other upregulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 10.1016/j.jacc.2013.09.041

  74. Sanchez-Mas J, Lax A, Asensio-Lopez MC, Fernandez-Del Palacio MJ, Caballero L, Garrido IP, Pastor F, Januzzi JL, Pascual-Figal DA (2014) Galectin-3 expression in cardiac remodeling after myocardial infarction. Int J Cardiol 172:e98–e101. doi:10.1016/j.ijcard.2013.12.129

    CAS  PubMed  Article  Google Scholar 

  75. Scheuermann JC, Boyer LA (2013) Getting to the heart of the matter: long non-coding RNAs in cardiac development and disease. EMBO J 32:1805–16. doi:10.1038/emboj.2013.134

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Schonrock N, Harvey RP, Mattick JS (2012) Long noncoding RNAs in cardiac development and pathophysiology. Circ Res 111:1349–62. doi:10.1161/CIRCRESAHA.112.268953

    CAS  PubMed  Article  Google Scholar 

  77. Schunke KJ, Coyle L, Merrill GF, Denhardt DT (2013) Acetaminophen attenuates doxorubicin-induced cardiac fibrosis via osteopontin and GATA4 regulation: reduction of oxidant levels. J Cell Physiol 228:2006–14. doi:10.1002/jcp.24367

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Sharma A (2014) Novel transcriptome data analysis implicates circulating microRNAs in epigenetic inheritance in mammals. Gene 538:366–72. doi:10.1016/j.gene.2014.01.051

    CAS  PubMed  Article  Google Scholar 

  79. Shyu KG, Wang BW, Wu GJ, Lin CM, Chang H (2013) Mechanical stretch via transforming growth factor-beta1 activates microRNA208a to regulate endoglin expression in cultured rat cardiac myoblasts. Eur J Heart Fail 15:36–45. doi:10.1093/eurjhf/hfs143

    CAS  PubMed  Article  Google Scholar 

  80. Stancheva I, Schirmer EC (2014) Nuclear envelope: connecting structural genome organization to regulation of gene expression. Adv Exp Med Biol 773:209–44. doi:10.1007/978-1-4899-8032-8_10

    CAS  PubMed  Article  Google Scholar 

  81. Stefani G, Slack FJ (2008) Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol 9:219–30. doi:10.1038/nrm2347

    CAS  PubMed  Article  Google Scholar 

  82. Stoller ML, Chang HC, Fekete DM (2013) Bicistronic gene transfer tools for delivery of miRNAs and protein coding sequences. Int J Mol Sci 14:18239–55. doi:10.3390/ijms140918239

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. Tao H, Shi KH, Yang JJ, Huang C, Liu LP, Li J (2013) Epigenetic regulation of cardiac fibrosis. Cell Signal 25:1932–8. doi:10.1016/j.cellsig.2013.03.024

    CAS  PubMed  Article  Google Scholar 

  84. Tao H, Shi KH, Yang JJ, Huang C, Zhan HY, Li J (2014) Histone deacetylases in cardiac fibrosis: current perspectives for therapy. Cell Signal 26:521–7. doi:10.1016/j.cellsig.2013.11.037

    CAS  PubMed  Article  Google Scholar 

  85. van Almen GC, Verhesen W, van Leeuwen RE, van de Vrie M, Eurlings C, Schellings MW, Swinnen M, Cleutjens JP, van Zandvoort MA, Heymans S, Schroen B (2011) MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure. Aging Cell 10:769–79. doi:10.1111/j.1474-9726.2011.00714.x

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, Hill JA, Olson EN (2008) Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A 105:13027–32. doi:10.1073/pnas.0805038105

    PubMed  PubMed Central  Article  Google Scholar 

  87. Veltri RW, Christudass CS (2014) Nuclear morphometry, epigenetic changes, and clinical relevance in prostate cancer. Adv Exp Med Biol 773:77–99. doi:10.1007/978-1-4899-8032-8_4

    CAS  PubMed  Article  Google Scholar 

  88. Verma SK, Lal H, Golden HB, Gerilechaogetu F, Smith M, Guleria RS, Foster DM, Lu G, Dostal DE (2011) Rac1 and RhoA differentially regulate angiotensinogen gene expression in stretched cardiac fibroblasts. Cardiovasc Res 90:88–96. doi:10.1093/cvr/cvq385

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Vettori S, Gay S, Distler O (2012) Role of microRNAs in fibrosis. Open Rheumatol J 6:130–9. doi:10.2174/1874312901206010130

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Wang J, Huang W, Xu R, Nie Y, Cao X, Meng J, Xu X, Hu S, Zheng Z (2012) MicroRNA-24 regulates cardiac fibrosis after myocardial infarction. J Cell Mol Med 16:2150–60. doi:10.1111/j.1582-4934.2012.01523.x

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun T, Zhang XJ, Li PF (2014) A long noncoding RNA, CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res 114:1377–88. doi:10.1161/CIRCRESAHA.114.302476

    CAS  PubMed  Article  Google Scholar 

  92. Wei C, Kim IK, Kumar S, Jayasinghe S, Hong N, Castoldi G, Catalucci D, Jones WK, Gupta S (2013) NF-kappaB mediated miR-26a regulation in cardiac fibrosis. J Cell Physiol 228:1433–42. doi:10.1002/jcp.24296

    CAS  PubMed  Article  Google Scholar 

  93. Wiegand S, Dietrich S, Hertel R, Bongaerts J, Evers S, Volland S, Daniel R, Liesegang H (2013) RNA-Seq of Bacillus licheniformis: active regulatory RNA features expressed within a productive fermentation. BMC Genomics 14:667. doi:10.1186/1471-2164-14-667

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Wostenberg C, Quarles KA, Showalter SA (2010) Dynamic origins of differential RNA binding function in two dsRBDs from the miRNA “microprocessor” complex. Biochemistry 49:10728–36. doi:10.1021/bi1015716

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Wu Y, Li Y, Zhang C, A X, Wang Y, Cui W, Li H, Du J (2014) S100a8/a9 Released by CD11b + Gr1+ neutrophils activates cardiac fibroblasts to initiate angiotensin II-induced cardiac inflammation and injury. Hypertension 63:1241–50. doi:10.1161/HYPERTENSIONAHA.113.02843

    CAS  PubMed  Article  Google Scholar 

  96. Yang KC, Ku YC, Lovett M, Nerbonne JM (2012) Combined deep microRNA and mRNA sequencing identifies protective transcriptomal signature of enhanced PI3Kalpha signaling in cardiac hypertrophy. J Mol Cell Cardiol 53:101–12. doi:10.1016/j.yjmcc.2012.04.012

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Yoon JH, Abdelmohsen K, Gorospe M (2013) Posttranscriptional gene regulation by long noncoding RNA. J Mol Biol 425:3723–30. doi:10.1016/j.jmb.2012.11.024

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Zhang SG, Liu CY, Li L, Sun TW, Luo YG, Yun WJ, Zhang JY (2013) Examination of artificial MiRNA mimics with centered-site complementarity for gene targeting. PLoS One 8:e72062. doi:10.1371/journal.pone.0072062

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Zhang X, Li D, Li M, Ye M, Ding L, Cai H, Fu D, Lv Z (2014) MicroRNA-146a targets PRKCE to modulate papillary thyroid tumor development. Int J Cancer 134:257–67. doi:10.1002/ijc.28141

    PubMed  Article  CAS  Google Scholar 

  100. Zhang Y, Pan T, Zhong X, Cheng C (2014) Nicotine upregulates microRNA-21 and promotes TGF-beta-dependent epithelial-mesenchymal transition of esophageal cancer cells. Tumour Biol 35:7063–72. doi:10.1007/s13277-014-1968-z

    CAS  PubMed  Article  Google Scholar 

  101. Zhou S, Liu Y, Prater K, Zheng Y, Cai L (2013) Roles of microRNAs in pressure overload- and ischemia-related myocardial remodeling. Life Sci 93:855–62. doi:10.1016/j.lfs.2013.08.023

    CAS  PubMed  Article  Google Scholar 

  102. Zhou L, Hang J, Zhou Y, Wan R, Lu G, Yin P, Yan C, Shi Y (2014) Crystal structures of the Lsm complex bound to the 3′ end sequence of U6 small nuclear RNA. Nature 506:116–20. doi:10.1038/nature12803

    CAS  PubMed  Article  Google Scholar 

  103. Zhu JN, Chen R, Fu YH, Lin QX, Huang S, Guo LL, Zhang MZ, Deng CY, Zou X, Zhong SL, Yang M, Zhuang J, Yu XY, Shan ZX (2013) Smad3 inactivation and MiR-29b upregulation mediate the effect of carvedilol on attenuating the acute myocardium infarction-induced myocardial fibrosis in rat. PLoS One 8:e75557. doi:10.1371/journal.pone.0075557

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgments

This project was supported by Anhui Provincial Natural Science Foundation (1408085MH175, 1308085MH117).

Author information

Affiliations

  1. Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, China

    Hui Tao & Kai-Hu Shi

  2. Cardiovascular Research Center, Anhui Medical University, Hefei, 230601, China

    Hui Tao & Kai-Hu Shi

  3. Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China

    Jing-Jing Yang & Wei Hu

  4. School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Jun Li

  5. Department of Scientific and Educational, The Second Hospital of Anhui Medical University, Hefei, China

    Zi-Yu Deng

  6. The Second Hospital of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China

    Kai-Hu Shi

Authors
  1. Hui Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing-Jing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kai-Hu Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zi-Yu Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kai-Hu Shi or Zi-Yu Deng.

Ethics declarations

Conflicts of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tao, H., Yang, JJ., Hu, W. et al. Noncoding RNA as regulators of cardiac fibrosis: current insight and the road ahead. Pflugers Arch - Eur J Physiol 468, 1103–1111 (2016). https://doi.org/10.1007/s00424-016-1792-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-016-1792-y

Keywords

  • Long noncoding RNA
  • MicroRNA
  • Cardiac fibrosis
  • Epigenetic