Vol 25, No 6 (2018)
Review articles — Basic science and experimental cardiology
Published online: 2017-12-14

open access

Page views 3297
Article views/downloads 1233
Get Citation

Connect on Social Media

Connect on Social Media

Non-coding RNAs in cardiac fibrosis: Emerging biomarkers and therapeutic targets

Zhongxiu Chen1, Chen Li1, Ke Lin1, Huawei Cai1, Weiqiang Ruan1, Junyang Han1, Li Rao1
Pubmed: 29240957
Cardiol J 2018;25(6):732-741.

Abstract

Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. ncRNAs are involved in cell proliferation, apoptosis, differentiation, metabolism, and other physiological processes as well as the pathogenesis of diseases. Cardiac fibrosis is increasingly recognized as a common final pathway in advanced heart diseases. Many studies have shown that the occurrence and development of cardiac fibrosis is closely related to the regulation of ncRNAs. This review will highlight recent updates regarding the involvement of ncRNAs in cardiac fibrosis, and their potential as emerging biomarkers and therapeutic targets.

Article available in PDF format

View PDF Download PDF file

References

  1. Bernaba BN, Chan JB, Lai CK, et al. Pathology of late-onset anthracycline cardiomyopathy. Cardiovasc Pathol. 2010; 19(5): 308–311.
  2. Asbun J, Villarreal FJ. The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol. 2006; 47(4): 693–700.
  3. Bharati S, Lev M. Cardiac conduction system involvement in sudden death of obese young people. Am Heart J. 1995; 129(2): 273–281.
  4. Perazzolo Marra M, De Lazzari M, Zorzi A, et al. Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy. Heart Rhythm. 2014; 11(5): 856–863.
  5. Dweck MR, Joshi S, Murigu T, et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. J Am Coll Cardiol. 2011; 58(12): 1271–1279.
  6. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014; 71(4): 549–574.
  7. Fan Z, Guan J. Antifibrotic therapies to control cardiac fibrosis. Biomater Res. 2016; 20: 13.
  8. Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nature. 2012; 489(7414): 101–108.
  9. Salmena L, Poliseno L, Tay Y, et al. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011; 146(3): 353–358.
  10. Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013; 495(7441): 384–388.
  11. Weber KT, Sun Y, Bhattacharya SK, et al. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol. 2013; 10(1): 15–26.
  12. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010; 79: 351–379.
  13. Krützfeldt J. Strategies to use microRNAs as therapeutic targets. Best Pract Res Clin Endocrinol Metab. 2016; 30(5): 551–561.
  14. Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008; 456(7224): 980–984.
  15. Lorenzen JM, Schauerte C, Hübner A, et al. Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis. Eur Heart J. 2015; 36(32): 2184–2196.
  16. Gupta SK, Itagaki R, Zheng X, et al. miR-21 promotes fibrosis in an acute cardiac allograft transplantation model. Cardiovasc Res. 2016; 110(2): 215–226.
  17. Verma SK, Garikipati VNS, Krishnamurthy P, et al. Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium. Circulation. 2017; 136(10): 940–953.
  18. van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A. 2008; 105(35): 13027–13032.
  19. Boon RA, Iekushi K, Lechner S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013; 495(7439): 107–110.
  20. Huang Y, Qi Y, Du JQ, et al. MicroRNA-34a regulates cardiac fibrosis after myocardial infarction by targeting Smad4. Expert Opin Ther Targets. 2014; 18(12): 1355–1365.
  21. Jazbutyte V, Fiedler J, Kneitz S, et al. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr). 2013; 35(3): 747–762.
  22. Hong Y, Cao H, Wang Q, et al. MiR-22 may Suppress Fibrogenesis by Targeting TGFβR I in Cardiac Fibroblasts. Cell Physiol Biochem. 2016; 40(6): 1345–1353.
  23. Tao L, Bei Y, Chen P, et al. Crucial Role of miR-433 in Regulating Cardiac Fibrosis. Theranostics. 2016; 6(12): 2068–2083.
  24. Nishiga M, Horie T, Kuwabara Y, et al. MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. Circ Res. 2017; 120(5): 835–847.
  25. Johnsson P, Lipovich L, Grandér D, et al. Evolutionary conservation of long non-coding RNAs; sequence, structure, function. Biochim Biophys Acta. 2014; 1840(3): 1063–1071.
  26. Tao H, Cao W, Yang JJ, et al. Long noncoding RNA H19 controls DUSP5/ERK1/2 axis in cardiac fibroblast proliferation and fibrosis. Cardiovasc Pathol. 2016; 25(5): 381–389.
  27. Tao H, Zhang JG, Qin RH, et al. LncRNA GAS5 controls cardiac fibroblast activation and fibrosis by targeting miR-21 via PTEN/MMP-2 signaling pathway. Toxicology. 2017; 386: 11–18.
  28. Jiang XY, Ning QL. Expression profiling of long noncoding RNAs and the dynamic changes of lncRNA-NR024118 and Cdkn1c in angiotensin II-treated cardiac fibroblasts. Int J Clin Exp Pathol. 2014; 7(4): 1325–1336.
  29. Huang ZP, Ding Y, Chen J, et al. Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy. Cardiovasc Res. 2016 [Epub ahead of print].
  30. Qu X, Song X, Yuan W, et al. Expression signature of lncRNAs and their potential roles in cardiac fibrosis of post-infarct mice. Biosci Rep. 2016; 36(3).
  31. Gao J, Xu W, Wang J, et al. The Role and Molecular Mechanism of Non-Coding RNAs in Pathological Cardiac Remodeling. Int J Mol Sci. 2017; 18(3).
  32. Zhou B, Yu JW. A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-β1. Biochem Biophys Res Commun. 2017; 487(4): 769–775.
  33. Tang CM, Zhang M, Huang L, et al. CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts. Sci Rep. 2017; 7: 40342.
  34. Tolonen AM, Magga J, Szabó Z, et al. Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice. Pharmacol Res Perspect. 2014; 2(4): e00056.
  35. Wang X, Wang HX, Li YL, et al. MicroRNA Let-7i negatively regulates cardiac inflammation and fibrosis. Hypertension. 2015; 66(4): 776–785.
  36. Karakikes I, Chaanine AH, Kang S, et al. Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling. J Am Heart Assoc. 2013; 2(2): e000078.
  37. Li J, Dai Y, Su Z, et al. MicroRNA-9 inhibits high glucose-induced proliferation, differentiation and collagen accumulation of cardiac fibroblasts by down-regulation of TGFBR2. Biosci Rep. 2016; 36(6).
  38. Tijsen AJ, van der Made I, van den Hoogenhof MM, et al. The microRNA-15 family inhibits the TGFβ-pathway in the heart. Cardiovasc Res. 2014; 104(1): 61–71.
  39. Liang H, Zhang C, Ban T, et al. A novel reciprocal loop between microRNA-21 and TGFβRIII is involved in cardiac fibrosis. Int J Biochem Cell Biol. 2012; 44(12): 2152–2160.
  40. Wang J, Huang W, Xu R, et al. MicroRNA-24 regulates cardiac fibrosis after myocardial infarction. J Cell Mol Med. 2012; 16(9): 2150–2160.
  41. Wei C, Kim IK, Kumar S, et al. NF-κB mediated miR-26a regulation in cardiac fibrosis. J Cell Physiol. 2013; 228(7): 1433–1442.
  42. Abonnenc M, Nabeebaccus AA, Mayr U, et al. Extracellular matrix secretion by cardiac fibroblasts: role of microRNA-29b and microRNA-30c. Circ Res. 2013; 113(10): 1138–1147.
  43. Duisters RF, Tijsen AJ, Schroen B, et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res. 2009; 104(2): 170–8, 6p following 178.
  44. Pan Z, Sun X, Shan H, et al. MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-β1 pathway. Circulation. 2012; 126(7): 840–850.
  45. Zhao X, Wang K, Liao Y, et al. MicroRNA-101a inhibits cardiac fibrosis induced by hypoxia via targeting TGFβRI on cardiac fibroblasts. Cell Physiol Biochem. 2015; 35(1): 213–226.
  46. Beaumont J, López B, Hermida N, et al. microRNA-122 down-regulation may play a role in severe myocardial fibrosis in human aortic stenosis through TGF-β1 up-regulation. Clin Sci (Lond). 2014; 126(7): 497–506.
  47. Nagpal V, Rai R, Place AT, et al. MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis. Circulation. 2016; 133(3): 291–301.
  48. Muraoka N, Yamakawa H, Miyamoto K, et al. MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J. 2014; 33(14): 1565–1581.
  49. Castoldi G, Di Gioia CRT, Bombardi C, et al. MiR-133a regulates collagen 1A1: potential role of miR-133a in myocardial fibrosis in angiotensin II-dependent hypertension. J Cell Physiol. 2012; 227(2): 850–856.
  50. Zhao N, Koenig SN, Trask AJ, et al. MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells. Circ Res. 2015; 116(1): 23–34.
  51. Wang BW, Wu GJ, Cheng WP, et al. MicroRNA-208a increases myocardial fibrosis via endoglin in volume overloading heart. PLoS One. 2014; 9(1): e84188.
  52. Nagalingam RS, Sundaresan NR, Noor M, et al. Deficiency of cardiomyocyte-specific microRNA-378 contributes to the development of cardiac fibrosis involving a transforming growth factor β (TGFβ1)-dependent paracrine mechanism. J Biol Chem. 2014; 289(39): 27199–27214.
  53. Poller W, Dimmeler S, Heymans S, et al. Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J. 2017 [Epub ahead of print].
  54. Villar AV, García R, Merino D, et al. Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients. Int J Cardiol. 2013; 167(6): 2875–2881.
  55. Beaumont J, López B, Ravassa S, et al. MicroRNA-19b is a potential biomarker of increased myocardial collagen cross-linking in patients with aortic stenosis and heart failure. Sci Rep. 2017; 7: 40696.
  56. Roncarati R, Viviani Anselmi C, Losi MA, et al. Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2014; 63(9): 920–927.
  57. Fang Lu, Ellims AH, Moore Xl, et al. Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy. J Transl Med. 2015; 13: 314.
  58. Rubiś P, Totoń-Żurańska J, Wiśniowska-Śmiałek S, et al. Relations between circulating microRNAs (miR-21, miR-26, miR-29, miR-30 and miR-133a), extracellular matrix fibrosis and serum markers of fibrosis in dilated cardiomyopathy. Int J Cardiol. 2017; 231: 201–206.
  59. Fitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2017; 376(1): 41–51.
  60. Abba ML, Patil N, Leupold JH, et al. MicroRNAs as novel targets and tools in cancer therapy. Cancer Lett. 2017; 387: 84–94.
  61. Ramanujam D, Sassi Y, Laggerbauer B, et al. Viral Vector-Based Targeting of miR-21 in Cardiac Nonmyocyte Cells Reduces Pathologic Remodeling of the Heart. Mol Ther. 2016; 24(11): 1939–1948.