MicroRNA in cardiology –  review for clinical practice

Authors: J. Novák
Authors‘ workplace: II. interní klinika LF MU a FN U sv. Anny v Brně 1;  Fyziologický ústav, LF MU Brno 2;  Ústav patologické fyziologie, LF MU Brno 3
Published in: Kardiol Rev Int Med 2016, 18(4): 258-267


MicroRNAs (miRNAs, miRs) are small, non-coding RNA molecules that are involved in the regulation and fine-tuning of gene expression. They regulate almost all thinkable signalling pathways and thus participate in the maintenance of homeostasis. The levels of individual miRNAs are affected by various external stimuli and they also change in the presence of diseases; these changes can be detected in tissues and bodily fluids (i.e. blood or urine). One miRNA commonly regulates more signalling cascades, either interconnected or independent, and this enables us to better understand the pathophysiology of cardiovascular diseases and reveal novel targets for therapy. Moreover, the presence of miRNAs in the extracellular space makes them potentially usable as diagnostic or prognostic biomarkers of various diseases that can be employed in differential diagnostics and risk stratification of individual patients. This review article summarises basic information about miRNAs and their function. Further, selected miRNAs and their roles in the pathophysiology of some cardiovascular diseases will be described, focusing on those potentially usable in clinical practice.

microRNA – cardiology – biomarkers


1. Djebali S, Davis CA, Merkel A et al. Landscape of transcription in human cells. Nature 2012; 489(7414): 101– 108. doi: 10.1038/ nature11233.

2. Grant B. The safe-neighborhood hypothesis of junk DNA. J Theor Biol 1981; 90(1): 149– 150.

3. Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci 2016; 17(10): pii E1712.

4. Valadkhan S, Gunawardane LS. Role of small nuclear RNAs in eukaryotic gene expression. Essays Biochem 2013; 54: 79– 90. doi: 10.1042/ bse0540079.

5. Stepanov GA, Filippova JA, Komissarov AB et al. Regulatory role of small nucleolar RNAs in human diseases. Bio Med Res Int 2015; 2015: 206849. doi: 10.1155/ 2015/ 206849.

6. Iwasaki YW, Siomi MC, Siomi H. PIWI-Interact­-ing RNA: Its Biogenesis and Functions. Annu Rev Biochem 2015; 84: 405– 433. doi: 10.1146/ annurev--bio­chem-060614-034258.

7. Bartel DP. MicroRNAs: genomics, bio­genesis, mechanism, and function. Cell 2004; 116(2): 281– 297.

8. Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 2014; 42(Database issue): D68– D73. doi: 10.1093/ nar/ gkt1181.

9. Fromm B, Billipp T, Peck LE et al. A Uniform System for the Annotation of Vertebrate microRNA Genes and the Evolution of the Human micro-RNAome. Annu Rev Genet 2015; 49: 213– 242. doi: 10.1146/ annurev-genet-120213-092023.

10. Desvignes T, Batzel P, Berezikov E et al. miRNA Nomenclature: a view incorporating genetic origins, bio­synthetic pathways, and sequence variants. Trends Genet 2015; 31(11): 613– 626. doi: 10.1016/ j.tig.2015.09.002.

11. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75(5): 843– 854.

12. Pasquinelli AE, Reinhart BJ, Slack F et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000; 408(6808): 86– 89.

13. Esteller M. Non-coding RNAs in human dis­ease. Nat Rev Genet 2011; 12(12): 861– 874. doi: 10.1038/ nrg3074.

14. Lim LP, Lau NC, Garrett-Engele P et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433(7027): 769– 773.

15. Chen X, Ba Y, Ma L et al. Characterization of microRNAs in serum: a novel class of bio­markers for dia­gnosis of cancer and other diseases. Cell Res 2008; 18(10): 997– 1006. doi: 10.1038/ cr.2008.282.

16. Weber JA, Baxter DH, Zhang S et al. The microRNA spectrum in 12 body fluids. Clin Chem 2010; 56(11): 1733– 1741. doi: 10.1373/ clinchem.2010.147405.

17. Gilad S, Meiri E, Yogev Y et al. Serum microRNAs are promising novel bio­markers. PloS One 2008; 3(9): e3148. doi: 10.1371/ journal.pone.0003148.

18. Mitchell PS, Parkin RK, Kroh EM et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008; 105(30): 10513– 10518. doi: 10.1073/ pnas.0804549105.

19. Turchinovich A, Weiz L, Langheinz A et al. Characterization of extracellular circulating microRNA. Nucleic Acids Res 2011; 39(16): 7223– 7233. doi: 10.1093/ nar/ gkr254.

20. Zernecke A, Bidzhekov K, Noels H et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2009; 2(100): 81. doi: 10.1126/ scisignal.2000610.

21. Tabet F, Vickers KC, Cuesta Torres LF et al. HDL-transferred microRNA-223 regulates ICAM-1 expres­sion in endothelial cells. Nat Commun 2014; 5: 3292. doi: 10.1038/ ncomms4292.

22. Vickers KC, Palmisano BT, Shoucri BM et al. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 2011; 13(4): 423– 433. doi: 10.1038/ ncb2210.

23. Arroyo JD, Chevillet JR, Kroh EM et al. Argonaute 2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 2011; 108(12): 5003– 5008. doi: 10.1073/ pnas.1019055108.

24. Wang K, Zhang S, Weber J et al. Export of micro­RNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res 2010; 38(20): 7248– 7259. doi: 10.1093/ nar/ gkq601.

25. Kosaka N, Iguchi H, Yoshioka Y et al. Secretory mechanisms and intercellular transfer of micro­RNAs in living cells. J Biol Chem 2010; 285(23): 17442– 17452. doi: 10.1074/ jbc.M110.107821.

26. Zhu H, Fan GC. Extracellular/ circulating micro­RNAs and their potential role in cardiovascular dis­ease. Am J Cardiovasc Dis 2011; 1(2): 138– 149.

27. Valadi H, Ekström K, Bossios A et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 200; 9(6): 654– 659.

28. Bang C, Batkai S, Dangwal S et al. Cardiac fibroblast- derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 2014; 124(5): 2136– 2146. doi: 10.1172/ JCI70577.

29. Navickas R, Gal D, Laucevičius A et al. Identifying circulating microRNAs as bio­markers of cardiovascular disease: a systematic review. Cardiovasc Res 2016; 111(4): 322– 337. doi: 10.1093/ cvr/ cvw174.

30. Volný O, Kašičková L, Coufalová D et al. micro­RNAs in cerebrovascular disease. Adv Exp Med Biol 2015; 888: 155– 195. doi: 10.1007/ 978-3-319-22671-2_9.

31. Romaine SP, Charchar FJ, Samani NJ et al. Circulat­ing microRNAs and hypertension-from new in­sights into blood pressure regulation to bio­markers of cardiovascular risk. Curr Opin Pharmacol 2016; 27: 1– 7. doi: 10.1016/ j.coph.2015.12.002.

32. Nishimura Y, Kondo C, Morikawa Y et al. Plasma miR-208 as a useful bio­marker for drug-induced cardiotoxicity in rats. J Appl Toxicol 2015; 35(2): 173– 180. doi: 10.1002/ jat.3044.

33. Heggermont WA, Heymans S. MicroRNAs are involved in end-organ damage during hypertension. Hypertension 2012; 60(5): 1088– 1093. doi: 10.1161/ HYPERTENSIONAHA.111.187104.

34. Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis. Circ Res 2016; 118(4): 703– 720. doi: 10.1161/ CIRCRESAHA.115.306300.

35. Novák J, Bienertová-Vašků J, Kára T et al. Micro­RNAs involved in the lipid metabolism and their possible implications for atherosclerosis development and treatment. Mediators Inflamm 2014; 2014: 275867. doi: 10.1155/ 2014/ 275867.

36. Najafi-Shoushtari SH, Kristo F, Li Y et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010; 328(5985): 1566– 1569. doi: 10.1126/ science.1189123.

37. Allen RM, Marquart TJ, Albert CJ et al. miR-33 cont­-rols the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity. EMBO Mol Med 2012; 4(9): 882– 895. doi: 10.1002/ emmm.201201228.

38. Vickers KC, Shoucri BM, Levin MG et al. MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia. Hepatol 2013; 57(2): 533– 542. doi: 10.1002/ hep.25846.

39. Goedeke L, Rotllan N, Canfrán-Duque A et al. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med 2015 21(11): 1280– 1289. doi: 10.1038/ nm.3949.

40. Vickers KC, Landstreet SR, Levin MG et al. MicroRNA-223 coordinates cholesterol homeostasis. Proc Natl Acad Sci U S A 2014; 111(40): 14518– 14523. doi: 10.1073/ pnas.1215767111.

41. Rayner KJ, Sheedy FJ, Esau CC et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest 2011; 121(7): 2921– 2931. doi: 10.1172/ JCI57275.

42. Duell PB, Santos RD, Kirwan BA et al. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol 2016; 10(4): 1011– 1021. doi: 10.1016/ j.jacl.2016.04.013.

43. Harris TA, Yamakuchi M, Ferlito M et al. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A 2008; 105(5): 1516– 15121. doi: 10.1073/ pnas.0707493105.

44. Sun X, He S, Wara AK et al. Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice. Circ Res 2014; 114(1): 32– 40. doi: 10.1161/ CIRCRESAHA.113.302089.

45. Matsumoto S, Sakata Y, Suna S et al. Circulating p53-Responsive MicroRNAs are predictive indicators of heart failure after acute myocardial infarction short communication. Circ Res 2013; 113(3): 322– 326. doi: 10.1161/ CIRCRESAHA.113.301209.

46. Matsumoto S, Sakata Y, Nakatani D et al. A subset of circulating microRNAs are predictive for cardiac death after discharge for acute myocardial infarction. Biochem Biophys Res Commun 2012; 427(2): 280– 284. doi: 10.1016/ j.bbrc.2012.09.039.

47. He F, Lv P, Zhao X et al. Predictive value of circulating miR-328 and miR-134 for acute myocardial infarction. Mol Cell Biochem 2014; 394(1– 2): 137– 144. doi: 10.1007/ s11010-014-2089-0.

48. Devaux Y, Vausort M, McCann GP et al. A panel of 4 microRNAs facilitates the prediction of left ventricular contractility after acute myocardial infarction. PloS One 2013; 8(8): e70644. doi: 10.1371/ journal.pone.0070644.

49. Wong LL, Wang J, Liew OW et al. MicroRNA and Heart Failure. Int J Mol Sci 2016; 17(4): 502. doi: 10.3390/ ijms17040502.

50. Arora P, Wu C, Khan AM, Bloch DB et al. Atrial natriuretic peptide is negatively regulated by microRNA-425. J Clin Invest 2013; 123(8): 3378– 3382. doi: 10.1172/ JCI67383.

51. Wong LL, Wee AS, Lim JY et al. Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100. J Mol Cell Cardiol 2015; 82: 13– 21. doi: 10.1016/ j.yjmcc.2015.02.019.

52. Ceolotto G, Papparella I, Bortoluzzi A et al. Interplay between miR-155, AT1R A1166C polymorphism, and AT1R expression in young untreated hypertensives. Am J Hypertens 2011; 24(2): 241– 246. doi: 10.1038/ ajh.2010.211.

53. Vítovec J, Špinarová L, Špinar J. Sacubitril-valsartan (LCZ696) in the treatment of heart failure. Kardiol Rev Int Med 2016; 18(2): 125– 128.

54. Watson CJ, Gupta SK, O’Connell E et al. MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. Eur J Heart Fail 2015; 17(4): 405– 415. doi: 10.1002/ ejhf.244.

55. Nair N, Kumar S, Gongora E et al. Circulating miRNA as novel markers for diastolic dysfunction. Mol Cell Biochem 2013; 376(1– 2): 33– 40. doi: 10.1007/ s11010-012-1546-x.

56. Seronde MF, Vausort M, Gayat E et al. Circulat­ing microRNAs and outcome in patients with acute heart failure. PloS One 2015; 10(11): e0142237. doi: 10.1371/ journal.pone.0142237.

57. Berry GJ, Burke MM, Andersen C et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic dia­gnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 2013; 32(12): 1147– 1162. doi: 10.1016/ j.healun.2013.08.011.

58. Sukma Dewi I, Torngren K, Gidlöf O et al. Altered serum miRNA profiles during acute rejection after heart transplantation: potential for non-invasive allograft surveillance. J Heart Lung Transplant 2013; 32(4): 463– 466. doi: 10.1016/ j.healun.2012.12.007.

59. Duong Van Huyen JP, Tible M, Gay A et al. Micro­RNAs as non-invasive bio­markers of heart transplant rejection. Eur Heart J 2014; 35(45): 3194– 3202. doi: 10.1093/ eurheartj/ ehu346.

60. Riley AB, Manning WJ. Atrial fibrillation: an epidemic in the elderly. Expert Rev Cardiovasc Ther 2011; 9(8): 1081– 1090. doi: 10.1586/ erc.11.107.

61. Santulli G, Iaccarino G, De Luca N et al. Atrial fibrillation and microRNAs. Front Physiol 2014; 5: 15. doi: 10.3389/ fphys.2014.00015.

62. Girmatsion Z, Biliczki P, Bonauer A et al. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm 2009; 6(12): 1802– 1809. doi: 10.1016/ j.hrthm.2009.08.035.

63. Musa H, Carlton L, Klos M et al. Arrhythmogenesis in a novel murine model with KCNJ2 mutation of familial atrial fibrillation. Heart Rhythm 2013; 10(11): 1749. doi: 10.1016/ j.hrthm.2013.09.077.

64. Zhang Y, Sun L, Zhang Y et al. Overexpres­sion of microRNA-1 causes atrioventricular block in rodents. Int J Biol Sci 2013; 9(5): 455– 462. doi: 10.7150/ ijbs.4630.

65. Luo X, Pan Z, Shan H et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium cur­rent changes in atrial fibrillation. J Clin Invest 2013; 123(5): 1939– 1951. doi: 10.1172/ JCI62185.

66. Ling TY, Wang XL, Chai Q et al. Regulation of the SK3 channel by microRNA-499 – potential role in atrial fibrillation. Heart Rhythm 2013; 10(7): 1001– 1009. doi: 10.1016/ j.hrthm.2013.03.005.

67. Lu Y, Zhang Y, Wang N et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 2010; 122(23): 2378– 2387. doi: 10.1161/ CIRCULATIONAHA.110.958967.

68. 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– 178, 6p following 178. doi: 10.1161/ CIRCRESAHA.108.182535.

69. Dawson K, Wakili R, Ordög B et al. MicroRNA29: a mechanistic contributor and potential bio­marker in atrial fibrillation. Circulation 2013; 127(14): 1466– 1475. doi: 10.1161/ CIRCULATIONAHA.112.001207.

70. 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. doi: 10.1038/ nature07511.

71. McManus DD, Tanriverdi K, Lin H et al. Plasma microRNAs are associated with atrial fibrillation and change after catheter ablation (the miRhythm study). Heart Rhythm 2015; 12(1): 3– 10. doi: 10.1016/ j.hrthm.2014.09.050.

72. Liu T, Zhong S, Rao F et al. Catheter ablation restores decreased plasma miR-409-3p and miR-432 in atrial fibrillation patients. Europace 2016; 18(1): 92– 99. doi: 10.1093/ europace/ euu366.

73. Nemecz M, Alexandru N, Tanko G et al. Role of MicroRNA in endothelial dysfunction and hypertension. Curr Hypertens Rep 2016; 18(12): 87.

74. Klimczak D, Jazdzewski K, Kuch M. Regulatory mechanisms in arterial hypertension: role of microRNA in pathophysiology and therapy. Blood Press 2016; 13: 1– 7.

75. Boettger T, Beetz N, Kostin S et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/ 145 gene cluster. J Clin Invest 2009; 119(9): 2634– 2647. doi: 10.1172/ JCI38864.

76. Sun HX, Zeng DY, Li RT et al. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension 2012; 60(6): 1407– 1414. doi: 10.1161/ HYPERTENSIONAHA.112.197301.

77. Marques-Rocha JL, Samblas M, Milagro FI et al. Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J 2015; 29(9): 3595– 3611. doi: 10.1096/ fj.14-260323.

78. Li S, Zhu J, Zhang W et al. Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. Circulation 2011; 124(2): 175– 184. doi: 10.1161/ CIRCULATIONAHA.110.012237.

79. Nkomo VT, Gardin JM, Skelton TN et al. Burden of valvular heart diseases: a population-based study. Lancet 2006; 368(9540): 1005– 1011.

80. Oury C, Servais L, Bouznad N et al. MicroRNAs in valvular heart diseases: potential role as markers and actors of valvular and cardiac remodeling. Int J Mol Sci 2016; 17(7): pii E1120. doi: 10.3390/ ijms17071120.

81. Yanagawa B, Lovren F, Pan Y et al. miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis. J Thorac Cardiovasc Surg 2012; 144(1): 256– 262. doi: 10.1016/ j.jtcvs.2011.10.097.

82. Ohukainen P, Syväranta S, Näpänkangas J et al. MicroRNA-125b and chemokine CCL4 expression are associated with calcific aortic valve disease. Ann Med 2015; 47(5): 423– 429. doi: 10.3109/ 07853890.2015.1059955.

83. Zhang M, Liu X, Zhang X et al. MicroRNA-30b is a multifunctional regulator of aortic valve interstitial cells. J Thorac Cardiovasc Surg 2014; 147(3): 1073– 1080.e2. doi: 10.1016/ j.jtcvs.2013.05.011.

84. Varrone F, Gargano B, Carullo P et al. The circulating level of FABP3 is an indirect bio­marker of microRNA-1. J Am Coll Cardiol 2013; 61(1): 88– 95. doi: 10.1016/ j.jacc.2012.08.1003.

85. Derda AA, Thum S, Lorenzen JM et al. Blood-based microRNA signatures differentiate various forms of cardiac hypertrophy. Int J Cardiol 2015; 196: 115– 122. doi: 10.1016/ j.ijcard.2015.05.185.

86. 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. doi: 10.1016/ j.ijcard.2012.07.021.

87. Chen Z, Li C, Xu Y et al. Circulating level of miR-378 predicts left ventricular hypertrophy in patients with aortic stenosis. PloS One 2014; 9(8): e105702. doi: 10.1371/ journal.pone.0105702.

88. Røsjø H, Dahl MB, Bye A et al. Prognostic value of circulating microRNA-210 levels in patients with moderate to severe aortic stenosis. PloS One 2014; 9(3): e91812. doi: 10.1371/ journal.pone.0091812.

89. Chen YT, Wang J, Wee AS et al. Differential microRNA expression profile in myxomatous mitral valve prolapse and fibroelastic deficiency valves. Int J Mol Sci 2016; 17(5): pii: E753. doi: 10.3390/ ijms17050753.

90. Li Q, Freeman LM, Rush JE et al. Expression profiling of circulating micrornas in canine myxomatous mitral valve disease. Int J Mol Sci 2015; 16(6): 14098– 14108. doi: 10.3390/ ijms160614098.

91. Corsten M, Heggermont W, Papageorgiou AP et al. The microRNA-221/ -222 cluster balances the antiviral and inflammatory response in viral myocarditis. Eur Heart J 2015; 36(42): 2909– 29019. doi: 10.1093/ eurheartj/ ehv321.

92. Wang H, Chen F, Tong J et al. Circulating micro­-RNAs as novel bio­markers for dilated cardiomyopathy. Cardiol J. In press 2016. doi: 10.5603/ CJ.a2016.0097. [Epub ahead of print].

93. Yu M, Liang W, Xie Y et al. Circulating miR-185 might be a novel bio­marker for clinical outcome in patients with dilated cardiomyopathy. Sci Rep 2016; 6: 33580. doi: 10.1038/ srep33580.

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

Paediatric cardiology Cardiac surgery Cardiology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account