ИСПОЛЬЗОВАНИЕ миРНК В КАЧЕСТВЕ ДИАГНОСТИЧЕСКИХ МАРКЕРОВ ОСТРОГО ИНФАРКТА МИОКАРДА И РЕМОДЕЛИРОВАНИЯ СЕРДЕЧНОЙ МЫШЦЫ

Cердечно-сосудистые заболевания, в частности инфаркт миокарда (ИМ), являются одной из самых распространенных причин смертности в мире. На сегодняшний день в стратегии оценки риска инфаркта и постинфарктных осложнений существенную проблему представляют чувствительность и прогностическая ценность современных методов и маркеров, поэтому выявление новых маркеров, обладающих высокой специфичностью и чувствительностью, является актуальной задачей. В последнее время большое внимание уделяется изучению внеклеточных РНК, которые относительно стабильны в биологических жидкостях и циркулируют, в том числе, в кровяном русле. В статье представлен обзор некоторых миРНК (miRNA), которые рассматриваются в качестве потенциальных маркеров для диагностики инфаркта миокарда и предсказания его неблагоприятных последствий.

инфаркт миокарда, ремоделирование миокарда, miRNA, миРНК, диагностические маркеры, РНК, экспрессия генов

1. Saleh M., Ambrose J.A. Understanding myocardial infarction // F1000Res. 2018. Vol. 7. ID 1378.

2. Mythili S., Malathi N. Diagnostic markers of acute myocardial infarction // Biomed. Rep. 2015. Vol.

3. , N 6. P. 743–748. 3. Ishii H., Amano T., Matsubara T., Murohara T. Pharmacological intervention for prevention of left ventricular remodeling and improving prognosis in myocardial infarction // Circulation. 2008. Vol. 118. P. 2710–2718.

4. Heil B., Tang W.H. Biomarkers: their potential in the diagnosis and treatment of heart failure // Cleve. Clin. J. Med. 2015. Vol. 82. P. S28–S35.

5. Daniels L.B., Laughlin G.A., Clopton P., Maisel A.S., Barrett-Connor E. Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study // J. Am. Coll. Cardiol. 2008. Vol. 52, N 6. P. 450–459.

6. Vasile V.C., Babuin L., Giannitsis E., Katus H.A., Jaffe A.S. Relationship of MRI-determined infarct size and cTnI measurements in patients with ST-elevation myocardial infarction // Clin. Chem. 2008. Vol. 54, N 3. P. 617–619.

7. Swaminathan R., Butt A.N. Circulating nucleic acids in plasma and serum: recent developments // Ann. N. Y. Acad. Sci. 2006. Vol. 1075. P. 1–9.

8. Chan K.C., Lo Y.M. Circulating nucleic acids as a tumor marker // Histol. Histopathol. 2002. Vol. 17. P. 937–943.

9. Fleischhacker M., Schmidt B. Circulating nucleic acids (CNAs) and cancer – a survey. Biochim. Biophys. Acta. 2007. Vol. 1775. P. 181–232.

10. Esteller M. Non-coding RNAs in human diseases // Nat. Rev. Genet. 2011. Vol. 12. P. 861–874.

11. Yuan T., Huang X., Woodcock M., Du M., Dittmar R., Wang Y., Tsai S., Kohli M., Boardman L., Patel T., Wang L. Plasma extracellular RNA profiles in healthy and cancer patients // Sci Rep. 2016. Vol. 6. ID 19413.

12. Melman Y.F., Shah R., Danielson K., Xiao J., Simonson B., Barth A., Chakir K., Lewis G.D., Lavender Z., Truong Q.A., Kleber A., Das R., Rosenzweig A., Wang Y., Kass D.A., Singh J.P., Das S. Circulating microRNA-30d is associated with response to cardiac resynchronization therapy in heart failure and regulates cardiomyocyte apoptosis: a translational pilot study // Circulation. 2015. Vol. 131, N 25. P. 2202–2216.

13. Dickinson B.A., Semus H.M., Montgomery R.L., Stack C., Latimer P.A., Lewton S.M., Lynch J.M., Hullinger T.G., Seto A.G., van Rooij E. Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure // Eur. J. Heart Failure. 2013. Vol. 15, N 6. P. 650–659.

14. Balaj L., Lessard R., Dai L., Cho Y.-J., Pomeroy S.L., Breakefield X.O., Skog J. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences // Nat. Commun. 2011. Vol. 2, N 1. ID 9.

15. Ohshima K., Inoue K., Fujiwara A., Hatakeyama K., Kanto K., Watanabe Y., Muramatsu K., Fukuda Y., Ogura S.-i., Yamaguchi K., Mochizuki T. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line // PloS One. 2010. Vol. 5, N 10. ID e13247.

16. Chen C., Zhou Y., Wang J., Yan Y., Peng L., Qiu W. Dysregulated microRNA involvement in multiple sclerosis by induction of T helper 17 cell differentiation // Front. Immunol. 2018. Vol. 9. ID 1256.

17. Gandhi R. miRNA in multiple sclerosis: search for novel biomarkers // Mult. Scler. J. 2015. Vol. 21, N 9. P. 1095–1103.

18. Sun T., Dong Y.H., Du W., Shi C.-Y., Wang K., Tariq M.-A., Wang J.-X., Li P.-F. The role of microRNAs in myocardial infarction: from molecular mechanism to clinical application // Int. J. Mol. Sci. 2017. Vol. 18, N. 4. ID 745.

19. O’Brien J., Hayder H., Zayed Y., Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation // Front. Endocrinol. (Lausanne). 2018. Vol. 9. ID 402.

20. Krol J., Loedige I., Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay // Nat. Rev. Genet. 2010. Vol. 11, N 9. P. 597–610.

21. Iftikhar H., Carney G.E. Evidence and potential in vivo functions for biofluid miRNAs: From expression profiling to functional testing: Potential roles of extracellular miRNAs as indicators of physiological change and as agents of intercellular information exchange // Bioessays. 2016. Vol. 38, N 4. P. 367–378. 22. Gallo A., Tandon M., Alevizos I., Illei G.G. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes // PLoS One. 2012. Vol. 7, N 3. ID e30679.

22. Vickers K.C., Palmisano B.T., Shoucri B.M., Shamburek R.D., Remaley A.T. MicroRNAs are transported in plasma and delivered to recipient cells by highdensity lipoproteins // Nat. Cell Biol. 2011. Vol. 13, N 4. P. 423–433.

23. Arroyo J.D., Chevillet J.R., Kroh E.M., Ruf I.K., Pritchard C.C., Gibson D.F., Mitchell P.S., Bennett C.F., Pogosova-Agadjanyan E.L., Stirewalt D.L., Tait J.F., Tewari M. Argonaute 2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma // Proc. Natl. Acad. Sci. U.S.A. 2011. Vol. 108, N 12. P. 5003–5008.

24. Poller W., Dimmeler S., Heymans S., Zeller T., Haas J., Karakas M., Leistner D.-M., Jakob P., Nakagawa S., Blankenberg S., Engelhardt S., Thum T., Weber C., Meder B., Hajjar R., Landmesser u. Noncoding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives // Eur. Heart J. 2018. Vol. 39, N 29. P. 2704–2716.

25. Sellers J.R. Myosins: a diverse superfamily // Biochim. Biophys. Acta. 2000. Vol. 1496, N 1. P. 3–22. 27. van Rooij E., Sutherland L.B., Qi X., Richardson J.A., Hill J., Olson E.N. Control of stress-dependent cardiac growth and gene expression by a microRNA // Science. 2007. Vol. 316, N 5824. P. 575–579.

26. Callis T.E., Pandya K., Seok H.Y., Tang R.-H., Tatsuguchi M., Huang Z.-P., Chen J.-F., Deng Z., Gunn B., Shumate J., Willis M.S., Selzman C.H., Wang D.-Z. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice // J. Clin. Invest. 2009. Vol. 119. P. 2772–2786.

27. Tony H., Meng K., Wu B., Yu A., Zeng Q., Yu K., Zhong Y. MicroRNA-208a dysregulates apoptosis genes expression and promotes cardiomyocyte apoptosis during ischemia and its silencing improves cardiac function after myocardial infarction // Mediators Inflamm. 2015. Vol. 25. ID 479123.

28. Xiao J., Shen B., Li J., Lv D., Zhao Y., Wang F., Xu J. Serum microRNA-499 and microRNA-208a as biomarkers of acute myocardial infarction // Int. J. Clin. Exp. Med. 2014. Vol. 7, N 1. P. 136–141.

29. Wang G.K., Zhu J.Q., Zhang J.-T., Li Q., Li Y., He J., Qin Y.-W., Jing Q. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans // Eur. Heart J. 2010. Vol. 31. P. 659–666.

30. D’Alessandra Y., Devanna P., Limana F., Straino S., di Carlo A., Brambilla P.G., Rubino M., Carena M.C., Spazzafumo L., de Simone M., Micheli B., Biglioli P., Achilli F., Martelli F., Maggiolini S., Marenzi G., Pompilio G., Capogrossi M.C. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction // Eur. Heart J. 2010. Vol. 31, N 22. P. 2765– 2773.

31. Han Z., Zhang L., Yuan L., Liu X., Chen X., Ye X., Yang C., Yan Z. Change of plasma microRNA-208 level in acute myocardial infarction patients and its clinical significance // Ann. Transl. Med. 2015. Vol. 3, N 20. ID 307.

32. Devaux Y., Vausort M., Goretti E., Nazarov P.V., Azuaje F., Gilson G., Corsten M.F., Schroen B., Lair M.L., Heymans S., Wagner D.R. Use of circulating microRNAs to diagnose acute myocardial infarction // Clin. Chem. 2012. Vol. 58. P. 559–567.

33. Corsten M.F., Dennert R., Jochems S., Kuznetsova T., Devaux Y., Hofstra L., Wagner D.R., Staessen J.A., Heymans S., Schroen B. Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease // Circ. Cardiovasc. Genet. 2010. Vol. 3, N 6. P. 499–506.

34. Widera C., Gupta S.K., Lorenzen J.M., Bang C., Bauersachs J., Bethmann K., Kempf T., Wollert K.C., Thum T. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome // J. Mol. Cell. Cardiol. 2011. Vol. 51. P. 872–875.

35. Gidlöf O., Andersson P., van der Pals J., Götberg M., Erlinge D. Cardiospecific microRNA plasma levels correlate with troponin and cardiac function in patients with ST elevation myocardial infarction, are selectively dependent on renal elimination, and can be detected in urine samples // Cardiology. 2011. Vol. 118, N 4. P. 217–226.

36. Liang Y., Ridzon D., Wong L., Chen C. Characterization of microRNA expression profiles in normal human tissues // BMC Genom. 2007. Vol. 8. ID 166.

37. Shieh J.T., Huang Y., Gilmore J., Srivastava D. Elevated miR-499 levels blunt the cardiac stress response // PLoS One. 2011. Vol. 6, N 5. ID e19481.

38. Adachi T., Nakanishi M., Otsuka Y., Nishimura K., Hirokawa G., Goto Y., Nonogi H., Iwai N. Plasma microRNA 499 as a biomarker of acute myocardial infarction // Clin. Chem. 2010. Vol. 56, N 7. P. 1183–1185.

39. Chen X., Zhang L., Su T., Li H., Huang Q., Wu D., Yang C., Han Z. Kinetics of plasma microRNA-499 expression in acute myocardial infarction // J. Thorac. Dis. 2015. Vol. 7, N 5. P. 890–896.

40. Shalaby S.M., El-Shal A.S., Shoukry A., Khedr M.H., Abdelraheim N. Serum miRNA-499 and miRNA-210: a potential role in early diagnosis of acute coronary syndrome // IUBMB Life. 2016. Vol. 68. P. 673–82.

41. Matkovich S.J., Wang W., Tu Y., Eschenbacher W.H., Dorn L.E., Condorelli G., Diwan A., Nerbonne J.M., Dorn G.W. MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts // Circ. Res. 2010. Vol. 106. P. 166–175.

42. Koutsoulidou A., Mastroyiannopoulos N.P., Furling D., uney J.B., Phylactou L.A. Expression of miR-1, miR133a, miR-133b and miR-206 increases during development of human skeletal muscle // BMC Dev. Biol. 2011. Vol. 11, N 1. ID 34.

43. Chen J.F., Mandel E.M., Thomson J.M., Wu Q., Callis T.E., Hammond S.M., Conlon F.L., Wang D.-Z. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation // Nat. Genet. 2006. Vol. 38, N 2. P. 228–233.

44. Townley-Tilson W.H., Callis T.E., Wang D. MicroRNAs 1, 133, and 206: Critical factors of skeletal and cardiac muscle development, function, and disease // Int. J. Biochem. Cell. Biol. 2010. Vol. 42. P. 1252– 1255.

45. Bostjancic E., Zidar N., Stajer D., Glavac D. MicroRNAs miR-1, miR-133a, miR-133b and miR-208 are dysregulated in human myocardial infarction // Cardiology. 2010. Vol. 115. P. 163–169.

46. Wang R., Li N., Zhang Y., Ran Y., Pu J. Circulating microRNAs are promising novel biomarkers of acute myocardial infarction // Intern. Med. 2011. Vol. 50. P. 1789–1795.

47. Ai J., Zhang R., Li Y., Pu J., Lu Y., Jiao J., Li K., Yu B., Li Z., Wang R., Wang L., Li Q., Wang N., Shan H., Li Z., Yang B. Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction // Biochem. Biophys. Res. Commun. 2010. Vol. 391. P. 73–77.

48. Сheng Y., Tan N., Yang J., Liu X., Cao X., He P., Dong X., Qin S., Zhang C. A translational study of circulating cell-free microRNA-1 in acute myocardial infarction // Clin. Sci. (Lond). 2010. Vol. 119. P. 87–95.

49. Li Y.Q., Zhang M.F., Wen H.Y., Hu C.L., Liu R., Wei H.Y., Ai C.M., Wang G., Liao X.X., Li X. Comparing the diagnostic values of circulating microRNAs and cardiac troponin T in patients with acute myocardial infarction // Clinics (Sao Paulo). 2013. Vol. 68, N 1. P. 75–80.

50. Eitel I., Adams V., Dieterich P., Fuernau G., de Waha S., Desch S., Schuler G., Thiele H. Relation of circulating microRNA-133a concentrations with myocardial damage and clinical prognosis in ST-elevation myocardial infarction // Am. Heart J. 2012. Vol. 164. P. 706–714.

51. Cheng C., Wang Q., You W., Chen M., Xia J. MiRNAs as biomarkers of myocardial infarction: a metaanalysis // PLoS One. 2014. Vol. 9, N 2. ID e88566.

52. Wang Q., Ma J., Jiang Z., Wu F., Ping J., Ming L. Identification of microRNAs as diagnostic biomarkers for acute myocardial infarction in Asian populations. A systematic review and meta-analysis // Medicine (Baltimore). 2017. Vol. 96, N. 24. ID e7173.

53. Zhu L., Liu F., Xie H., Feng J. Diagnostic performance of microRNA-133a in acute myocardial infarction: A meta-analysis // Cardiol. J. 2018. Vol. 25, N 2. P. 260–267.

54. Zhang W.Q., Xie B.Q. A meta-analysis of the relations between blood microRNA-208b detection and acute myocardial infarction // Eur. Rev. Med. Pharmacol. Sci. 2017. Vol. 21. P. 848–854.

55. Coskunpinar E., Cakmak H.A., Kalkan A.K., Tiryakioglu N.O., Erturk M., Ongen Z. Circulating miR221-3p as a novel marker for early prediction of acute myocardial infarction // Gene. 2016. Vol. 591, N 1. P. 90–96.

56. Guo M.L., Guo L.L., Weng Y.Q. Implication of peripheral blood miRNA-124 in predicting acute myocardial infarction // Eur. Rev. Med. Pharmacol. Sci. 2017. Vol. 21. P. 1054–1059.

57. Ren X.P., Wu J., Wang X., Sartor M.A., Qian J., Jones K., Nicolaou P., Pritchard T.J., Fan G.-C. MicroRNA-320 is involved in the regulation of cardiac ischemia/reperfusion injury by targeting heat-shock protein 20 // Circulation. 2009. Vol. 119, N 17. P. 2357–2366.

58. Loyer X., Potteaux S., Vion A.-C., Guérin C.L., Boulkroun S., Rautou P.-E., Ramkhelawon B., Esposito B., Dalloz M., Paul J.-L., Julia P., Maccario J., Boulanger C.M., Mallat Z., Tedgui A. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice // Circ. Res. 2014. Vol. 114, N 3. P. 434–443.

59. Bonauer A., Carmona G., Iwasaki M., Mione M., Koyanagi M., Fischer A., Burchfield J., Fox H., Doebele C., Ohtani K., Chavakis E., Potente M., Tjwa M., urbich C., Zeiher A.M., Dimmeler S. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice // Science. 2009. Vol. 324, N 5935. P. 1710–1713.

60. Nomura S. Microparticle and atherothrombotic diseases // J. Atheroscler. Thromb. 2016. Vol. 23, N 1. P. 1–9.

61. Zhang Y., Cheng J., Chen F., Wu C., Zhang J., Ren X., Pan Y., Nie B., Li Q., Li Y. Circulating endothelial microparticles and miR-92a in acute myocardial infarction // Biosci. Rep. 2017. Vol. 37, N 2. pii BSR20170047.

62. van Rooij E., Sutherland L.B., Thatcher J.E., DiMaio J.M., Naseem R.H., Marshall W.S., Hill J.A., Olson E.N. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis // Proc. Natl. Acad. Sci. U.S.A. 2008. Vol. 105. P. 13027–13032.

63. Liu X., Xu Y., Deng Y., Li H. MicroRNA-223 regulates cardiac fibrosis after myocardial infarction by targeting RASA1 // Cell. Physiol. Biochem. 2018. Vol. 46, N 4. P. 1439–1454.

64. Zhang J., Xing Q., Zhou X., Li J., Li Y., Zhang L., Zhou Q., Tang B. Circulating miRNA-21 is a promising biomarker for heart failure // Mol. Med. Rep. 2017. Vol. 16, N 5. P. 7766–7774.

65. Zhang Y., Liu Y.J., Liu T., Zhang H., Yang S.J. Plasma microRNA-21 is a potential diagnostic biomarker of acute myocardial infarction // Eur. Rev. Med. Pharmacol. Sci. 2016. Vol. 20, N 2. P. 323–329.

66. Song Y., Zhang C., Zhang J., Jiao Z., Dong N., Wang G., Wang Z., Wang L. Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction // Theranostics. 2019. Vol. 9, N 8. P. 2346–2360.

67. Li N., Rochette L., Rosenblatt-Velin N. Heart regeneration after myocardial infarction: the role of microRNAs // Non-coding RNA Investigation. 2018. Vol. 2, N 5. ID 26.

68. Heusch G., Libby P., Gersh B., Yellon D., Böhm M., Lopaschuk G., Opie L. Cardiovascular remodelling in coronary artery disease and heart failure // Lancet. 2014 Vol. 383. P. 1933–1943.

69. Abbate A., Kontos M.C., Abouzaki N.A., Melchior R.D., Thomas C., van Tassell B.W., Oddi C., Carbone S., Trankle C.R., Roberts C.S., Mueller G.H., Gambill M.L., Christopher S., Markley R., Vetrovec G.W., Dinarello C.A., Biondi-Zoccai G. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies) // Am. J. Cardiol. 2015. Vol. 115. P. 288–292.

70. Talwar S., Squire I.B., Downie P.F., McCullough A.M., Campton M.C., Davies J.E., Barnett D.B., Ng L.L. Profile of plasma N-terminal proBNP following acutemyocardial infarction; correlation with left ventricular systolic dysfunction // Eur. Heart J. 2000. Vol. 21. P. 1514–1521.

71. Sanders-van Wijk S., van Empel V., Davarzani N., Maeder M.T., Handschin R., Pfisterer M.E., Brunner-La Rocca H.P. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction // Eur. J. Heart Fail. 2015. Vol. 17. P. 1006–1014. 74. Burchfield J.S., Xie M., Hill J.A. Pathological ventricular remodeling: mechanisms: part 1 of 2 // Circulation. 2013. Vol. 128. P. 388–400.

72. Anzai T. Post-infarction inflammation and left ventricular remodeling: a double-edged sword // Circ. J. 2013. Vol. 77. P. 580–587.

73. Gupta S., Chatterjee P. Role of non-coding RNA in cardiac remodeling // Non-coding RNA Investigation. 2019. Vol. 3. ID 12.

74. Shah R., Ziegler O., Yeri A., Liu X., Murthy V., Rabideau D., Xiao C.Y., Hanspers K., Belcher A., Tackett M., Rosenzweig A., Pico A.R., Januzzi J.L., Das S. MicroRNAs associated with reverse left ventricular remodeling in humans identify pathways of heart failure progression // Circ. Heart Fail. 2018. Vol. 11. ID e004278.

75. Danielson K.M., Shah R., Yeri A., Liu X., Camacho Garcia F., Silverman M., Tanriverdi K., Das A., Xiao C., Jerosch-Herold M., Heydari B., Abbasi S., Van Keuren-Jensen K., Freedman J.E., Wang Y.E., Rosenzweig A., Kwong R.Y., Das S. Plasma circulating extracellular RNAs in left ventricular remodeling post-myocardial infarction // EBio Medicine. 2018. Vol. 32. P. 172–181.