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MicroRNAs in the diagnosis and prevention of drug-induced cardiotoxicity

  • Mikuláš Skála
  • Barbora Hanousková
  • Lenka Skálová
  • Petra MatouškováEmail author
Review Article
  • 200 Downloads

Abstract

Drug-induced cardiotoxicity is a serious problem associated with the administration of many drugs. MicroRNAs (miRNAs) have been reported to be affected by drugs and other xenobiotics, and the potential of miRNAs as biomarkers and diagnostic tools has been considered. In recent years, an association of certain miRNAs with the cardiotoxicity of some drugs, namely anthracyclines, bevacizumab, cyclosporine A and isoprenaline, has already been found. This review article summarizes available information about the changes in miRNA levels induced by cardiotoxic drugs. Three aspects are discussed: the altered expression of miRNAs in the heart upon treatment with cardiotoxic drugs, circulating miRNAs as promising early biomarkers of cardiotoxicity, and the potential of miRNAs in the prevention and/or attenuation of drug-induced cardiotoxicity. The targeted changes in the level of certain miRNAs by antagomiRs and miRNA mimics are also described and evaluated. In addition, the cardioprotective mechanism of various natural compounds via their effect on miRNA levels are examined.

Keywords

Cardiotoxicity Circulating microRNA Biomarkers Doxorubicin 

Notes

Acknowledgements

This project was supported by the Grant Agency of Charles University, Grant no. 814316 and by the Charles University in Prague (Research Project SVV 260 416). This work was supported by the project EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) and co-funded by ERDF.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Bellin M, Mummery CL (2016) The cancer’s gone, but did chemotherapy damage your heart? Nat Rev Cardiol 13(7):383–384.  https://doi.org/10.1038/nrcardio.2016.88 CrossRefPubMedGoogle Scholar
  2. Bernardo BC, Nguyen SS, Winbanks CE et al (2014) Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy. FASEB J 28(12):5097–5110.  https://doi.org/10.1096/fj.14-253856 CrossRefPubMedGoogle Scholar
  3. Calvano J, Achanzar W, Murphy B et al (2016) Evaluation of microRNAs-208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats. Toxicol Appl Pharmacol 312:53–60.  https://doi.org/10.1016/j.taap.2015.11.015 CrossRefPubMedGoogle Scholar
  4. Cardinale D, Biasillo G, Cipolla CM (2016) Curing cancer, saving the heart: a challenge that cardioncology should not miss. Curr Cardiol Rep 18(6):51.  https://doi.org/10.1007/s11886-016-0731-z CrossRefPubMedGoogle Scholar
  5. Cheng YH, Tan N, Yang JA et al (2010) A translational study of circulating cell-free microRNA-1 in acute myocardial infarction. Clin Sci 119(1–2):87–95.  https://doi.org/10.1042/cs20090645 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Creemers EE, Tijsen AJ, Pinto YM (2012) Circulating microRNAs novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 110(3):483–495.  https://doi.org/10.1161/circresaha.111.247452 CrossRefPubMedGoogle Scholar
  7. Desai VG, Kwekel JC, Vijay V et al (2014) Early biomarkers of doxorubicin-induced heart injury in a mouse model. Toxicol Appl Pharmacol 281(2):221–229.  https://doi.org/10.1016/j.taap.2014.10.006 CrossRefPubMedGoogle Scholar
  8. Devaux Y, Vausort M, Goretti E et al (2012) Use of circulating microRNAs to diagnose acute myocardial infarction. Clin Chem 58(3):559–567.  https://doi.org/10.1373/clinchem.2011.173823 CrossRefPubMedGoogle Scholar
  9. Doka G, Malikova E, Galkova K et al (2017) Downregulation of myogenic microRNAs in sub-chronic but not in sub-acute model of daunorubicin-induced cardiomyopathy. Mol Cell Biochem 432(1–2):79–89.  https://doi.org/10.1007/s11010-017-2999-8 CrossRefPubMedGoogle Scholar
  10. Duan QL, Yang L, Gong W et al (2015) MicroRNA-214 is upregulated in heart failure patients and suppresses XBP1-mediated endothelial cells angiogenesis. J Cell Physiol 230(8):1964–1973.  https://doi.org/10.1002/jcp.24942 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Esteller M (2011) Non-coding RNAs in human disease. Nat Rev Genet 12(12):861–874.  https://doi.org/10.1038/nrg3074 CrossRefPubMedGoogle Scholar
  12. Farias JG, Molina VM, Carrasco RA et al (2017) Antioxidant therapeutic strategies for cardiovascular conditions associated with oxidative stress. Nutrients 9(9)  https://doi.org/10.3390/nu9090966 CrossRefGoogle Scholar
  13. Ferri N, Siegl P, Corsini A, Herrmann J, Lerman A, Benghozi R (2013) Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity. Pharmacol Ther 138(3):470–484.  https://doi.org/10.1016/j.pharmthera.2013.03.005 CrossRefPubMedGoogle Scholar
  14. Fu J, Peng CK, Wang WY, Jin HF, Tang QQ, Wei XT (2012) Let-7g is involved in doxorubicin induced myocardial injury. Environ Toxicol Pharmacol 33(2):312–317.  https://doi.org/10.1016/j.etap.2011.12.023 CrossRefPubMedGoogle Scholar
  15. Fu BC, Lang JL, Zhang DY et al (2017) Suppression of miR-34a expression in the myocardium protects against ischemia-reperfusion injury through SIRT1 protective pathway. Stem Cells Dev 26(17):1270–1282.  https://doi.org/10.1089/scd.2017.0062 CrossRefPubMedGoogle Scholar
  16. Harrill AH, McCullough SD, Wood CE, Kahle JJ, Chorley BN (2016) MicroRNA biomarkers of toxicity in biological matrices. Toxicol Sci 152(2):264–272.  https://doi.org/10.1093/toxsci/kfw090 CrossRefPubMedGoogle Scholar
  17. Holmgren G, Synnergren J, Andersson CX, Lindahl A, Sartipy P (2016) MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity. Toxicol In Vitro 34:26–34.  https://doi.org/10.1016/j.tiv.2016.03.009 CrossRefPubMedGoogle Scholar
  18. Horie T, Ono K, Nishi H et al (2010) Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. Cardiovasc Res 87(4):656–664.  https://doi.org/10.1093/cvr/cvq148 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Jain A, Rani V (2018) Anti-hypotensive drug induced cardiotoxicity: an in vitro study. In Vitro Cell Dev Biol Anim 54(2):92–98.  https://doi.org/10.1007/s11626-017-0222-6 CrossRefPubMedGoogle Scholar
  20. Koturbash I, Tolleson WH, Guo L et al (2015) microRNAs as pharmacogenomic biomarkers for drug efficacy and drug safety assessment. Biomark Med 9(11):1153–1176.  https://doi.org/10.2217/bmm.15.89 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Krauskopf J, Verheijen M, Kleinjans JC, de Kok TM, Caiment F (2015) Development and regulatory application of microRNA biomarkers. Biomark Med 9(11):1137–1151.  https://doi.org/10.2217/bmm.15.50 CrossRefPubMedGoogle Scholar
  22. Kuwabara Y, Ono K, Horie T et al (2011) Increased MicroRNA-1 and MicroRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet 4(4):446–454.  https://doi.org/10.1161/circgenetics.110.958975 CrossRefPubMedGoogle Scholar
  23. Leger KJ, Leonard D, Nielson D, de Lemos JA, Mammen PPA, Winick NJ (2017) Circulating microRNAs: potential markers of cardiotoxicity in children and young adults treated with anthracycline chemotherapy. J Am Heart Assoc 6(4):e004653.  https://doi.org/10.1161/jaha.116.004653 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Li JZ, Tang XN, Li TT et al (2016) Paeoniflorin inhibits doxorubicin-induced cardiomyocyte apoptosis by downregulating microRNA-1 expression. Exp Ther Med 11(6):2407–2412.  https://doi.org/10.3892/etm.2016.3182 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Liu L, Aguirre SA, Evering WEN et al (2014) miR-208a as a biomarker of isoproterenol-induced cardiac injury in Sod2(+/−) and C57BL/6J wild-type mice. Toxicol Pathol 42(7):1117–1129.  https://doi.org/10.1177/0192623314525684 CrossRefPubMedGoogle Scholar
  26. Liu L, Ning BB, Cui JG, Zhang T, Chen Y (2017) miR-29c is implicated in the cardioprotective activity of Panax notoginseng saponins against isoproterenol-induced myocardial fibrogenesis. J Ethnopharmacol 198:1–4.  https://doi.org/10.1016/j.jep.2016.12.036 CrossRefPubMedGoogle Scholar
  27. Ludwig N, Leidinger P, Becker K et al (2016) Distribution of miRNA expression across human tissues. Nucleic Acids Res 44(8):3865–3877.  https://doi.org/10.1093/nar/gkw116 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Madonna R (2017) Early diagnosis and prediction of anticancer drug-induced cardiotoxicity: from cardiac imaging to “Omics” technologies. Rev Espanol Cardiol 70(7):576–582.  https://doi.org/10.1016/j.recesp.2016.12.032 CrossRefGoogle Scholar
  29. Marques FZ, Vizi D, Khammy O, Mariani JA, Kaye DM (2016) The transcardiac gradient of cardio-microRNAs in the failing heart. Eur J Heart Fail 18(8):1000–1008.  https://doi.org/10.1002/ejhf.517 CrossRefPubMedGoogle Scholar
  30. Marrone AK, Beland FA, Pogribny IP (2015) The role for microRNAs in drug toxicity and in safety assessment. Expert Opin Drug Metab Toxicol 11(4):601–611.  https://doi.org/10.1517/17425255.2015.1021687 CrossRefPubMedGoogle Scholar
  31. McCubrey JA, Lertpiriyapong K, Steelman LS et al (2017) Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging-US 9(6):1477–1536.  https://doi.org/10.18632/aging.101250 CrossRefGoogle Scholar
  32. Mikaelian I, Scicchitano M, Mendes O, Thomas RA, LeRoy BE (2013) Frontiers in preclinical safety biomarkers: microRNAs and messenger RNAs. Toxicol Pathol 41(1):18–31.  https://doi.org/10.1177/0192623312448939 CrossRefPubMedGoogle Scholar
  33. Min PK, Chan SY (2015) The biology of circulating microRNAs in cardiovascular disease. Eur J Clin Investig 45(8):860–874.  https://doi.org/10.1111/eci.12475 CrossRefGoogle Scholar
  34. Min AJ, Zhu C, Peng SP, Rajthala S, Costea DE, Sapkota D (2015) MicroRNAs as important players and biomarkers in oral carcinogenesis. Biomed Res Int.  https://doi.org/10.1155/2015/186904 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Montgomery RL, Hullinger TG, Semus HM et al (2011) Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124(14):1537–1547.  https://doi.org/10.1161/circulationaha.111.030932 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Moutinho C, Esteller M (2017) MicroRNAs and epigenetics. In: Croce CM, Fisher PB (eds) Mirna and cancer. Advances in Cancer Research, vol 135, pp 189–220Google Scholar
  37. Ning BB, Zhang Y, Wu DD et al (2017) Luteolin-7-diglucuronide attenuates isoproterenol-induced myocardial injury and fibrosis in mice. Acta Pharmacol Sin 38(3):331–341.  https://doi.org/10.1038/aps.2016.142 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Nishimura Y, Kondo C, Morikawa Y et al (2015) Plasma miR-208 as a useful biomarker for drug-induced cardiotoxicity in rats. J Appl Toxicol 35(2):173–180.  https://doi.org/10.1002/jat.3044 CrossRefPubMedGoogle Scholar
  39. Novak J, Sana J, Stracina T, Novakova M, Slaby O (2017) Doxorubicin and liposomal doxorubicin differentially affect expression of miR-208a and let-7g in rat ventricles and atria. Cardiovasc Toxicol 17(3):355–359.  https://doi.org/10.1007/s12012-016-9393-8 CrossRefPubMedGoogle Scholar
  40. Oliveira-Carvalho V, Ferreira LRP, Bocchi EA (2015) Circulating mir-208a fails as a biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. J Appl Toxicol 35(9):1071–1072.  https://doi.org/10.1002/jat.3185 CrossRefPubMedGoogle Scholar
  41. Page RL, O’Bryant CL, Cheng D et al (2016) Drugs that may cause or exacerbate heart failure a scientific statement from the American Heart Association. Circulation 134(6):E32–E69.  https://doi.org/10.1161/cir.0000000000000426 CrossRefPubMedGoogle Scholar
  42. Piegari E, Russo R, Cappetta D et al (2016) MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat. Oncotarget 7(38):62312–62326.  https://doi.org/10.18632/oncotarget.11468 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rainer PP, Doleschal B, Kirk JA et al (2012) Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes. BJU Int 110(10):1455–1462.  https://doi.org/10.1111/j.1464-410X.2012.11134.x CrossRefPubMedGoogle Scholar
  44. Rigaud VOC, Ferreira LRP, Ayub-Ferreira SM et al (2017) Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. Oncotarget 8(4):6994–7002.  https://doi.org/10.18632/oncotarget.14355 CrossRefPubMedGoogle Scholar
  45. Roca-Alonso L, Castellano L, Mills A et al (2015) Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in beta-adrenergic signaling and enhances apoptosis. Cell Death Disease.  https://doi.org/10.1038/cddis.2015.89 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Romaine SPR, Tomaszewski M, Condorelli G, Samani NJ (2015) MicroRNAs in cardiovascular disease: an introduction for clinicians. Heart 101(12):921–928.  https://doi.org/10.1136/heartjnl-2013-305402 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Rotini A, Martinez-Sarra E, Pozzo E, Sarripaolesi M (2018) Interactions between microRNAs and long non-coding RNAs in cardiac development and repair. Pharmacol Res 157:58–66.  https://doi.org/10.1016/j.phrs.2017.05.029 CrossRefGoogle Scholar
  48. Ruggeri C, Gioffre S, Achilli F, Colombo GI, D’Alessandra Y (2018) Role of microRNAs in doxorubicin-induced cardiotoxicity: an overview of preclinical models and cancer patients. Heart Fail Rev 23(1):109–122.  https://doi.org/10.1007/s10741-017-9653-0 CrossRefPubMedGoogle Scholar
  49. Sayed ASM, Xia K, Salma U, Yang TL, Peng J (2014) Diagnosis, prognosis and therapeutic role of circulating miRNAs in cardiovascular diseases. Heart Lung Circ 23(6):503–510.  https://doi.org/10.1016/j.hlc.2014.01.001 CrossRefPubMedGoogle Scholar
  50. Singh BK, Haque SE, Pillai KK (2014) Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity. Expert Opin Drug Metab Toxicol 10(2):143–156.  https://doi.org/10.1517/17425255.2014.856881 CrossRefPubMedGoogle Scholar
  51. Slordal L, Spigset O (2006) Heart failure induced by non-cardiac drugs. Drug Saf 29(7):567–586CrossRefGoogle Scholar
  52. Sun M, Yu HY, Zhang YY, Li ZJ, Gao W (2015) MicroRNA-214 mediates isoproterenol-induced proliferation and collagen synthesis in cardiac fibroblasts. Sci Rep.  https://doi.org/10.1038/srep18351 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Tabernero J, Brana I (2011) Cardiotoxicity induced by anticancer drugs. EJHP Pract 17(6):5–7Google Scholar
  54. Thum T, Catalucci D, Bauersachs J (2008) MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res 79(4):562–570.  https://doi.org/10.1093/cvr/cvn137 CrossRefPubMedGoogle Scholar
  55. Todorova VK, Makhoul I, Wei JN, Klimberg VS (2017) Circulating miRNA profiles of doxorubicin-induced cardiotoxicity in breast cancer patients. Ann Clin Lab Sci 47(2):115–119PubMedGoogle Scholar
  56. Tong ZY, Jiang BM, Wu YY et al (2015) MiR-21 protected cardiomyocytes against doxorubicin-induced apoptosis by targeting BTG2. Int J Mol Sci 16(7):14511–14525.  https://doi.org/10.3390/ijms160714511 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Tony H, Yu KW, Zeng QT (2015) MicroRNA-208a silencing attenuates doxorubicin induced myocyte apoptosis and cardiac dysfunction. Oxid Med Cell Longev.  https://doi.org/10.1155/2015/597032 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tu YF, Wan L, Zhao DL et al (2014) In vitro and in vivo direct monitoring of miRNA-22 expression in isoproterenol-induced cardiac hypertrophy by bioluminescence imaging. Eur J Nucl Med Mol Imaging 41(5):972–984.  https://doi.org/10.1007/s00259-013-2596-3 CrossRefPubMedGoogle Scholar
  59. Ucar A, Gupta SK, Fiedler J et al (2012) The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun.  https://doi.org/10.1038/ncomms2090 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Vacchi-Suzzi C, Bauer Y, Berridge BR et al (2012) Perturbation of microRNAs in rat heart during chronic doxorubicin treatment. PLos One.  https://doi.org/10.1371/journal.pone.0040395 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Varga ZV, Ferdinandy P, Liaudet L, Pacher P (2015) Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol 309(9):H1453–H1467.  https://doi.org/10.1152/ajpheart.00554.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Viereck J, Thum T (2017) Circulating noncoding RNAs as biomarkers of cardiovascular disease and injury. Circ Res 120(2):381–399.  https://doi.org/10.1161/circresaha.116.308434 CrossRefPubMedGoogle Scholar
  63. Wang Y, Li M, Xu L et al (2017) Expression of Bcl-2 and microRNAs in cardiac tissues of patients with dilated cardiomyopathy. Mol Med Rep 15(1):359–365.  https://doi.org/10.3892/mmr.2016.5977 CrossRefPubMedGoogle Scholar
  64. Yang QB, Cui JG, Wang PW et al (2016) Changes in interconnected pathways implicating microRNAs are associated with the activity of apocynin in attenuating myocardial fibrogenesis. Eur J Pharmacol 784:22–32.  https://doi.org/10.1016/j.ejphar.2016.05.007 CrossRefPubMedGoogle Scholar
  65. Yin ZW, Zhao YR, Li HP et al (2016) miR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway. Aging-US 8(1):192–207.  https://doi.org/10.18632/aging.100876 CrossRefGoogle Scholar
  66. Yokoi T, Nakajima M (2013) microRNAs as mediators of drug toxicity. In: Insel PA (ed) Annual review of pharmacology and toxicology, vol 53, p 377–400CrossRefGoogle Scholar
  67. Zhang WQ, Chang H, Zhang HX, Zhang L (2017) MiR-30e attenuates isoproterenol-induced cardiac fibrosis through suppressing snail/TGF-beta signaling. J Cardiovasc Pharmacol 70(6):362–368PubMedPubMedCentralGoogle Scholar
  68. Zhao ZY, He J, Zhang J et al (2014) Dysregulated miR1254 and miR579 for cardiotoxicity in patients treated with bevacizumab in colorectal cancer. Tumor Biol 35(6):5227–5235.  https://doi.org/10.1007/s13277-014-1679-5 CrossRefGoogle Scholar
  69. Zhu XD, Chi JY, Liang HH et al (2016) MicroRNA-377 mediates cardiomyocyte apoptosis induced by cyclosporin A. Can J Cardiol 32(10):1249–1259.  https://doi.org/10.1016/j.cjca.2015.11.012 CrossRefPubMedGoogle Scholar
  70. Zhu JN, Fu YH, Hu ZQ et al (2017a) Activation of miR-34a-5p/Sirt1/p66shc pathway contributes to doxorubicin-induced cardiotoxicity. Sci Rep.  https://doi.org/10.1038/s41598-017-12192-y CrossRefPubMedPubMedCentralGoogle Scholar
  71. Zhu ML, Yin YL, Ping S et al (2017b) Berberine promotes ischemia-induced angiogenesis in mice heart via upregulation of microRNA-29b. Clin Exp Hypertens 39(7):672–679.  https://doi.org/10.1080/10641963.2017.1313853 CrossRefPubMedGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of Medicine in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
  2. 2.Department of PulmologyUniversity Hospital in Hradec KrálovéHradec KrálovéCzech Republic
  3. 3.Faculty of PharmacyCharles UniversityHradec KrálovéCzech Republic

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