Abstract
Identification of early biomarkers of heart injury and drug-induced cardiotoxicity is important to eliminate harmful drug candidates early in preclinical development and to prevent severe drug effects. The main objective of this study was to investigate the expression of microRNAs (miRNAs) in human-induced pluripotent stem cell cardiomyocytes (hiPSC-CM) in response to a broad range of cardiotoxic drugs. Next generation sequencing was applied to hiPSC-CM treated for 72 h with 40 drugs falling into the categories of functional (i.e., ion channel blockers), structural (changes in cardiomyocytes structure), and general (causing both functional and structural) cardiotoxicants as well as non-cardiotoxic drugs. The largest changes in miRNAs expression were observed after treatments with structural or general cardiotoxicants. The number of deregulated miRNAs was the highest for idarubicin, mitoxantrone, and bortezomib treatments. RT-qPCR validation confirmed upregulation of several miRNAs across multiple treatments at therapeutically relevant concentrations: hsa-miR-187-3p, hsa-miR-146b-5p, hsa-miR-182-5p (anthracyclines); hsa-miR-365a-5p, hsa-miR-185-3p, hsa-miR-184, hsa-miR-182-5p (kinase inhibitors); hsa-miR-182-5p, hsa-miR-126-3p and hsa-miR-96-5p (common some anthracyclines, kinase inhibitors and bortezomib). Further investigations showed that an upregulation of hsa-miR-187-3p and hsa-miR-182-5p could serve as a potential biomarker of structural cardiotoxicity and/or an additional endpoint to characterize cardiac injury in vitro.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ando H, Yoshinaga T, Yamamoto W et al (2017) A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes. J Pharmacol Toxicol Methods 84:111–127. https://doi.org/10.1016/j.vascn.2016.12.003
Bailey WJ, Glaab WE (2018) Accessible miRNAs as Novel Toxicity Biomarkers. Int J Toxicol 37(2):116–120. https://doi.org/10.1177/1091581817752405
Blinova K, Dang Q, Millard D et al (2018) International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell Rep 24(13):3582–3592. https://doi.org/10.1016/j.celrep.2018.08.079
Burridge PW, Li YF, Matsa E et al (2016) Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22(5):547–556. https://doi.org/10.1038/nm.4087
Carley AN, Taegtmeyer H, Lewandowski ED (2014) Matrix revisited: mechanisms linking energy substrate metabolism to the function of the heart. Circ Res 114(4):717–729. https://doi.org/10.1161/CIRCRESAHA.114.301863
Chaudhari U, Nemade H, Gaspar JA, Hescheler J, Hengstler JG, Sachinidis A (2016) MicroRNAs as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol 90(12):3087–3098. https://doi.org/10.1007/s00204-016-1668-0
Cross MJ, Berridge BR, Clements PJ et al (2015) Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury. Br J Pharmacol 172(4):957–974. https://doi.org/10.1111/bph.12979
Damiani RM, Moura DJ, Viau CM, Caceres RA, Henriques JAP, Saffi J (2016) Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Arch Toxicol 90(9):2063–2076. https://doi.org/10.1007/s00204-016-1759-y
Deidda M, Mercurio V, Cuomo A, Noto A, Mercuro G, Cadeddu Dessalvi C (2019) Metabolomic perspectives in antiblastic cardiotoxicity and cardioprotection. Int J Mol Sci 20(19). https://doi.org/10.3390/ijms20194928
Di YF, Li DC, Shen YQ et al (2017) MiR-146b protects cardiomyocytes injury in myocardial ischemia/reperfusion by targeting Smad4. Am J Transl Res 9(2):656–663
Ektesabi AM, Mori K, Tsoporis JN et al (2021) Mesenchymal stem/stromal cells increase cardiac miR-187-3p expression in a polymicrobial animal model of sepsis. Shock 56(1):133–141. https://doi.org/10.1097/SHK.0000000000001701
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
Garcia R, Villar AV, Cobo M et al (2013) Circulating levels of miR-133a predict the regression potential of left ventricular hypertrophy after valve replacement surgery in patients with aortic stenosis. J Am Heart Assoc 2(4):e000211. https://doi.org/10.1161/JAHA.113.000211
Glineur SF, De Ron P, Hanon E, Valentin JP, Dremier S, Nogueira da Costa A (2016) Paving the route to plasma miR-208a-3p as an acute cardiac injury biomarker: preclinical rat data supports its use in drug safety assessment. Toxicol Sci 149(1):89–97. https://doi.org/10.1093/toxsci/kfv222
Holmgren G, Synnergren J, Bogestal Y et al (2015) Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology 328:102–111. https://doi.org/10.1016/j.tox.2014.12.018
Kalozoumi G, Yacoub M, Sanoudou D (2014) MicroRNAs in heart failure: small molecules with major impact. Glob Cardiol Sci Pract 2:79–102. https://doi.org/10.5339/gcsp.2014.30
Kim JS, Pak K, Goh TS et al (2018) Prognostic value of micrornas in coronary artery diseases: a meta-analysis. Yonsei Med J 59(4):495–500. https://doi.org/10.3349/ymj.2018.59.4.495
Koci B, Luerman G, Duenbostell A et al (2017) An impedance-based approach using human iPSC-derived cardiomyocytes significantly improves in vitro prediction of in vivo cardiotox liabilities. Toxicol Appl Pharmacol 329:121–127. https://doi.org/10.1016/j.taap.2017.05.023
Lamore SD, Ahlberg E, Boyer S et al (2017) Deconvoluting kinase inhibitor induced cardiotoxicity. Toxicol Sci 158(1):213–226. https://doi.org/10.1093/toxsci/kfx082
Larupa Santos J, Rodriguez I, M SO, Hjorth Bentzen B, Schmitt N (2020) Investigating gene-microRNA networks in atrial fibrillation patients with mitral valve regurgitation. PLoS One 15(5):e0232719. https://doi.org/10.1371/journal.pone.0232719
Laverty H, Benson C, Cartwright E et al (2011) How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? Br J Pharmacol 163(4):675–693. https://doi.org/10.1111/j.1476-5381.2011.01255.x
Li J, Hua Y, Miyagawa S et al (2020) hiPSC-derived cardiac tissue for disease modeling and drug discovery. Int J Mol Sci 21(23). https://doi.org/10.3390/ijms21238893
Mamoshina P, Rodriguez B, Bueno-Orovio A (2021) Toward a broader view of mechanisms of drug cardiotoxicity. Cell Rep Med 2(3):100216. https://doi.org/10.1016/j.xcrm.2021.100216
Matsumoto S, Sakata Y, Suna S et al (2013) Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. Circ Res 113(3):322–326. https://doi.org/10.1161/CIRCRESAHA.113.301209
Mirna M, Paar V, Rezar R et al (2019) MicroRNAs in inflammatory heart diseases and sepsis-induced cardiac dysfunction: a potential scope for the future? Cells 8(11). https://doi.org/10.3390/cells8111352
Mumby S, Perros F, Hui C et al (2021) Extracellular matrix degradation pathways and fatty acid metabolism regulate distinct pulmonary vascular cell types in pulmonary arterial hypertension. Pulm Circ 11(1):2045894021996190. https://doi.org/10.1177/2045894021996190
Nemade H, Chaudhari U, Acharya A et al (2018) Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol 92(4):1507–1524. https://doi.org/10.1007/s00204-018-2170-7
Nowis D, Maczewski M, Mackiewicz U et al (2010) Cardiotoxicity of the anticancer therapeutic agent bortezomib. Am J Pathol 176(6):2658–2668. https://doi.org/10.2353/ajpath.2010.090690
Palmer JA, Smith AM, Gryshkova V, Donley ELR, Valentin JP, Burrier RE (2020) A targeted metabolomics-based assay using human induced pluripotent stem cell-derived cardiomyocytes identifies structural and functional cardiotoxicity potential. Toxicol Sci 174(2):218–240. https://doi.org/10.1093/toxsci/kfaa015
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
Shi J, Abdelwahid E, Wei L (2011) Apoptosis in anthracycline cardiomyopathy. Curr Pediatr Rev 7(4):329–336. https://doi.org/10.2174/157339611796892265
Skala M, Hanouskova B, Skalova L, Matouskova P (2019) MicroRNAs in the diagnosis and prevention of drug-induced cardiotoxicity. Arch Toxicol 93(1):1–9. https://doi.org/10.1007/s00204-018-2356-z
Tantawy M, Pamittan FG, Singh S, Gong Y (2021) Epigenetic changes associated with anthracycline-induced cardiotoxicity. Clin Transl Sci 14(1):36–46. https://doi.org/10.1111/cts.12857
Vegter EL, van der Meer P, de Windt LJ, Pinto YM, Voors AA (2016) MicroRNAs in heart failure: from biomarker to target for therapy. Eur J Heart Fail 18(5):457–468. https://doi.org/10.1002/ejhf.495
Wang JX, Gao J, Ding SL et al (2015) Oxidative Modification of miR-184 Enables It to Target Bcl-xL and Bcl-w. Mol Cell 59(1):50–61. https://doi.org/10.1016/j.molcel.2015.05.003
Wang J, Dong G, Chi W, Nie Y (2021) MiR-96 promotes myocardial infarction-induced apoptosis by targeting XIAP. Biomed Pharmacother 138:111208. https://doi.org/10.1016/j.biopha.2020.111208
Weaver RJ, Valentin JP (2019) Today’s challenges to de-risk and predict drug safety in human “Mind-the-Gap”. Toxicol Sci 167(2):307–321. https://doi.org/10.1093/toxsci/kfy270
Wu H, Wang Y, Wang X, Li R, Yin D (2017) MicroRNA-365 accelerates cardiac hypertrophy by inhibiting autophagy via the modulation of Skp2 expression. Biochem Biophys Res Commun 484(2):304–310. https://doi.org/10.1016/j.bbrc.2017.01.108
Wu HB, Yang CS, Wang YC et al (2020) Proteasome inhibitor-related cardiotoxicity: mechanisms, diagnosis, and management. Curr Oncol Rep 22(7):66. https://doi.org/10.1007/s11912-020-00931-w
Wu HB, Yang CS, Wang YC (2021) The expression of miR-365 in serum of hypertension patients with left ventricular hypertrophy was up-regulated, which was positively correlated with left ventricular mass index. Pharmgenomics Pers Med 14:905–913. https://doi.org/10.2147/PGPM.S319945
Yan ZX, Wu LL, Xue K et al (2014) MicroRNA187 overexpression is related to tumor progression and determines sensitivity to bortezomib in peripheral T-cell lymphoma. Leukemia 28(4):880–887. https://doi.org/10.1038/leu.2013.291
Yang HH, Chen Y, Gao CY, Cui ZT, Yao JM (2017) Protective effects of MicroRNA-126 on human cardiac microvascular endothelial cells against hypoxia/reoxygenation-induced injury and inflammatory response by activating PI3K/Akt/eNOS signaling pathway. Cell Physiol Biochem 42(2):506–518. https://doi.org/10.1159/000477597
Yu M, Liang W, Xie Y et al (2016) Circulating miR-185 might be a novel biomarker for clinical outcome in patients with dilated cardiomyopathy. Sci Rep 6:33580. https://doi.org/10.1038/srep33580
Zhang X, Guo L, Zeng H et al (2016) Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: a tool for cardiac safety assessment. J Pharmacol Toxicol Methods 81:201–216. https://doi.org/10.1016/j.vascn.2016.06.004
Zhu L, Chen T, Ye W et al (2019) Circulating miR-182-5p and miR-5187-5p as biomarkers for the diagnosis of unprotected left main coronary artery disease. J Thorac Dis 11(5):1799–1808. https://doi.org/10.21037/jtd.2019.05.24
Acknowledgements
The present project was supported by a grant from the Walloon Region (Belgium) – DGO6 (Convention N°7245). We are thankful to Andre da Costa for his advice on miRNA profiling experiments set up and to Michael Colwell for his help with cell culture and pellet collection.
Funding
Walloon region,DGO6 (Convention N°7245),Vitalina Gryshkova
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Some of the authors are employees of UCB Biopharma and hold shares/stock options of UCB Biopharma.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Gryshkova, V., Lushbough, I., Palmer, J. et al. microRNAs signatures as potential biomarkers of structural cardiotoxicity in human-induced pluripotent stem-cell derived cardiomyocytes. Arch Toxicol 96, 2033–2047 (2022). https://doi.org/10.1007/s00204-022-03280-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-022-03280-8