Background: Anthracycline cardiotoxicity is a well-known complication of cancer treatment, and miRNAs have emerged as a key driver in the pathogenesis of cardiovascular diseases. This study aimed to investigate the expression of miRNAs in the myocardium in early and late stages of chronic anthracycline induced cardiotoxicity to determine whether this expression is associated with the severity of cardiac damage. Method: Cardiotoxicity was induced in rabbits via daunorubicin administration (daunorubicin, 3 mg/kg/week; for five and 10 weeks), while the control group received saline solution. Myocardial miRNA expression was first screened using TaqMan Advanced miRNA microfluidic card assays, after which 32 miRNAs were selected for targeted analysis using qRT-PCR. Results: The first subclinical signs of cardiotoxicity (significant increase in plasma cardiac troponin T) were observed after 5 weeks of daunorubicin treatment. At this time point, 10 miRNAs (including members of the miRNA-34 and 21 families) showed significant upregulation relative to the control group, with the most intense change observed for miRNA-1298-5p (29-fold change, p < 0.01). After 10 weeks of daunorubicin treatment, when a further rise in cTnT was accompanied by significant left ventricle systolic dysfunction, only miR-504-5p was significantly (p < 0.01) downregulated, whereas 10 miRNAs were significantly upregulated relative to the control group; at this time-point, the most intense change was observed for miR-34a-5p (76-fold change). Strong correlations were found between the expression of multiple miRNAs (including miR-34 and mir-21 family and miR-1298-5p) and quantitative indices of toxic damage in both the early and late phases of cardiotoxicity development. Furthermore, plasma levels of miR-34a-5p were strongly correlated with the myocardial expression of this miRNA. Conclusion: To the best of our knowledge, this is the first study that describes alterations in miRNA expression in the myocardium during the transition from subclinical, ANT-induced cardiotoxicity to an overt cardiotoxic phenotype; we also revealed how these changes in miRNA expression are strongly correlated with quantitative markers of cardiotoxicity.

Department of Clinical Biochemistry and Diagnostics Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove Hradec Kralove Czechia

Department of Histology and Embryology Charles University Prague Hradec Kralove Czechia

Department of Pharmacology Hradec Kralove Czechia

Department of Physiology Hradec Kralove Czechia

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Adamcová M., Geršl V., Hrdina R., Mělka M., Mazurová Y., Vávrová J., et al. (1999). Cardiac troponin T as a marker of myocardial damage caused by antineoplastic drugs in rabbits. J. Cancer Res. Clin. Oncol. 125 (5), 268–274. 10.1007/s004320050273 PubMed DOI

Adamcova M., Kawano I., Simko F. (2021). The impact of microRNAs in renin–angiotensin-system-induced cardiac remodelling. Int. J. Mol. Sci. 22, 4762. 10.3390/ijms22094762 PubMed DOI PMC

Adamcova M., Lencova-Popelova O., Jirkovsky E., Mazurova Y., Palicka V., Simko F., et al. (2015). Experimental determination of diagnostic window of cardiac troponins in the development of chronic anthracycline cardiotoxicity and estimation of its predictive value. Int. J. Cardiol. 15 (201), 358–367. 10.1016/j.ijcard.2015.07.103 PubMed DOI

Alves M. T., da Conceição I. M. C. A., de Oliveira A. N., Oliveira H. H. M., Soares C. E., de Paula Sabino A., et al. (2022). microRNA miR-133a as a biomarker for doxorubicin-induced cardiotoxicity in women with breast cancer: a signaling pathway investigation. Cardiovasc Toxicol. 22, 655–662. 10.1007/s12012-022-09748-4 PubMed DOI

Bartel D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297. 10.1016/S0092-8674(04)00045-5 PubMed DOI

Barwari T., Joshi A., Mayr M. (2016). MicroRNAs in cardiovascular disease. J. Am. Coll. Cardiol. 68, 2577–2584. 10.1016/j.jacc.2016.09.945 PubMed DOI

Bidwell P. A., Haghighi K., Kranias E. G. (2018). The antiapoptotic protein HAX-1 mediates half of phospholamban’s inhibitory activity on calcium cycling and contractility in the heart. J. Biol. Chem. 293, 359–367. 10.1074/jbc.RA117.000128 PubMed DOI PMC

Brown C., Mantzaris M., Nicolaou E., Karanasiou G., Papageorgiou E., Curigliano G., et al. (2022). A systematic review of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients reveals potentially clinically informative panels as well as key challenges in miRNA research. Cardio-Oncology 8, 16. 10.1186/s40959-022-00142-1 PubMed DOI PMC

Capaccia C., Diverio S., Zampini D., Guelfi G. (2022). The complex interaction between P53 and miRNAs joins new awareness in physiological stress responses. Cells 11, 1631. 10.3390/cells11101631 PubMed DOI PMC

Chaudhari U., Nemade H., Gaspar J. A., Hescheler J., Hengstler J. G., Sachinidis A. (2016). MicroRNAs as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes. Arch. Toxicol. 90, 3087–3098. 10.1007/s00204-016-1668-0 PubMed DOI PMC

Chen C., Ponnusamy M., Liu C., Gao J., Wang K., Li P. (2017). MicroRNA as a therapeutic target in cardiac remodeling. Biomed. Res. Int. 2017, 1278436. 10.1155/2017/1278436 PubMed DOI PMC

Chen L., Xu Y. (2021). MicroRNAs as biomarkers and therapeutic targets in doxorubicin-induced cardiomyopathy: a review. Front. Cardiovasc Med. 8, 740515. 10.3389/fcvm.2021.740515 PubMed DOI PMC

Chen Y., Xu Y., Deng Z., Wang Y., Zheng Y., Jiang W., et al. (2021). MicroRNA expression profiling involved in doxorubicin-induced cardiotoxicity using high-throughput deep-sequencing analysis. Oncol. Lett. 22, 560. 10.3892/ol.2021.12821 PubMed DOI PMC

Cheng Y., Zhang C. (2010). MicroRNA-21 in cardiovascular disease. J. Cardiovasc Transl. Res. 3, 251–255. 10.1007/s12265-010-9169-7 PubMed DOI PMC

Chistiakov D. A., Orekhov A. N., Bobryshev Y. V. (2016). Cardiac-specific miRNA in cardiogenesis, heart function, and cardiac pathology (with focus on myocardial infarction). J. Mol. Cell Cardiol. 94, 107–121. 10.1016/j.yjmcc.2016.03.015 PubMed DOI

Choo K. B., Soon Y. L., Nguyen P. N. N., Hiew M. S. Y., Huang C.-J. (2014). MicroRNA-5p and -3p co-expression and cross-targeting in colon cancer cells. J. Biomed. Sci. 21, 95. 10.1186/s12929-014-0095-x PubMed DOI PMC

Desai V. G., Kwekel C., Vijay V., Moland C. L., Herman E. H., Lee T., et al. (2014). Early biomarkers of doxorubicin-induced heart injury in a mouse model. Toxicol. Appl. Pharmacol. 281, 221–229. 10.1016/j.taap.2014.10.006 PubMed DOI

Dhingra R., Vasan R. S. (2017). Biomarkers in cardiovascular disease: statistical assessment and section on key novel heart failure biomarkers. Trends Cardiovasc Med. 27, 123–133. 10.1016/j.tcm.2016.07.005 PubMed DOI PMC

Ewer M. S., Ewer S. M. (2015). Erratum: cardiotoxicity of anticancer treatments. Nat. Rev. Cardiol. 12, 620. 10.1038/nrcardio.2015.133 PubMed DOI

Fabiani I., Aimo A., Grigoratos C., Castiglione V., Gentile F., Saccaro L. F., et al. (2021). Oxidative stress and inflammation: determinants of anthracycline cardiotoxicity and possible therapeutic targets. Heart Fail Rev. 26 (4), 881–890. 10.1007/s10741-020-10063-9 PubMed DOI PMC

Gargiulo P., Marzano F., Salvatore M., Basile C., Buonocore D., Parlati A. L. M., et al. (2023). MicroRNAs: diagnostic, prognostic and therapeutic role in heart failure—a review. Esc. Heart Fail 10, 753–761. 10.1002/ehf2.14153 PubMed DOI PMC

Grzybowska E. A., Zayat V., Konopiński R., Trębińska A., Szwarc M., Sarnowska E., et al. (2013). HAX-1 is a nucleocytoplasmic shuttling protein with a possible role in mRNA processing. FEBS J. 280, 256–272. 10.1111/febs.12066 PubMed DOI

Guo J., Liu H.-B., Sun C., Yan X.-Q., Hu J., Yu J., et al. (2019). MicroRNA-155 promotes myocardial infarction-induced apoptosis by targeting RNA-binding protein QKI. Oxid. Med. Cell Longev. 2019, 4579806–4579814. 10.1155/2019/4579806 PubMed DOI PMC

Guo X.-B., Deng X., Wei Y. (2018). Hematopoietic substrate-1-associated protein X-1 regulates the proliferation and apoptosis of endothelial progenitor cells through akt pathway modulation. Stem Cells 36, 406–419. 10.1002/stem.2741 PubMed DOI

Ha T.-Y. (2011). MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw. 11, 135–154. 10.4110/in.2011.11.3.135 PubMed DOI PMC

Harada M., Luo X., Murohara T., Yang B., Dobrev D., Nattel S. (2014). MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential. Circ. Res. 114, 689–705. 10.1161/CIRCRESAHA.114.301798 PubMed DOI

Hasinoff B. B., Patel D., Wu X. (2020). The role of topoisomerase IIβ in the mechanisms of action of the doxorubicin cardioprotective agent dexrazoxane. Cardiovasc Toxicol. 20, 312–320. 10.1007/s12012-019-09554-5 PubMed DOI

Haybar H., Shahrouzian M., Gatavizadeh Z., Saki N., Maniati M., Zayeri Z. D. (2021). Cyclin D1: a golden gene in cancer, cardiotoxicity, and cardioprotection jundishapur J chronic dis Care . Jundishapur J. Chronic Dis. Care 10 (3), e112413. 10.5812/jjcdc.112413 DOI

Herman E. H., Ferrans V. J. (1986). Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin cardiotoxicity in rabbits. Cancer Chemother. Pharmacol. 16 (2), 102–106. 10.1007/BF00256157 PubMed DOI

Herman E. H., Ferrans V. J., Jordan W., Ardalan B. (1981). Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits. Res. Commun. Chem. Pathol. Pharmacol. 31 (1), 85–97. PubMed

Holmgren G., Synnergren J., Andersson C. X., Lindahl A., Sartipy P. (2016). MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity. Toxicol. Vitro 34, 26–34. 10.1016/j.tiv.2016.03.009 PubMed DOI

Hornyik T., Rieder M., Castiglione A., Major P., Baczko I., Brunner M., et al. (2022). Transgenic rabbit models for cardiac disease research. Br. J. Pharmacol. 179 (5), 938–957. 10.1111/bph.15484 PubMed DOI

Hu W., Chan C. S., Wu R., Zhang C., Sun Y., Song J. S., et al. (2010). Negative regulation of tumor suppressor p53 by MicroRNA miR-504. Mol. Cell 38, 689–699. 10.1016/j.molcel.2010.05.027 PubMed DOI PMC

Hua C.-C., Liu X.-M., Liang L.-R., Wang L.-F., Zhong J.-C. (2022). Targeting the microRNA-34a as a novel therapeutic strategy for cardiovascular diseases. Front. Cardiovasc Med. 8, 784044. 10.3389/fcvm.2021.784044 PubMed DOI PMC

Ilieva M., Panella R., Uchida S. (2022). MicroRNAs in cancer and cardiovascular disease. Cells 11, 3551. 10.3390/cells11223551 PubMed DOI PMC

Jirkovská A., Karabanovich G., Kubeš J., Skalická V., Melnikova I., Korábečný J., et al. (2021). Structure–activity relationship study of dexrazoxane analogues reveals ICRF-193 as the most potent bisdioxopiperazine against anthracycline toxicity to cardiomyocytes due to its strong topoisomerase IIβ interactions. J. Med. Chem. 64, 3997–4019. 10.1021/acs.jmedchem.0c02157 PubMed DOI

Jirkovský E., Jirkovská A., Bavlovič-Piskáčková H., Skalická V., Pokorná Z., Karabanovich G., et al. (2021). Clinically translatable prevention of anthracycline cardiotoxicity by dexrazoxane is mediated by topoisomerase II beta and not metal chelation. Circ. Heart Fail 14, e008209. 10.1161/CIRCHEARTFAILURE.120.008209 PubMed DOI

Jirkovský E., Lenčová-Popelová O., Hroch M., Adamcová M., Mazurová Y., Vávrová J., et al. (2013). Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits. Toxicology 311, 191–204. 10.1016/j.tox.2013.06.012 PubMed DOI

Jirkovský E., Popelová O., Křiváková-Staňková P., Vávrová A., Hroch M., Hašková P., et al. (2012). Chronic anthracycline cardiotoxicity: molecular and functional analysis with focus on nuclear factor erythroid 2-related factor 2 and mitochondrial biogenesis pathways. J. Pharmacol. Exp. Ther. 343, 468–478. 10.1124/jpet.112.198358 PubMed DOI

Kawano I., Adamcova M. (2022). MicroRNAs in doxorubicin-induced cardiotoxicity: the DNA damage response. Front. Pharmacol. 13, 1055911. 10.3389/fphar.2022.1055911 PubMed DOI PMC

Kern F., Aparicio-Puerta E., Li Y., Fehlmann T., Kehl T., Wagner V., et al. (2021). miRTargetLink 2.0—interactive miRNA target gene and target pathway networks. Nucleic Acids Res. 49, W409–W416. 10.1093/nar/gkab297 PubMed DOI PMC

Kollárová-Brázdová P., Lenčová-Popelová O., Karabanovich G., Kocúrová-Lengvarská J., Kubeš J., Váňová N., et al. (2021). Prodrug of ICRF-193 provides promising protective effects against chronic anthracycline cardiotoxicity in a rabbit model in vivo . Clin. Sci. 135, 1897–1914. 10.1042/CS20210311 PubMed DOI

Kuang Z., Wu J., Tan Y., Zhu G., Li J., Wu M. (2023). MicroRNA in the diagnosis and treatment of doxorubicin-induced cardiotoxicity. Biomolecules 13, 568. 10.3390/biom13030568 PubMed DOI PMC

Laggerbauer B., Engelhardt S. (2022). MicroRNAs as therapeutic targets in cardiovascular disease. J. Clin. Investigation 132, e159179. 10.1172/JCI159179 PubMed DOI PMC

Li H., Zhan J., Chen C., Wang D. (2022). MicroRNAs in cardiovascular diseases. Med. Rev. 2, 140–168. 10.1515/mr-2021-0001 PubMed DOI PMC

Liu Y., Duan C., Liu W., Chen X., Wang Y., Liu X., et al. (2019). Upregulation of let-7f-2-3p by long noncoding RNA NEAT1 inhibits XPO1-mediated HAX-1 nuclear export in both in vitro and in vivo rodent models of doxorubicin-induced cardiotoxicity. Arch. Toxicol. 93, 3261–3276. 10.1007/s00204-019-02586-4 PubMed DOI

Moulin M., Piquereau J., Mateo P., Fortin D., Rucker-Martin C., Gressette M., et al. (2015). Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling. Circ. Heart Fail 8, 98–108. 10.1161/CIRCHEARTFAILURE.114.001180 PubMed DOI

Navarro F., Lieberman J. (2015). miR-34 and p53: new insights into a complex functional relationship. PLoS One 10, e0132767. 10.1371/journal.pone.0132767 PubMed DOI PMC

Nishimura Y., Kondo C., Morikawa Y., Tonomura Y., Torii M., Yamate J., et al. (2015). Plasma miR-208 as a useful biomarker for drug-induced cardiotoxicity in rats. J. Appl. Toxicol. 35, 173–180. 10.1002/jat.3044 PubMed DOI

O’Brien J., Hayder H., Zayed Y., Peng C. (2018). Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. (Lausanne) 9, 402. 10.3389/fendo.2018.00402 PubMed DOI PMC

Oliveira-Carvalho V., Ferreira L. R. P., Bocchi E. A. (2015). Circulating mir-208a fails as a biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. J. Appl. Toxicol. 35, 1071–1072. 10.1002/jat.3185 PubMed DOI

Ooi J. Y. Y., Bernardo B. C., McMullen J. R. (2016). Therapeutic potential of targeting microRNAs to regulate cardiac fibrosis: miR-433 a new fibrotic player. Ann. Transl. Med. 4, 548. 10.21037/atm.2016.12.01 PubMed DOI PMC

Ouyang C., Huang L., Ye X., Ren M., Han Z. (2022). Overexpression of miR-1298 attenuates myocardial ischemia–reperfusion injury by targeting PP2A. J. Thromb. Thrombolysis 53, 136–148. 10.1007/s11239-021-02540-1 PubMed DOI

Pellegrini L., Sileno S., D’Agostino M., Foglio E., Florio M. C., Guzzanti V., et al. (2020). MicroRNAs in cancer treatment-induced cardiotoxicity. Cancers (Basel) 12, 704. 10.3390/cancers12030704 PubMed DOI PMC

Pereira J. D., Tosatti J. A. G., Simões R., Luizon M. R., Gomes K. B., Alves M. T. (2020). microRNAs associated to anthracycline-induced cardiotoxicity in women with breast cancer: a systematic review and pathway analysis. Biomed. Pharmacother. 131, 110709. 10.1016/j.biopha.2020.110709 PubMed DOI

Peters L. J. F., Biessen E. A. L., Hohl M., Weber C., van der Vorst E. P. C., Santovito D. (2020). Small things matter: relevance of MicroRNAs in cardiovascular disease. Front. Physiol. 11, 793. 10.3389/fphys.2020.00793 PubMed DOI PMC

Piegari E., Cozzolino A., Ciuffreda L. P., Cappetta D., De Angelis A., Urbanek K., et al. (2020). Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity. Sci. Rep. 10, 12250. 10.1038/s41598-020-69038-3 PubMed DOI PMC

Piegari E., Russo R., Cappetta D., Esposito G., Urbanek K., Dell’Aversana C., et al. (2016). MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat. Oncotarget 7, 62312–62326. 10.18632/oncotarget.11468 PubMed DOI PMC

Pilié P. G., Tang C., Mills G. B., Yap T. A. (2019). State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol. 16, 81–104. 10.1038/s41571-018-0114-z PubMed DOI PMC

Qiu Y., Cheng R., Liang C., Yao Y., Zhang W., Zhang J., et al. (2020). MicroRNA-20b promotes cardiac hypertrophy by the inhibition of mitofusin 2-mediated inter-organelle Ca2+ cross-talk. Mol. Ther. Nucleic Acids 19, 1343–1356. 10.1016/j.omtn.2020.01.017 PubMed DOI PMC

Renu K., Abilash V. G., Tirupathi Pichiah P. B., Arunachalam S. (2018). Molecular mechanism of doxorubicin-induced cardiomyopathy – an update. Eur. J. Pharmacol. 818, 241–253. 10.1016/j.ejphar.2017.10.043 PubMed DOI

Rigaud V. O.-C., Ferreira L. R. P., Ayub-Ferreira S. M., Ávila M. S., Brandão S. M. G., Cruz F. D., et al. (2017). Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. Oncotarget 8, 6994–7002. 10.18632/oncotarget.14355 PubMed DOI PMC

Romaine S. P. R., Tomaszewski M., Condorelli G., Samani N. J. (2015). MicroRNAs in cardiovascular disease: an introduction for clinicians. Heart 101, 921–928. 10.1136/heartjnl-2013-305402 PubMed DOI PMC

Ruggeri C., Gioffré S., Achilli F., Colombo G. I., D’Alessandra Y. (2018a). Role of microRNAs in doxorubicin-induced cardiotoxicity: an overview of preclinical models and cancer patients. Heart Fail Rev. 23, 109–122. 10.1007/s10741-017-9653-0 PubMed DOI PMC

Ruggeri C., Gioffré S., Chiesa M., Buzzetti M., Milano G., Scopece A., et al. (2018b). A specific circulating MicroRNA cluster is associated to late differential cardiac response to doxorubicin-induced cardiotoxicity in vivo . Dis. Markers 2018, 8395651–8395659. 10.1155/2018/8395651 PubMed DOI PMC

Sawicki K. T., Sala V., Prever L., Hirsch E., Ardehali H., Ghigo A. (2021). Preventing and treating anthracycline cardiotoxicity: new insights. Annu. Rev. Pharmacol. Toxicol. 61, 309–332. 10.1146/annurev-pharmtox-030620-104842 PubMed DOI

Sayed D., He M., Hong C., Gao S., Rane S., Yang Z., et al. (2010). MicroRNA-21 is a downstream effector of AKT that mediates its antiapoptotic effects via suppression of fas ligand. J. Biol. Chem. 285, 20281–20290. 10.1074/jbc.M110.109207 PubMed DOI PMC

Šimůnek T., Klimtová I., Adamcová M., Geršl V., Hrdina R., Štěrba M., et al. (2003). Cardiac troponin T as an indicator of reduced left ventricular contractility in experimental anthracycline-induced cardiomyopathy. Cancer Chemother. Pharmacol. 52, 43–434. 10.1007/s00280-003-0675-z PubMed DOI

Šimůnek T., Štěrba M., Popelová O., Adamcová M., Hrdina R., Geršl V. (2009). Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol. Rep. 61, 154–171. 10.1016/S1734-1140(09)70018-0 PubMed DOI

Solomon J. M., Pasupuleti R., Xu L., McDonagh T., Curtis R., DiStefano P. S., et al. (2006). Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol. Cell Biol. 26, 28–38. 10.1128/MCB.26.1.28-38.2006 PubMed DOI PMC

Štěrba M., Popelová O., Vávrová A., Jirkovský E., Kovaříková P., Geršl V., et al. (2013). Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid. Redox Signal 18, 899–929. 10.1089/ars.2012.4795 PubMed DOI PMC

Sterba M., Simůnek T., Popelová O., Potácová A., Adamcová M., Mazurová Y., et al. (2007). Early detection of anthracycline cardiotoxicity in a rabbit model: left ventricle filling pattern versus troponin T determination. Physiol. Res. 56 (5), 535–545. 10.33549/physiolres.931025 PubMed DOI

Surina S., Fontanella R. A., Scisciola L., Marfella R., Paolisso G., Barbieri M. (2021). miR-21 in human cardiomyopathies. Front. Cardiovasc Med. 8, 767064. 10.3389/fcvm.2021.767064 PubMed DOI PMC

Tao L., Bei Y., Chen P., Lei Z., Fu S., Zhang H., et al. (2016). Crucial role of miR-433 in regulating cardiac fibrosis. Theranostics 6, 2068–2083. 10.7150/thno.15007 PubMed DOI PMC

Thum T., Galuppo P., Wolf C., Fiedler J., Kneitz S., van Laake L. W., et al. (2007). MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116, 258–267. 10.1161/CIRCULATIONAHA.107.687947 PubMed DOI

Tijsen A. J., Pinto Y. M., Creemers E. E. (2012). Non-cardiomyocyte microRNAs in heart failure. Cardiovasc Res. 93, 573–582. 10.1093/cvr/cvr344 PubMed DOI

Tong Z., Jiang B., Wu Y., Liu Y., Li Y., Gao M., et al. (2015). MiR-21 protected cardiomyocytes against doxorubicin-induced apoptosis by targeting BTG2. Int. J. Mol. Sci. 16, 14511–14525. 10.3390/ijms160714511 PubMed DOI PMC

Vacchi-Suzzi C., Bauer Y., Berridge B. R., Bongiovanni S., Gerrish K., Hamadeh H. K., et al. (2012). Perturbation of microRNAs in rat heart during chronic doxorubicin treatment. PLoS One 7, e40395. 10.1371/journal.pone.0040395 PubMed DOI PMC

Vejpongsa P., Yeh E. T. H. (2013). Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clin. Pharmacol. Ther. 95, 45–52. 10.1038/clpt.2013.201 PubMed DOI

Voellenkle C., van Rooij J., Cappuzzello C., Greco S., Arcelli D., Di Vito L., et al. (2010). MicroRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients. Physiol. Genomics 42, 420–426. 10.1152/physiolgenomics.00211.2009 PubMed DOI

Wang Y., Ouyang M., Wang Q., Jian Z. (2016). MicroRNA-142-3p inhibits hypoxia/reoxygenation-induced apoptosis and fibrosis of cardiomyocytes by targeting high mobility group box 1. Int. J. Mol. Med. 38, 1377–1386. 10.3892/ijmm.2016.2756 PubMed DOI PMC

Wang Y.-S., Zhou J., Hong K., Cheng X.-S., Li Y.-G. (2015). MicroRNA-223 displays a protective role against cardiomyocyte hypertrophy by targeting cardiac troponin I-interacting kinase. Cell. Physiology Biochem. 35, 1546–1556. 10.1159/000373970 PubMed DOI

Wang Z. (2010). MicroRNAs and cardiovascular disease. Bentham e-Book. SBN: 978-1-60805-184-7. 10.2174/97816080518471100101 DOI

Xiao Z., Wei S., Huang J., Liu J., Liu J., Zhang B., et al. (2022). Noncoding RNA-associated competing endogenous RNA networks in doxorubicin-induced cardiotoxicity. DNA Cell Biol. 41, 657–670. 10.1089/dna.2022.0022 PubMed DOI

Yamakuchi M., Lowenstein C. J. (2009). MiR-34, SIRT1, and p53: the feedback loop. Cell Cycle 8, 712–715. 10.4161/cc.8.5.7753 PubMed DOI

Yarmohammadi F., Ebrahimian Z., Karimi G. (2023). MicroRNAs target the PI3K/Akt/p53 and the Sirt1/Nrf2 signaling pathways in doxorubicin‐induced cardiotoxicity. J. Biochem. Mol. Toxicol. 37, e23261. 10.1002/jbt.23261 PubMed DOI

Yoshida M., Shiojima I., Ikeda H., Komuro I. (2009). Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity. J. Mol. Cell Cardiol. 47, 698–705. 10.1016/j.yjmcc.2009.07.024 PubMed DOI

Zhan L., Lei S., Li W., Zhang Y., Wang H., Shi Y., et al. (2017). Suppression of microRNA-142-5p attenuates hypoxia-induced apoptosis through targeting SIRT7. Biomed. Pharmacother. 94, 394–401. 10.1016/j.biopha.2017.07.083 PubMed DOI

Zhang M.-W., Shen Y.-J., Shi J., Yu J.-G. (2021). MiR-223-3p in cardiovascular diseases: a biomarker and potential therapeutic target. Front. Cardiovasc Med. 7, 610561. 10.3389/fcvm.2020.610561 PubMed DOI PMC

Zhang S., Liu X., Bawa-Khalfe T., Lu L.-S., Lyu Y. L., Liu L. F., et al. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 18, 1639–1642. 10.1038/nm.2919 PubMed DOI

Zhu J.-N., Fu Y.-H., Hu Z., Li W.-Y., Tang C.-M., Fei H.-W., et al. (2017). Activation of miR-34a-5p/Sirt1/p66shc pathway contributes to doxorubicin-induced cardiotoxicity. Sci. Rep. 7, 11879. 10.1038/s41598-017-12192-y PubMed DOI PMC