Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model

Michaela Adamcova; Helena Parova; Olga Lencova-Popelova; Petra Kollarova-Brazdova; Ivana Baranova; Marcela Slavickova; Tereza Stverakova; Petra Sauer Mikyskova; Yvona Mazurova; Martin Sterba

doi:10.3389/fphar.2023.1298172

Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model

Front Pharmacol. 2024 Jan 3:14:1298172. doi: 10.3389/fphar.2023.1298172. eCollection 2023.

Affiliations

¹ Department of Physiology, Hradec Kralove, Czechia.
² Department of Clinical Biochemistry and Diagnostics, Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Hradec Kralove, Czechia.
³ Department of Pharmacology, Hradec Kralove, Czechia.
⁴ Department of Histology and Embryology, Charles University in Prague, Hradec Kralove, Czechia.

Abstract

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.

Keywords: DNA damage response; anthracyclines; cardiotoxicity; chronic cardiomyopathy; miRNA; myocardium.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by project INOMED reg. No. CZ.02.1.01/0.0/0.0/18_069/0010046: The pre-application research into innovative medicines and medical technologies project was co-funded by the ERDF and the Czech Science Foundation (GAČR) (Grant No. 23-06558S).