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Early biomarkers of doxorubicin-induced heart injury in a mouse model

Authors
Desai, Varsha G.Kwekel, Joshua C.Vijay, VikrantMoland, Carrie L.Herman, Eugene H.Lee, TaewonHan, TaoLewis, Sherry M.Davis, Kelly J.Muskhelishvili, LevanKerr, SusanFuscoe, James C.
Issue Date
1-12월-2014
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Keywords
Doxorubicin; Heart; MicroRNA profiling; Biomarker; Mouse
Citation
TOXICOLOGY AND APPLIED PHARMACOLOGY, v.281, no.2, pp.221 - 229
Indexed
SCIE
SCOPUS
Journal Title
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume
281
Number
2
Start Page
221
End Page
229
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/96544
DOI
10.1016/j.taap.2014.10.006
ISSN
0041-008X
Abstract
Cardiac troponins, which are used as myocardial injury markers, are released in plasma only after tissue damage has occurred. Therefore, there is a need for identification of biomarkers of earlier events in cardiac injury to limit the extent of damage. To accomplish this, expression profiling of 1179 unique microRNAs (miRNAs) was performed in a chronic cardiotoxicity mouse model developed in our laboratory. Male B6C3F(1) mice were injected intravenously with 3 mg/kg doxorubicin (DOX; an anti-cancer drug), or saline once a week for 2, 3, 4, 6, and 8 weeks, resulting in cumulative DOX doses of 6, 9, 12, 18, and 24 mg/kg, respectively. Mice were euthanized a week after the last dose. Cardiac injury was evidenced in mice exposed to 18 mg/kg and higher cumulative DOX dose whereas examination of hearts by light microscopy revealed cardiac lesions at 24 mg/kg DOX. Also, 24 miRNAs were differentially expressed in mouse hearts, with the expression of 1, 1, 2, 8, and 21 miRNAs altered at 6, 9, 12, 18, and 24 mg/kg DOX, respectively. A pro-apoptotic miR-34a was the only miRNA that was upregulated at all cumulative DOX doses and showed a significant dose-related response. Up-regulation of miR-34a at 6 mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice. At 12 mg/kg DOX, up-regulation of miR-34a was associated with down-regulation of hypertrophy-related miR-150; changes observed before cardiac injury. These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins. Published by Elsevier Inc.
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