Plasmatic and chamber-specific modulation of cardiac microRNAs in an acute model of DOX-induced cardiotoxicity.

Details

Serval ID
serval:BIB_AAEA1CF6BC5F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Plasmatic and chamber-specific modulation of cardiac microRNAs in an acute model of DOX-induced cardiotoxicity.
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Author(s)
Gioffré S., Ricci V., Vavassori C., Ruggeri C., Chiesa M., Alfieri I., Zorzan S., Buzzetti M., Milano G., Scopece A., Castiglioni L., Sironi L., Pompilio G., Colombo G.I., D'Alessandra Y.
ISSN
1950-6007 (Electronic)
ISSN-L
0753-3322
Publication state
Published
Issued date
02/2019
Peer-reviewed
Oui
Volume
110
Pages
1-8
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Doxorubicin (DOX) is a chemotherapeutic drug limited in its usefulness by an adverse side effect, cardiotoxicity. The mechanisms leading to this detrimental occurrence are not completely clear, and lately many authors focused their attention on the possible role of microRNAs (miRNAs), small regulators of cardiovascular functions, in this phenomenon. Notably, these molecules recently emerged also as potential circulating biomarkers of several cardiac diseases. Thus, the aim of this study was the simultaneous investigation of circulating and cardiac tissue miRNAs expression upon DOX treatment in vivo.
Twenty C57BL/6 female mice were administered with 24 mg/Kg cumulative dose of DOX or saline (CTRL) for 2 weeks. Echocardiography was performed at baseline and at the end of treatment (T1). Plasma and heart samples were collected at T1, separating atria from left (LV) and right (RV) ventricles, and miRNAs expression was tested by RT-qPCR-based arrays. All putatively DOX-regulated candidates were then validated by single assays in vivo and then evaluated also in murine immortalized cardiomyocytes (HL-1) treated with 1 μM DOX for 24 h. In the end, bioinformatics target prediction was performed for all DOX-miRNAs.
Cardiotoxicity onset was diagnosed upon impairment of six cardiac functional parameters in DOX-treated mice at T1. Samples collection, followed by screening and validation steps, identified eleven miRNAs dysregulated by the drug in plasma, while seven resulted as altered in separate heart chambers. Interestingly, miR-34a-5p and miR-451a showed a dysregulation in both plasma and tissue samples of DOX-administered animals, whereas five additional miRNAs presented chamber specific modulation. Of note, in vitro experiments showed a very modest overlap with in vivo results. Bioinformatics prediction analysis performed on miR-34a-5p and miR-451a identified several putative targets presenting no significant association with cardiotoxicity. Anyhow, the same analyses, conducted by combining all miRNAs regulated by DOX in each heart chamber, evidenced a possible dysregulation of the adherens junctions gene network, known to be involved in the onset and progression of dilated cardiomyopathy, an established detrimental side effect of the drug.
This is the first work investigating miRNAs regulation by DOX both in plasma and heart districts of treated animals. Our results indicate a strong association of miR-34a-5p and miR-451a to DOX-induced cardiotoxicity. In addition, the observed altered expression of diverse miRNAs in separated cardiac chambers hints at a specific response to the drug, implying the existence of different players and pathways leading to dysfunction onset.
Keywords
Animals, Antibiotics, Antineoplastic/toxicity, Biomarkers/blood, Biomarkers/metabolism, Cardiotoxicity/blood, Cardiotoxicity/pathology, Cardiotoxins/toxicity, Cells, Cultured, Doxorubicin/toxicity, Female, Mice, Mice, Inbred C57BL, MicroRNAs/biosynthesis, MicroRNAs/genetics, Myocytes, Cardiac/drug effects, Myocytes, Cardiac/metabolism, Myocytes, Cardiac/pathology, Biomarkers, Cardiotoxicity, Circulating microRNA, Doxorubicin, Heart chambers, microRNAs
Pubmed
Web of science
Open Access
Yes
Create date
26/11/2018 13:19
Last modification date
20/08/2019 15:14
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