Universität zu Köln

Chaudhari, Umesh ORCID: 0000-0002-7743-4371, Nemade, Harshal, Gaspar, John Antonydas, Hescheler, Jurgen, Hengstler, Jan G. and Sachinidis, Agapios (2016). MicroRNAs as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes. Arch. Toxicol., 90 (12). S. 3087 - 3099. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

An in depth investigation at the genomic level is needed to identify early human-relevant cardiotoxicity biomarkers that are induced by drugs and environmental toxicants. The main objective of this study was to investigate the role of microRNAs (miRNAs) as cardiotoxicity biomarkers using human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) that were exposed to doxorubicin (DOX) as a gold standard cardiotoxicant. hiPSC-CMs were exposed to 156 nM DOX for 2 days or for 6 days of repeated exposure, followed by drug washout and incubation in drug-free culture medium up to day 14 after the onset of exposure. The induced miRNAs were profiled using miRNA microarrays, and the analysis of the data was performed using the miRWalk 2.0 and DAVID bioinformatics tools. DOX induced early deregulation of 14 miRNAs (10 up-regulated and 4 down-regulated) and persistent up-regulation of 5 miRNAs during drug washout. Computational miRNA gene target predictions suggested that several DOX-responsive miRNAs might regulate the mRNA expression of genes involved in cardiac contractile function. The hiPSC-CMs exposed to DOX in a range from 39 to 156 nM did not show a significant release of the cytotoxicity marker lactate dehydrogenase (LDH) compared to controls. Quantitative real-time PCR analyses confirmed the early deregulation of miR-187-3p, miR-182-5p, miR-486-3p, miR-486-5p, miR-34a-3p, miR-4423-3p, miR-34c-3p, miR-34c-5p and miR-1303, and also the prolonged up-regulation of miR-182-5p, miR-4423-3p and miR-34c-5p. Thus, we identified and validated miRNAs showing differential DOX-responsive expression before the occurrence of cytotoxicity markers such as LDH, and these miRNAs also demonstrated the significant involvement in heart failure in patients and animal models. These results suggest that the DOX-induced deregulated miRNAs in human CMs may be used as early sensitive cardiotoxicity biomarkers for screening potential drugs and environmental cardiotoxicants with a similar mechanism of action.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chaudhari, Umesh UNSPECIFIED orcid.org/0000-0002-7743-4371 UNSPECIFIED Nemade, Harshal UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaspar, John Antonydas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Jurgen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-254645
DOI:	10.1007/s00204-016-1668-0
Journal or Publication Title:	Arch. Toxicol.
Volume:	90
Number:	12
Page Range:	S. 3087 - 3099
Date:	2016
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; CARDIAC TROPONIN-I; HEART-FAILURE; CULTURED CARDIOMYOCYTES; INDUCED CARDIOMYOPATHY; SIGNALING PATHWAYS; MOUSE MODEL; DNA-REPAIR; BIOMARKERS Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25464