Perturbation of microRNAs in rat heart during chronic doxorubicin treatment
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Vacchi-Suzzi, Caterina, Moggs, Jonathan, Pognan, Francois, Grenet, Olivier, Bauer, Yasmina, Gerrish, Kevin, Hamadeh, Hisham K., Letzkus, Martin, Paules, Richard, Lyon, Jonathan, Vidgeon-Hart, Martin, Berridge, Brian and Couttet, Philippe (2012) Perturbation of microRNAs in rat heart during chronic doxorubicin treatment. PLoS ONE, 7 (7). e40395. ISSN 1932-6203
Abstract
Anti-cancer therapy based on anthracyclines (DNA intercalating Topoisomerase II inhibitors) is limited by adverse effects of
these compounds on the cardiovascular system, ultimately causing heart failure. Despite extensive investigations into the
effects of doxorubicin on the cardiovascular system, the molecular mechanisms of toxicity remain largely unknown.
MicroRNAs are endogenously transcribed non-coding 22 nucleotide long RNAs that regulate gene expression by decreasing
mRNA stability and translation and play key roles in cardiac physiology and pathologies. Increasing doses of doxorubicin,
but not etoposide (a Topoisomerase II inhibitor devoid of cardiovascular toxicity), specifically induced the up-regulation of
miR-208b, miR-216b, miR-215, miR-34c and miR-367 in rat hearts. Furthermore, the lowest dosing regime (1 mg/kg/week for
2 weeks) led to a detectable increase of miR-216b in the absence of histopathological findings or alteration of classical
cardiac stress biomarkers. In silico microRNA target predictions suggested that a number of doxorubicin-responsive
microRNAs may regulate mRNAs involved in cardiac tissue remodeling. In particular miR-34c was able to mediate the DOXinduced
changes of Sipa1 mRNA (a mitogen-induced Rap/Ran GTPase activating protein) at the post-transcriptional level
and in a seed sequence dependent manner. Our results show that integrated heart tissue microRNA and mRNA profiling can
provide valuable early genomic biomarkers of drug-induced cardiac injury as well as novel mechanistic insight into the
underlying molecular pathways.
| Item Type: | Article |
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| Additional Information: | Disclosure of ancillary gene expression profiles on ArrayExpress (study ID IEP 756) has been approved by Frank Staedtler |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/6526 |