Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.

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,...

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Autores principales:	Caterina Vacchi-Suzzi, Yasmina Bauer, Brian R Berridge, Sandrine Bongiovanni, Kevin Gerrish, Hisham K Hamadeh, Martin Letzkus, Jonathan Lyon, Jonathan Moggs, Richard S Paules, François Pognan, Frank Staedtler, Martin P Vidgeon-Hart, Olivier Grenet, Philippe Couttet
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1bf1e6df5257478dabeac3b061a4a4f0
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spelling	oai:doaj.org-article:1bf1e6df5257478dabeac3b061a4a4f02021-11-18T07:10:20ZPerturbation of microRNAs in rat heart during chronic doxorubicin treatment.1932-620310.1371/journal.pone.0040395https://doaj.org/article/1bf1e6df5257478dabeac3b061a4a4f02012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22859947/?tool=EBIhttps://doaj.org/toc/1932-6203Anti-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 DOX-induced 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.Caterina Vacchi-SuzziYasmina BauerBrian R BerridgeSandrine BongiovanniKevin GerrishHisham K HamadehMartin LetzkusJonathan LyonJonathan MoggsRichard S PaulesFrançois PognanFrank StaedtlerMartin P Vidgeon-HartOlivier GrenetPhilippe CouttetPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e40395 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Caterina Vacchi-Suzzi Yasmina Bauer Brian R Berridge Sandrine Bongiovanni Kevin Gerrish Hisham K Hamadeh Martin Letzkus Jonathan Lyon Jonathan Moggs Richard S Paules François Pognan Frank Staedtler Martin P Vidgeon-Hart Olivier Grenet Philippe Couttet Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.
description	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 DOX-induced 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.
format	article
author	Caterina Vacchi-Suzzi Yasmina Bauer Brian R Berridge Sandrine Bongiovanni Kevin Gerrish Hisham K Hamadeh Martin Letzkus Jonathan Lyon Jonathan Moggs Richard S Paules François Pognan Frank Staedtler Martin P Vidgeon-Hart Olivier Grenet Philippe Couttet
author_facet	Caterina Vacchi-Suzzi Yasmina Bauer Brian R Berridge Sandrine Bongiovanni Kevin Gerrish Hisham K Hamadeh Martin Letzkus Jonathan Lyon Jonathan Moggs Richard S Paules François Pognan Frank Staedtler Martin P Vidgeon-Hart Olivier Grenet Philippe Couttet
author_sort	Caterina Vacchi-Suzzi
title	Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.
title_short	Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.
title_full	Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.
title_fullStr	Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.
title_full_unstemmed	Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.
title_sort	perturbation of micrornas in rat heart during chronic doxorubicin treatment.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/1bf1e6df5257478dabeac3b061a4a4f0
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Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.

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