title: Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.
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 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.
authors.affiliation: Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Caterina
authors.initials: C
authors.lastname: Vacchi-Suzzi
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Bauer
authors.forename: Brian R
authors.initials: BR
authors.lastname: Berridge
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bongiovanni
authors.forename: Kevin
authors.initials: K
authors.lastname: Gerrish
authors.forename: Hisham K
authors.initials: HK
authors.lastname: Hamadeh
authors.forename: Martin
authors.initials: M
authors.lastname: Letzkus
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lyon
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moggs
authors.forename: Richard S
authors.initials: RS
authors.lastname: Paules
authors.forename: François
authors.initials: F
authors.lastname: Pognan
authors.forename: Frank
authors.initials: F
authors.lastname: Staedtler
authors.forename: Martin P
authors.initials: MP
authors.lastname: Vidgeon-Hart
authors.forename: Olivier
authors.initials: O
authors.lastname: Grenet
authors.forename: Philippe
authors.initials: P
authors.lastname: Couttet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000187:drug effects; D059467:Transcriptome; D015854:Up-Regulation / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D020690:GTPase-Activating Proteins; D035683:MicroRNAs; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D004317:Doxorubicin