Perturbation of microRNAs in Rat Heart during Chronic Doxorubicin Treatment 英文参考文献.docVIP

PerturbationofmicroRNAsinRatHeartduringChronic DoxorubicinTreatment CaterinaVacchi-Suzzi1,YasminaBauer2,BrianR.Berridge3,SandrineBongiovanni6,KevinGerrish4, HishamK.Hamadeh5,MartinLetzkus6,JonathanLyon7,JonathanMoggs1,RichardS.Paules4, Franc?oisPognan1,FrankStaedtler6,MartinP.Vidgeon-Hart7,OlivierGrenet1,PhilippeCouttet1* 1Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland, 2Translational Science Biology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland, 3Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America, 4National Institute of Environmental HealthScience,NationalInstitutesofHealth,ResearchTrianglePark,NorthCarolina,UnitedStatesofAmerica,5ComparativeBiologyandSafetySciences,AmgenInc., ThousandOaks,California,UnitedStatesofAmerica,6BiomarkerDevelopment,NovartisInstitutesforBiomedicalResearch,Basel,Switzerland,7InvestigativePreclinical Toxicology,GlaxoSmithKline,Ware,UnitedKingdom Abstract Anti-cancertherapybasedonanthracyclines(DNAintercalatingTopoisomeraseIIinhibitors)islimitedbyadverseeffectsof thesecompoundsonthecardiovascularsystem,ultimatelycausingheartfailure.Despiteextensiveinvestigationsintothe effects of doxorubicin on the cardiovascular system, the molecular mechanisms of toxicity remain largely unknown. MicroRNAsareendogenouslytranscribednon-coding22nucleotidelongRNAsthatregulategeneexpressionbydecreasing mRNAstabilityandtranslationandplaykeyrolesincardiacphysiologyandpathologies.Increasingdosesofdoxorubicin, butnotetoposide(aTopoisomeraseIIinhibitordevoidofcardiovasculartoxicity),specificallyinducedtheup-regulationof miR-208b,miR-216b,miR-215,miR-34candmiR-367inrathearts.Furthermore,thelowestdosingregime(1mg/kg/weekfor 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