Retinoic Acid Signalling Is Activated in the Postischemic Heart and May Influence Remodelling 英文参考文献.docVIP

RetinoicAcidSignallingIsActivatedinthePostischemic HeartandMayInfluenceRemodelling DusanBilbija1,4*,FredHaugen1,4,JuliaSagave1,4,AntonBaysa1,4,NasserBastani2,FinnOlavLevy3,4, AllanSirsjo¨5,RuneBlomhoff2,GuroValen1,4 1Department of Physiology, University of Oslo, Oslo, Norway, 2Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway, 3Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 4Center for Heart Failure Research, University of Oslo, Oslo, Norway, 5DivisionofBiomedicine,DepartmentofClinicalMedicine,O¨rebroUniversity,O¨rebro,Sweden Abstract Background:All-transretinoicacid(atRA),anactivederivativeofvitaminA,regulatescelldifferentiation,proliferationand cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE).We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemicremodelling. MethodsandFindings:Myocardialinfarctionwasinducedthroughligatingtheleftcoronaryarteryinmice.Invivocardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genesandproteinsbyrealtimeRT-PCRandwesternblot.Endogenousretinoidsinpostinfarctedheartswereanalysedby triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolatedfrominfarctedandshamoperatedRAREluciferasereporterheartsandmonitoredforRARactivityandexpressionof targetgenes.TheeffectofatRAonCFproliferationwasevaluatedbyEdUincorporation.Myocardialinfarctionincreased thoracicRARactivityinvivo(p,0.001),whichwasascribedtotheheartthroughexvivoimaging(p=0.002)withthelargest signal1weekpostinfarct.ThiswasaccompaniedbyincreasedcardiacgeneandproteinexpressionoftheRARtargetgenes retinol binding protein 1 (p=0.01 for RNA, p=0,006 for protein) and aldehyde dehydrogenase 1A2 (p=0.04 for RNA, p=0,014 for protei