ERK12 Signaling Dominates Over RhoA Signaling in Regulating Early Changes in RNA Expression Induced by Endothelin-1 in Neonatal Rat Cardiomyocytes 英文参考文献.docVIP

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ERK12 Signaling Dominates Over RhoA Signaling in Regulating Early Changes in RNA Expression Induced by Endothelin-1 in Neonatal Rat Cardiomyocytes 英文参考文献.doc

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ERK12 Signaling Dominates Over RhoA Signaling in Regulating Early Changes in RNA Expression Induced by Endothelin-1 in Neonatal Rat Cardiomyocytes 英文参考文献

ERK1/2SignalingDominatesOverRhoASignalingin RegulatingEarlyChangesinRNAExpressionInducedby Endothelin-1inNeonatalRatCardiomyocytes AndrewK.Marshall,OliverP.T.Barrett,TimothyE.Cullingford,AchchuthanShanmugasundram, PeterH.Sugden,AngelaClerk* NationalHeartandLungInstitute,FacultyofMedicine,ImperialCollegeLondon,London,UnitedKingdom Abstract Background: Cardiomyocyte hypertrophy is associated with changes in gene expression. Extracellular signal-regulated kinases1/2(ERK1/2)andRhoA[activatedbyhypertrophicagonists(e.g.endothelin-1)]regulategeneexpressionandare implicatedintheresponse,buttheirrelativesignificanceinregulatingthecardiomyocytetranscriptomeisunknown.Our aim was to establish the significance of ERK1/2 and/or RhoA in the early cardiomyocyte transcriptomic response to endothelin-1. Methods/PrincipalFindings:Cardiomyocyteswereexposedtoendothelin-1(1h)with/withoutPD184352(toinhibitERK1/ 2) or C3 transferase (C3T, to inhibit RhoA). RNA expression was analyzed using microarrays and qPCR. ERK1/2 signaling positivelyregulated,65%oftheearlygeneexpressionresponsetoET-1withasmall(,2%)negativeeffect,whereasRhoA signaling positively regulated ,10% of the early gene expression response to ET-1 with a greater (,14%) negative contribution. Of RNAs non-responsive to endothelin-1, 66 or 448 were regulated by PD184352 or C3T, respectively, indicating that RhoA had a more significant effect on baseline RNA expression. mRNAs upregulated by endothelin-1 encoded a number of receptor ligands (e.g. Ereg, Areg, Hbegf) and transcription factors (e.g. Abra/Srf) that potentially propagatetheresponse. Conclusions/Significance:ERK1/2dominatesoverRhoAintheearlytranscriptomicresponsetoendothelin-1.RhoAplaysa majorroleinmaintainingbaselineRNAexpressionbut,withupregulationofAbra/Srfbyendothelin-1,RhoAmayregulate changesinRNAexpressionoverlongertimes.OurdataidentifyERK1/2asamoresignificantnodethanRhoAinregulating theearlystagesofcardiomyocytehypertrophy. Citation:MarshallAK,BarrettOPT,Cullingf