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ReciprocalRepressionbetweenMicroRNA-133andCalcineurinControlsCardiacHypertrophy:ANovelMechanismforProgressiveCardiacHypertrophyDe-LiDong,Yan-JieLu,Bao-FengYang(董德利吕延杰杨宝峰)DepartmentofPharmacologyHarbinMedicalUniversity,P.R.China
Aug.20-22,2009.DalianReciprocalRepressionbetween1BackgroundCalcineurin/NFATpathwayinducesCardiacHypertrophy
CalcineurinactivationincardiachypertrophyDecreasedmiR-133expressionincardiachypertrophy
OverexpressionofmiR-133inhibitscardiachypertrophy
InhibitionofmiR-133inducescardiachypertrophyAug.20-22,2009.DalianBackgroundCalcineurin/NFATpat21.Calcineurin-DependentCardiacHypertrophyJefferyD.Molkentinetal.Cell,1998;93,215–228.
Aug.20-22,2009.Dalian1.Calcineurin-DependentCardi31.Calcineurin-DependentCardiacHypertrophyJefferyD.Molkentinetal.Cell,1998;93,215–228.
Aug.20-22,2009.Dalian1.Calcineurin-DependentCardi41.Calcineurin-DependentCardiacHypertrophyJefferyD.Molkentinetal.Cell,1998;93,215–228.
Aug.20-22,2009.Dalian1.Calcineurin-DependentCardia5OverexpressionofcalcineurininmousecausessuddencardiacdeathassociatedwithdecreaseddensityofKchannelsDeliDong.etal.CardiovascularResearch57(2003)320–332Aug.20-22,2009.DalianOverexpressionofcalcineurin62.CalcineurinActivationincardiachypertrophyHaeW.Limetal.Circulation.2000;101:2431-2437.Aug.20-22,2009.Dalian2.CalcineurinActivationinc73.Calcineurin/NFATCouplingParticipatesinPathological,butnotPhysiological,CardiacHypertrophyWilkinsBJ,etal.CircRes.2004;94:110-118.Aug.20-22,2009.Dalian3.Calcineurin/NFATCouplingP8CarèAetal.NatMed.2007;13(5):613-8.
4.DecreasedmiR-133expressionincardiachypertrophyAug.20-22,2009.DalianCarèAetal.NatMed.2007;1395.OverexpressionofmiR-133inhibitscardiachypertrophyCarèAetal.NatMed.2007;13(5):613-8.
Aug.20-22,2009.Dalian5.OverexpressionofmiR-133i106.InhibitionofmiR-133inducescardiachypertrophyCarèAetal.NatMed.2007;13(5):613-8.
Aug.20-22,2009.Dalian6.InhibitionofmiR-133induc11Hypothesis:
InteractionbetweenmiR-133andcalcineurinincardiachypertrophy?◆CalcineurinisthetargetofmiR-133;◆
TheexpressionofmiR-133isregulatedbycalcineurin/NFATsignalingpathway.CalcineurinmiR-133CardiachypertrophyAug.20-22,2009.DalianHypothesis:Interactionbetwee12Results
1.miR-133TargetsCalcineurinFigure1.Post-transcriptionalRepressionofCalcineurinbymiR-133.(A)ThesequencesshowingtheuniquesitesofmiRNA::mRNAcomplementarybetweenmiR-133andcalcineurinforratandmousegenes.(B)Co-transfectionofmiR-133withtheluciferasereportergenelinkedtothe3’UTRofcalcineurinreducedluciferaseactivityinratandmousespecies.**P<0.01vsControl;#P<0.05vs
miR-133.
00.51.0
Relativeluciferaseactivity
00.51.0NCmiR-133+AMO-133miR-133AMO-133Mut-133**##**BMouse
(n=8)Rat
(n=10)5’-UUGGUCCCCUUCAACCAGCUGU-3’mmu-miR-133a/rno-miR-133aRatPP2B3’UTR(NM_017042)RatmiR-1333’-UGUCGACCAACUUCCCCUGGUU-5’1600-AACCAUAGUGCCCAGUGACCAG-1621
2225-UGAACAAGAUCCAAAAAACCAA-22463’-UGUCGACCAACUUCCCCUGGUU-5’RatPP2B3’UTR(NM_017042)Site1Site2MousePP2B3’UTR(NM_008914)MousemiR-1333’-UGUCGACCAACUUCCCCUGGUU-5’1739-AGGAGCUGGAGGGGUUGACCAA-1760AAug.20-22,2009.DalianResults
1.miR-133TargetsC13Results:miR-133TargetsCalcineurinFig.2.(A)transfectionofmiR-133specificallyincreasedmiR-133levelinculturedcardiomyocytes.**P<0.01vsnon-transfectiongroup.(B)Thenegativecontrol(NC)hadnoeffectonmiR-133level,butAMO-133decreasedmiR-133level.**P<0.01vscontrol(lipofectaminetransfectionagents).n=3.ABAug.20-22,2009.DalianResults:miR-133TargetsCalc14Results:miR-133TargetsCalcineurinFig.3.EffectsofmiR-133oncalcineurinproteinlevels(n=5),mRNAlevel(n=5)andcellarea(Thenumberwasinbrackets)innormalculturedcardiomyoctes.**P<0.01vsControl.
Aug.20-22,2009.DalianA
B
C
Results:miR-133TargetsCalc151.miR-133TargetsCalcineurinFigure4.EffectsofmiR-133oncalcineurinproteinlevels(n=5),mRNAlevel(n=5)andcellarea(Thenumberofcellswasinbrackets)incardiomyoctestreatedwithPE(50μM).A
B
C
Aug.20-22,2009.Dalian1.miR-133TargetsCalcineuri16Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.5.CalcineurininhibitorCsAinhibitedcardiachypertrophyinducedbytransverseaorticconstrictioninmice.Sham
TACTAC+CsAAug.20-22,2009.DalianA
B
Results:Calcineurin/NFATSign17Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.6.CalcineurininhibitorCsAinhibitedcardiachypertrophy(Thenumberwasinbrackets),calcineurinexpression(n=5)andactivity(n=5).**P<0.01vsControl;##P<0.01vsTAC.
Aug.20-22,2009.DalianA
B
C
Results:Calcineurin/NFATSign18Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.7.CsArestoredthedecreasedmiR-133expressionbutnottheincreasedmiR-195expressioninTAC-inducedhypertrophicheart.**P<0.01vsControl.##P<0.01vsTAC;n=5.
Aug.20-22,2009.DalianA
B
Results:Calcineurin/NFATSign19Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.8.Primaryratscardiomyocytesinserum-freemediumwerestimulatedwithPEandPE+CsA.Cardiomyocyteswereidentifiedwitha-actininantibody(redsignal)andnucleiwerestainedwithbis-benzamide(blue).
ControlPEPE+CsAAug.20-22,2009.DalianA
B
Results:Calcineurin/NFATSign20Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.9.CsAinhibitedhypertrophy(Thenumberwasinbrackets),calcineurinexpression(n=5)andactivity(n=5)incardiomyocytestreatedwithPE(50μM).**P<0.01vsControl.##P<0.01vsPE.
Aug.20-22,2009.DalianA
B
C
Results:Calcineurin/NFATSign21Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.10.CsAalleviatedthedecreasedmiR-133expressioninPE-treatedcardiomyocyes.**P<0.01vsControl.#P<0.05vsPE;n=5.Aug.20-22,2009.DalianResults:Calcineurin/NFATSign22Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.11.Calcineurin/NFAT-dependentRegulationofmiR-133.(A)Antisense-AβODNsincreasedtheexpressionofmiR-133inculturedcardiomyocytes.**P<0.01vsControl;n=4.(B)NFATdecoyODNsincreasedtheexpressionofmiR-133inculturedcardiomyocytes.**P<0.01vsControl;n=5.Aug.20-22,2009.DalianResults:Calcineurin/NFATSign23Conclusion:Aug.20-22,2009.DalianConclusion:Aug.20-22,2009.Dali24ChangChen,RongHuo,NingWang,ZheLi,Yu-JieTu,
AcknowledgmentsJun-TaoHu,XiaChu,WeiHuang,Yan-JieLuBao-FengYangAug.20-22,2009.DalianChangChen,AcknowledgmentsJun25ThankyouThankyou26ReciprocalRepressionbetweenMicroRNA-133andCalcineurinControlsCardiacHypertrophy:ANovelMechanismforProgressiveCardiacHypertrophyDe-LiDong,Yan-JieLu,Bao-FengYang(董德利吕延杰杨宝峰)DepartmentofPharmacologyHarbinMedicalUniversity,P.R.China
Aug.20-22,2009.DalianReciprocalRepressionbetween27BackgroundCalcineurin/NFATpathwayinducesCardiacHypertrophy
CalcineurinactivationincardiachypertrophyDecreasedmiR-133expressionincardiachypertrophy
OverexpressionofmiR-133inhibitscardiachypertrophy
InhibitionofmiR-133inducescardiachypertrophyAug.20-22,2009.DalianBackgroundCalcineurin/NFATpat281.Calcineurin-DependentCardiacHypertrophyJefferyD.Molkentinetal.Cell,1998;93,215–228.
Aug.20-22,2009.Dalian1.Calcineurin-DependentCardi291.Calcineurin-DependentCardiacHypertrophyJefferyD.Molkentinetal.Cell,1998;93,215–228.
Aug.20-22,2009.Dalian1.Calcineurin-DependentCardi301.Calcineurin-DependentCardiacHypertrophyJefferyD.Molkentinetal.Cell,1998;93,215–228.
Aug.20-22,2009.Dalian1.Calcineurin-DependentCardia31OverexpressionofcalcineurininmousecausessuddencardiacdeathassociatedwithdecreaseddensityofKchannelsDeliDong.etal.CardiovascularResearch57(2003)320–332Aug.20-22,2009.DalianOverexpressionofcalcineurin322.CalcineurinActivationincardiachypertrophyHaeW.Limetal.Circulation.2000;101:2431-2437.Aug.20-22,2009.Dalian2.CalcineurinActivationinc333.Calcineurin/NFATCouplingParticipatesinPathological,butnotPhysiological,CardiacHypertrophyWilkinsBJ,etal.CircRes.2004;94:110-118.Aug.20-22,2009.Dalian3.Calcineurin/NFATCouplingP34CarèAetal.NatMed.2007;13(5):613-8.
4.DecreasedmiR-133expressionincardiachypertrophyAug.20-22,2009.DalianCarèAetal.NatMed.2007;13355.OverexpressionofmiR-133inhibitscardiachypertrophyCarèAetal.NatMed.2007;13(5):613-8.
Aug.20-22,2009.Dalian5.OverexpressionofmiR-133i366.InhibitionofmiR-133inducescardiachypertrophyCarèAetal.NatMed.2007;13(5):613-8.
Aug.20-22,2009.Dalian6.InhibitionofmiR-133induc37Hypothesis:
InteractionbetweenmiR-133andcalcineurinincardiachypertrophy?◆CalcineurinisthetargetofmiR-133;◆
TheexpressionofmiR-133isregulatedbycalcineurin/NFATsignalingpathway.CalcineurinmiR-133CardiachypertrophyAug.20-22,2009.DalianHypothesis:Interactionbetwee38Results
1.miR-133TargetsCalcineurinFigure1.Post-transcriptionalRepressionofCalcineurinbymiR-133.(A)ThesequencesshowingtheuniquesitesofmiRNA::mRNAcomplementarybetweenmiR-133andcalcineurinforratandmousegenes.(B)Co-transfectionofmiR-133withtheluciferasereportergenelinkedtothe3’UTRofcalcineurinreducedluciferaseactivityinratandmousespecies.**P<0.01vsControl;#P<0.05vs
miR-133.
00.51.0
Relativeluciferaseactivity
00.51.0NCmiR-133+AMO-133miR-133AMO-133Mut-133**##**BMouse
(n=8)Rat
(n=10)5’-UUGGUCCCCUUCAACCAGCUGU-3’mmu-miR-133a/rno-miR-133aRatPP2B3’UTR(NM_017042)RatmiR-1333’-UGUCGACCAACUUCCCCUGGUU-5’1600-AACCAUAGUGCCCAGUGACCAG-1621
2225-UGAACAAGAUCCAAAAAACCAA-22463’-UGUCGACCAACUUCCCCUGGUU-5’RatPP2B3’UTR(NM_017042)Site1Site2MousePP2B3’UTR(NM_008914)MousemiR-1333’-UGUCGACCAACUUCCCCUGGUU-5’1739-AGGAGCUGGAGGGGUUGACCAA-1760AAug.20-22,2009.DalianResults
1.miR-133TargetsC39Results:miR-133TargetsCalcineurinFig.2.(A)transfectionofmiR-133specificallyincreasedmiR-133levelinculturedcardiomyocytes.**P<0.01vsnon-transfectiongroup.(B)Thenegativecontrol(NC)hadnoeffectonmiR-133level,butAMO-133decreasedmiR-133level.**P<0.01vscontrol(lipofectaminetransfectionagents).n=3.ABAug.20-22,2009.DalianResults:miR-133TargetsCalc40Results:miR-133TargetsCalcineurinFig.3.EffectsofmiR-133oncalcineurinproteinlevels(n=5),mRNAlevel(n=5)andcellarea(Thenumberwasinbrackets)innormalculturedcardiomyoctes.**P<0.01vsControl.
Aug.20-22,2009.DalianA
B
C
Results:miR-133TargetsCalc411.miR-133TargetsCalcineurinFigure4.EffectsofmiR-133oncalcineurinproteinlevels(n=5),mRNAlevel(n=5)andcellarea(Thenumberofcellswasinbrackets)incardiomyoctestreatedwithPE(50μM).A
B
C
Aug.20-22,2009.Dalian1.miR-133TargetsCalcineuri42Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.5.CalcineurininhibitorCsAinhibitedcardiachypertrophyinducedbytransverseaorticconstrictioninmice.Sham
TACTAC+CsAAug.20-22,2009.DalianA
B
Results:Calcineurin/NFATSign43Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.6.CalcineurininhibitorCsAinhibitedcardiachypertrophy(Thenumberwasinbrackets),calcineurinexpression(n=5)andactivity(n=5).**P<0.01vsControl;##P<0.01vsTAC.
Aug.20-22,2009.DalianA
B
C
Results:Calcineurin/NFATSign44Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.7.CsArestoredthedecreasedmiR-133expressionbutnottheincreasedmiR-195expressioninTAC-inducedhypertrophicheart.**P<0.01vsControl.##P<0.01vsTAC;n=5.
Aug.20-22,2009.DalianA
B
Results:Calcineurin/NFATSign45Results:
Calcineurin/NFATSignalingRegulatesmiR-133ExpressionFig.8.Primaryratscardiomyocytesinserum-freemediumwerestimulatedwithPEandPE+CsA.Cardiomyocyteswereidentifiedwitha-actininantibody(redsignal)andnucleiwere
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