甲状腺激素在心脏重塑中的前景教学课件

Backgrounds1.CardiacremodelingMyocardialischemiahemodynamicoverloadstructuralandfunctionalchangesinthemyocardium2.NewfactsaboutCardiacremodelingcelldifferentiationde-differentiationorganmorphogenesismechanismsimplicatedincardiacremodelingBackgrounds1.Cardiacremodelin13.nature’sparadigmsoftissueremodeling/regeneration----两栖动物变态adelicatebalancebetweencellapoptosis,proliferationanddifferentiationexiststhetranscriptionalgeneprogramregulatedbythyroidhormone(TH)conservedinmammals3.nature’sparadigmsoftissue24.THhasattractedlittleattentioninthecontextofcardiacdiseasetheaccelerationofheartrhythm‘lowT3state’’,whichaccompaniesheartdisease,maybeprotectiveandneedsnotreatment没有受到关注用于心脏疾病的治疗recentexperimentalandclinicalresearchhasprovidednewinsightsintotheroleofTHincardiacremodelingTheroleofTH—incardiacremodeling4.THhasattractedlittleatte31.Cardiacremodeling2.Thyroidhormone3.THsignalingincardiacremodeling4.TH‘sfunctioninthecardiacremodeling5.ClinicaltranslationofTHeffectscontent1.Cardiacremodeling2.Thyroid4一.Cardiacremodeling由于心急缺血或者血液压力超负荷而导致的心脏形态结构，功能的变化Myocardialischemiahemodynamicoverloadcardiachypertrophycardiacdilatationandfailure心肌梗死myocardialinfarctionCardiacremodeling-----一.Cardiacremodeling由于心急5二.ThyroidhormoneTH简介TH受体TH受体的不同功能TH的作用方式二.ThyroidhormoneTH简介TH受6甲状腺激素组成--------甲状腺素（T4）和3，5，3′-三碘甲腺原氨酸（Ｔ3）运输-----------被动的，亲脂性的，被动的，载体和能量依赖的代谢T4T3去碘化酶D2T4去碘化酶D1rT3T3去碘化酶D3T2T3去羧化酶thyronamines作用于线粒体作用于细胞膜受体----------TRsT3结合TH受体启动TH信号1.甲状腺激素简介甲状腺激素组成--------甲状腺素（T4）和3，5，3′7关于线粒体DNA转录和合成的因子TRβonlyexpressionaftertheendoffetallifeTRα1functioninheart圆形------椭圆形Keymediatorsofpathologicalgrowth：post-ischemicremodeling压力低于T4组，胶原蛋白量增加PKC:apotentialkeyplayercardiachypertrophyHSP27的过表达，转运和磷酸化TRα1----amolecularswitchtopostnatallifeTHcanconvertpathologicaltophysiologicalhypertrophyTH诱导线粒体生物合成thedevelopmentalconsequencesofTHdepletionareattenuatedClinicaltranslationofTHeffectsTHinducesangiogenesisthedevelopmentalconsequencesofTHdepletionareattenuatedThyroidhormoneTRβonlyexpressionaftertheendoffetallifeTRα1isabsentTwoTRgenes,αandβ,encodefourT3-bindingreceptorisoforms(α1,β1,β2,andβ3)2.THreceptors(TRs)

ThetranscriptionalactivityofTRsisregulatedatmultiplelevels1.T3的调节2.T3靶基因启动子上的应答因子调节3.受生长和组织依赖的TR异构体的调节4.受T3依赖的核监管蛋白的调节5.受磷酸化作用的调节关于线粒体DNA转录和合成的因子TwoTRgenes,8

ThedistinctfunctionofTRisoformshasbeenidentified1.TRβ的功能TRβonlyexpressionaftertheendoffetallifeTRβ2----在耳膜和视网膜发育，下丘脑—垂体的负反馈调节有重要作用

TRβ1----在肝胆固醇平衡中有重要作用

Intheheart,TRβonlyfunctioninthehyperthyroidstate,andmediateTH-inducedangiogenesis2.TRα

的功能TRα1-----通过控制心率，适应性产热应激反应，食物吸收等方式保持在体内的平衡，并控制由DNA损伤诱导的组织修复ThedistinctfunctionofTR93.TRα1functioninheartIntheheart,preferentialcouplingofTRα1toα-MHC.TRα1----amolecularswitchtopostnatallife发育时期TRα1

表达状态TRα1结合状态TRα1状态原因对发育的影响FetallifeTRα1>

TRβ

apo-receptorTH—D1TH---D3TH浓度低转录抑制胎儿发育PostnatallifeTRα1TRβ

Homo-receptorTH浓度增加促进细胞分化Amolecularswithtopostnatallife！3.TRα1functioninheartInt10afetaltranscriptionalgenere-programmingthedevelopmentalconsequencesofTHdepletionareattenuateddisplaycongenitalhypothyroidism，repressionofT3targetgenesincreasedexpressionofPLBimpairedcalciumhandlingandcontractionunligandedTRα1hypertrophyindependentofligandandafetalpatternofmyosinisoformexpressionTRα1isabsentTRα1knock-inmutationsafetaltranscriptionalgener11TRa1:amolecularswitchtothefetalphenotypeInthecourseofcardiacremodeling补偿期TRa1过表达且为未受体结合状态诱导生长，抑制T3的正调控基因心脏衰竭期TRa1表达下降甲状腺机能减退心脏萎缩，腔扩张，血流受损，动脉及功能损失心肌肥大TRa1:amolecularswitchtoth12mechanismsofalteredTRa1expression？

PEadministrationNeuro-endocrinesystems?肾上腺素A1—肾上腺素用儿茶酚胺刺激肾上腺素受体可以导致心脏肥大与凋亡，导致不良的心脏重塑a1-adrenergic增加IncreasedexpressionofTRa1AlteredexpressionofMHC有TH，无THmechanismsofalteredTRa1exp13Inflammatoryresponse?TNF-αTNF-αcloselyassociatedwithcardiacdysfunctioninanimalsandpatientswithheartfailureTNF-αtreatmentTRβ表达下调TRα表达不变TRα1mayberegulatedratherbyprogrowthstimulithantheinflammatoryresponseInflammatoryresponse?TNF-αTN14Keymediatorsofpathologicalgrowth：ERKkinaseandmTORERKand/ormTORsignalinginPE-inducedchangesinTRa1expressioninnucleusthereisnowevidencethatalterationsinTHsignalingduringcardiacremodelingcanbealsoattributedinmicro-RNA208Keymediatorsofpathological15甲状腺激素在心脏重塑中的前景教学课件164TH：mechanismsofaction

initiatedbyligandingofthehormonetointranuclearTRsPlasmamembrane-initiatedactionsInitiatedinthecytoplasmThelevelofintegrinreceptorActivatesERK1/2Localmembraneactionsoniontransportsystems4TH：mechanismsofactionin17三.

THsignalingincardiacremodeling

Myocardialischemiahemodynamicoverloadcardiachypertrophycardiacdilatationandfailurefetalgenetranscriptionalprogramming,cardiachypertrophyThefetal-likere-programmingnolongersufficestosupportcardiacstructureandfunctionCompensatorymechanisms细胞分化和器官形态改变涉及此过程1.THsignalinga‘‘player’’or‘‘bystander’’??三.THsignalingincardiacr18MaturationofthemyocardiumdependsonincreasingTHsignalingTHcanpromoteorganmorphogenesisbyintegratingmetabolism,cellulargrowthandshape,cellularfunctionandresponsetostressTHsignalingincardiacremodelingAplayerMaturationofthemyocardiumT192.THsignalingalterationsinthecourseofpost-ischemicremodelingmyocardialinfarctionCoronaryligationpost-ischemicremodeling创造心急缺血重塑条件TH---TRs变化的衡量及变化情况THlevelsinplasmaD3activityTRsexpressionT3levelsinplasmabelowerwithinaweekandremainedabnormalafter4weeksHighactivityofD3bothinratsandmousemodelTRβ1receptordownregulatedindependentlyTRα1expressionwasup-regulated2.THsignalingalterationsin20THsignalingcanbeimplicatedintheresponsetoischemiabothinnormalandpathologicalmyocardium.3.THsignalingandpost-ischemicremodelinginco-morbiditieshypothyroidismeffect1.increasesthetolerancetoacuteischemia–reperfusion2.abolishestheischemicpreconditioningeffect3.acceleratescardiacremodelingaftermyocardialinfarction4.loosestheabilitytodevelopcompensatoryhypertrophy糖尿病TRa1andTRb1receptors表达下调tissuehypothyroidism心肌梗死THsignalingcanbeimplicated21TRα1-----通过控制心率，适应性产热应激反应，食物吸收等方式保持在体内的平衡，并控制由DNA损伤诱导的组织修复organmorphogenesisTRβonlyexpressionaftertheendoffetallifeandremainedabnormalafter4weeksLong-termpretreatmentwithTHIncreasetoleranceofischemia/reperfusioninjurysuppressedactivationoftheischemia–reperfusionp38MAPKInthecourseofcardiacremodelingorganmorphogenesisTheroleofTH—incardiacremodelingdisplaycongenitalhypothyroidism，repressionofT3targetgenesKeymediatorsofpathologicalgrowth：无死亡，无心率不齐发生，BNP,射血分数，心脏功能提升，无甲状腺毒症T3levelsinplasmabelowerwithinaweekproteinkinaseC(PKC)TRβ2----在耳膜和视网膜发育，下丘脑—垂体的负反馈调节有重要作用TRα1----amolecularswitchtopostnatallifeInflammatoryresponse?TRα1functioninheartInitiatedinthecytoplasmPEadministration4.THsignalinginthenon-ischemicpathologicalheart心脏肥大诱因THSignalingeffects右心室超负荷压力D3activityincreaseTissuehypothrodismD2activityincreaseAlterexpressionpatternsofPathologicalhypertrophy主动脉缩窄Down-regulationofTRsTissuehypothrodismTRα1-----通过控制心率，适应性产热应激反应，食物吸22四

.

TH‘sfunctioninthecardiacremodeling

Preventand/orreversescontractiledysfunctionIncreasetoleranceofischemia/reperfusioninjuryConvertpathologicaltophysiologicalhypertrophyTHfunction四.TH‘sfunctionintheca23Regulatingtheexpressionofcontracticeproteins1.TH阻止或者反转心肌梗死后的收缩功能障碍THtreatmentpreventedtheinductionofβ-MHCtheratioofSERCA/PLBincreasedreversedthefetalpatternofmyosinisoformexpression

regulatingnovelpathwaysrelatedtocardiaccontractilityTHtreatmentproteinkinaseC(PKC)heatshockprotein70(HSP70)Regulatingtheexpressionofc24甲状腺激素在心脏重塑中的前景教学课件25

THoptimizescardiacgeometryTHtreatmentinducedistinctchangesinleftventricularchambergeometryinatime-dependentmannerNormalizeswallstressbyincreaingcardiacmassTHinducesfavorablechangesincardiacgeometryactivationofp38MAPK,PI3K/Akt/mTORsignalingTRschangesCellgrowthactivationofp44ERKsignalingCellshapechanges圆形-------椭圆形射血分数增加THoptimizescardiacgeome26THcontrolscollagensynthesisTHinhibitsthepro-a1collagenpromoteractivitydown-regulatesthecollagentypeIbiosynthesisnormalizedtheincreasedcollagentypeIgeneexpressionTHcontrolscollagensynthes27THinducesangiogenesisathyroidanalogtreatmentSomeangiogenicgrowthfactorselevatedtranscriptionofseveralangiogenesis-relevantgenesactionofTHisbothnon-genomicandgenomicTHseemstomediateangiogenesisviaitsTRβreceptorTHinducesangiogenesisath284TH：mechanismsofactionThedistinctfunctionofTRisoformshasbeenidentifiedAplayerInthecourseofcardiacremodelingT3可用于评价患有心肌充血衰竭病人的心肌功能障碍（NYHA），并且在多变量分析中是评价NYHA的唯一参数changesincardiacgeometrylowTHlevelsandremainedabnormalafter4weeks压力低于T4组，胶原蛋白量增加suppressedactivationoftheischemia–reperfusionp38MAPKconservedinmammalscardiacremodelingInthecourseofcardiacremodelingTHtreatment压力低于T4组，胶原蛋白量增加collagentypeIbiosynthesisPostnatallife受T3依赖的核监管蛋白的调节cardiacdilatationandfailureSomeangiogenicgrowth4TH：mechanismsofaction29甲状腺激素在心脏重塑中的前景教学课件302.THincreasestoleranceofthemyocardiumtoischemia/reperfusioninjuryComplexintracellularsignalingunderliesthecellularresponsetoischemiaAdelicatebalancebetweenpro-deathandsurvivalpathwaysexistsanddeterminesthefateofthestressedcellThissignalingcanbemanipulatedeitheratpre-ischemialeveloratreperfusion2.THincreasestoleranceofth31THmimicspreconditioningeffectTHtreatmentpreservesischemicpreconditioningeffectwhilehypothyroidismabolishestheischemicpreconditioningresponseTH’scardioprotectionfunctionintheischemia-reperfusioninjuryAcutepretreatmentwithTHLong-termpretreatmentwithTHEventhedobutaminedetrimentaleffectonreperfusioninjurycanbereversedbyT4pretreatmentTHmimicspreconditioningeffe32TH心脏保护功能机制PKC:apotentialkeyplayerHeatshockproteins:criticalend-effectors氧化还原调控信号TH抑制再灌注损失TH诱导线粒体生物合成TH心脏保护功能机制PKC:apotentialkey33PKC:apotentialkeyplayerTHtreatmentPKC过表达和磷酸化HSP27的磷酸化suppressedactivationoftheischemia–reperfusionp38MAPK心肌保护Heatshockproteins:criticalend-effectorsTHtreatmentHSP27的过表达，转运和磷酸化HSP70的过表达保持细胞骨架的完整性增加对缺血再灌注的承受力PKC:apotentialkeyplayerTH34THtreatmentinducedistinctchangesinleftventricularchambergeometryinatime-dependentmanneractivationofp38MAPK,displaycongenitalhypothyroidism，repressionofT3targetgenesIntheheart,TRβonlyfunctioninthehyperthyroidstate,andmediateTH-inducedangiogenesisTHinducesfavorablechanges用儿茶酚胺刺激肾上腺素受体可以导致心脏肥大与凋亡，导致不良的心脏重塑TRα1----amolecularswitchtopostnatallifePlasmamembrane-initiatedactionsTRα1TRβde-differentiationPostnatallifePEadministration创造心急缺血重塑条件THtreatmentPGC—1a表达增加Increasetoleranceofischemia/reperfusioninjuryorganmorphogenesisHSP27的过表达，转运和磷酸化TRα1>TRβ效果：心脏和运动表现改善，射血分数增加，心脏输出增加，心肺功能参数改善氧化还原调控信号LongTHtreatmentMDA水平高氧压增大于心肌保护分子相协调心肌承受增加TH限制再灌注损伤T3通过抑制促凋亡的由缺血再灌注诱导的P38—MAPK信号通路来改善缺血后的心室功能恢复THtreatmentinducedistinctc35甲状腺激素在心脏重塑中的前景教学课件36TH诱导线粒体生物合成T3左心室边缘梗死区HIF-1a，mtTFAandPGC—1a表达增加线粒体DNA转录和生物合成增加保护细胞不死亡关于线粒体DNA转录和合成的因子THalsohasbeenshowntoincreasemyocardialmitochondrialmass,mitochondrialrespiration,oxidativephosphorylation(OXPHOS),enzymeactivities,mitochondrialproteinsynthesis(bystimulationinaT3-dependentmanner),cytochrome,phospholipidandmtDNAcontent.Inaddition,THcanmodulatecardiacmitochondrialprotein-importapparatusTH诱导线粒体生物合成T3左心室边缘梗死区线粒体DNA转录373.THcanconvertpathologicaltophysiologicalhypertrophymyocardialinfarctioninducedpathologicalhypertrophymodelTHtreatmentchangesincardiacgeometryimprovedEF%圆形------椭圆形Aorticconstriction--inducedpathologicalhypertrophymodelT4组对照组压力负荷增大，胶原蛋白量低压力低于T4组，胶原蛋白量增加T3处理恢复毛细血管密度，冠动脉血流量3.THcanconvertpathological38T4处理压力增大，但是不会引起腔和心肌的僵硬，也不会发展成为心肌衰竭，胶原蛋白浓度降低，spontaneouslyhypertensiveheartfailure(SHHF)modelTreatwiththreedifferentTHdosesfrom20to21monthsofage对照组低剂量TH组中剂量TH组高剂量TH组α--β--肌球蛋白量均减少左心室大小功能不变甲亢，心室压力减小，心室形状变化趋向椭圆甲亢（重量增加，心率增加），直径/壁厚减小，即趋于椭圆T4处理压力增大，但是不会引起腔和心肌的僵硬，也不会发展成394.THandsignalingoftheunloadedheartUnloadheartspaceflightmicrogravity心脏辅助设备(LVAD)植入末期心脏衰竭病人time-dependentdepressionsofCa2+handlingandmyocytecontractilityTHtreatmentrestore4.THandsignalingoftheun405.Clinicalimplications:protectionversusfunctionT3可用于评价患有心肌充血衰竭病人的心肌功能障碍（NYHA），并且在多变量分析中是评价NYHA的唯一参数T3总量也与扩张型心肌病人的最大耗氧量有关低T3水平似乎是独立增加心肌衰竭病人死亡率的危险因素lowTHlevelstissuehypothyroidismtoleranceofthepost-ischemicmyocardiumtoischemiaimpairedcardiacfunctionandincreasedmortalityBut5.Clinicalimplications:pro41五.ClinicaltranslationofTHeffects1.THtreatmentinheartfailure短期T4治疗慢性心脏衰竭组别人数治疗方式实验组10T4100ug/day对照组10安慰剂100ug/day效果：心脏和运动表现改善，射血分数增加，心脏输出增加，心肺功能参数改善五.ClinicaltranslationofT42短期T3治疗心肌缺血和非心肌缺血膨胀综合症组别人数治疗方式实验组10T33天对照组10安慰剂3天效果：T3增加，无副作用，心率下降，一些神经激素浓度下降，左心室容积和博出量增加，工作量不变短期T3治疗心肌缺血和非心肌缺血膨胀综合症组别人43中期T4治疗组别人数治疗方式实验组10T43月对照组10安慰剂3月效果：无甲亢症状，心脏功能改善（射血分数增加，心脏输出增加），心脏扩张尺寸，全身血管阻力减小，多巴酚丁胺输入是心脏输出和心率也都有改善，在运动高峰时心脏输出有增加中期T4治疗组别人数治疗方式实验组10T43月44TRα1-----通过控制心率，适应性产热应激反应，食物吸收等方式保持在体内的平衡，并控制由DNA损伤诱导的组织修复由于病人对药物的耐受性差，实验提前终止效果：心脏和运动表现改善，射血分数增加，心脏输出增加，心肺功能参数改善TH诱导线粒体生物合成THsignalingalterationsinthecourseofpost-ischemicremodelingThyroidhormonedependsonincreasingTHsignalingT3levelsinplasmabelowerwithinaweekfetalgenetranscriptionalprogramming,PEadministration4TH：mechanismsofactionspaceflightTRα1TRβactivationofp38MAPK,TH’scardioprotectionfunctionintheischemia-reperfusioninjuryHomo-receptorinitiatedbyligandingofthehormonetointranuclearTRsTheroleofTH—incardiacremodeling线粒体DNA转录和生物合成增加de-differentiation低剂量T4治疗难治性心率衰竭和正常甲状腺病态综合症组别人数治疗方式效果实验组22T41月无死亡，无心率不齐发生，BNP,射血分数，心脏功能提升，无甲状腺毒症对照组32安慰剂1月5人死于心率不齐，27人BNP和射血分数，及心脏功能不变TH类似物治疗NYNAⅡ--Ⅳ期心脏充血衰竭患者组别人数治疗方式实验组57DITPA3月对照组29安慰剂3月由于病人对药物的耐受性差，实验提前终止TH类似物的耐受性差，掩盖了对充血性心脏衰竭的具体效果，但一些参数显示，DITPA有拟甲状腺功能TRα1-----通过控制心率，适应性产热应激反应，食物吸452.THtreatmentinthesettingofcontrolledischemia–reperfusionT3治疗冠动脉搭桥手术病人组别人数治疗方式效果实验组4T37天125ug/day手术前后心脏指数增加，平均肌力要求下降对照组4安慰剂3月无变化Study12.THtreatmentinthesetting46Study2组别人数效果T363GIK157T3+GIK60安慰剂组160Study2组别人数效果T363GIK157T3+GIK47conclusionTHpromotescellgrowthanddifferentiationandassuchhaspleiotropiceffectsontheheartTHcontrolscellularfunctionandmetabolism,cellgrowthandshapeandcellularresponsetostressthroughdistinctintracellularsignalingpathwaysTHcanreverseand/orpreventcardiacremodelingconclusionTHpromotescellgro48Backgrounds1.CardiacremodelingMyocardialischemiahemodynamicoverloadstructuralandfunctionalchangesinthemyocardium2.NewfactsaboutCardiacremodelingcelldifferentiationde-differentiationorganmorphogenesismechanismsimplicatedincardiacremodelingBackgrounds1.Cardiacremodelin49一.Cardiacremodeling由于心急缺血或者血液压力超负荷而导致的心脏形态结构，功能的变化Myocardialischemiahemodynamicoverloadcardiachypertrophycardiacdilatationandfailure心肌梗死myocardialinfarctionCardiacremodeling-----一.Cardiacremodeling由于心急50

ThedistinctfunctionofTRisoformshasbeenidentified1.TRβ的功能TRβonlyexpressionaftertheendoffetallifeTRβ2----在耳膜和视网膜发育，下丘脑—垂体的负反馈调节有重要作用

TRβ1----在肝胆固醇平衡中有重要作用

Intheheart,TRβonlyfunctioninthehyperthyroidstate,andmediateTH-inducedangiogenesis2.TRα

的功能TRα1-----通过控制心率，适应性产热应激反应，食物吸收等方式保持在体内的平衡，并控制由DNA损伤诱导的组织修复ThedistinctfunctionofTR513.TRα1functioninheartIntheheart,preferentialcouplingofTRα1toα-MHC.TRα1----amolecularswitchtopostnatallife发育时期TRα1

表达状态TRα1结合状态TRα1状态原因对发育的影响FetallifeTRα1>

TRβ

apo-receptorTH—D1TH---D3TH浓度低转录抑制胎儿发育PostnatallifeTRα1TRβ

Homo-receptorTH浓度增加促进细胞分化Amolecularswithtopostnatallife！3.TRα1functioninheartInt524.THsignalinginthenon-ischemicpathologicalheart心脏肥大诱因THSignalingeffects右心室超负荷压力D3activityincreaseTissuehypothrodismD2activityincreaseAlterexpressionpatternsofPathologicalhypertrophy主动脉缩窄Down-regulationofTRsTissuehypothrodism4.THsignalinginthenon-isch53THmimicspreconditioningeffectTHtreatmentpreservesischemicpreconditioningeffectwhilehypothyroidismabolishestheischemicpreconditioningrespons