1、Backgrounds1.Cardiac remodelingMyocardial ischemia hemodynamic overloadstructural and functional changes in the myocardium2.New facts about Cardiac remodeling cell differentiationde-differentiation organ morphogenesismechanisms implicated in cardiac remodeling3.natures paradigms of tissue remodeling
2、/regeneration-两栖动物变态a delicate balance between cell apoptosis,proliferation and differentiation existsthe transcriptional gene program regulated by thyroid hormone(TH)conserved in mammals4.TH has attracted little attention in the context of cardiac diseasethe acceleration of heart rhythmlow T3 state
3、,which accompanies heart disease,may be protective and needs no treatment没有受到关注用于心脏疾病的治疗recent experimental and clinical research has provided new insights into the role of TH in cardiac remodelingThe role of THin cardiac remodeling1.Card1.Cardiac iac remoderemodelingling2.Thyr2.Thyroid oid hormonho
4、rmone e 3.TH 3.TH signalsignaling in ing in cardiacardiac c remoderemodelingling4.TH 4.TH s s functifunction in on in the the cardiacardiac c remoderemodeling ling 5.5.ClinicClinical al transltranslation ation of TH of TH effecteffects scontent一.Cardiac remodeling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Myoca
5、rdial ischemiahemodynamic overloadcardiac hypertrophy cardiac dilatation and failure心肌梗死myocardial infarctionCardiac remodeling Cardiac remodeling -二.Thyroid hormone TH简介TH受体TH受体的不同功能TH的作用方式甲状腺激素甲状腺激素组成-甲状腺素（T4）和3，5，3-三碘甲腺原氨酸（3）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thyronam
6、ines作用于线粒体作用于细胞膜受体-TRs T3结合TH受体启动TH信号1.甲状腺激素简介关于线粒体DNA转录和合成的因子TR only expression after the end of fetal lifeTR 1 function in heart圆形-椭圆形Key mediators of pathological growth：post-ischemic remodeling压力低于T4组，胶原蛋白量增加PKC:a potential key playercardiac hypertrophyHSP27的过表达，转运和磷酸化TR 1-a molecular switch to
7、postnatal lifeTH can convert pathological to physiological hypertrophyTH 诱导线粒体生物合成the developmental consequences of TH depletion are attenuatedClinical translation of TH effectsTH induces angiogenesisthe developmental consequences of TH depletion are attenuatedThyroid hormoneTR only expression after
8、 the end of fetal lifeTR1 is absent Two TR genes,and,encode four T3-binding receptor isoforms(1,1,2,and 3)2.TH receptors (TRs)The transcriptional activity of TRs is regulated at multiple levels1.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 The distinct function of TR isoform
9、s has been identified1.TR1.TR的功能的功能TR only expression after the end of fetal life TR2-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 TR1-在肝胆固醇平衡中有重要作用 In the heart,TR only function in the hyperthyroid state,and mediate TH-induced mediate TH-induced angiogenesis angiogenesis 2.TR2.TR 的功能的功能TR 1-通过控制心率，适应性产热应激反应，食物吸收等方式保
10、持在体内的平衡，并控制由DNA损伤诱导的组织修复3.TR 1 function in heart In the heart,preferential coupling of TRIn the heart,preferential coupling of TR1 to 1 to-MHC-MHC.TRTR 1-a molecular switch to postnatal life 1-a molecular switch to postnatal life发育时期发育时期TRTR 1 1 表达表达状态状态TRTR 1 1结合状结合状态态TRTR 1 1状状态原因态原因对发育的对发育的影响影响Fe
11、tal lifeTR 1 TR apo-receptorTHD1TH-D3TH浓度低转录抑制胎儿发育Postnatal lifeTR 1 TR Homo-receptorTH浓度增加促进细胞分化A molecular swith to postnatal A molecular swith to postnatal life life！a fetal transcriptional gene re-programmingthe developmental consequences of TH depletion are attenuated display congenital hypothy
12、roidism，repression of T3 target genesincreased expression of PLB impaired calcium handling and contraction unliganded TR1hypertrophy independent of ligand and a fetal pattern of myosin isoform expressionTR1 is absentTR 1 knock-in mutationsTRa1:a molecular switch to the fetal phenotypeIn the course o
13、f In the course of cardiac remodelingcardiac remodeling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mechanisms of altered TRa1 expression？PE administration Neuro-endocrine Neuro-endocrine systems systems?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I
14、ncreased expression of TRa1Altered expression of MHC有TH，无THInflammatory response?TNF-TNF-closely associated with cardiac dysfunction in animals and patients with heart failureTNF-treatmentTR表达下调TR表达不变TR1 may be regulated rather by progrowth stimuli than the inflammatory responseKey mediators of path
15、ological growth：ERK kinase and mTORERK and/or mTOR signaling in PE-induced changes in TRa1 expression in nucleusthere is now evidence that alterations in THsignaling during cardiac remodeling can be also attributed in micro-RNA 2084 TH：mechanisms of action initiated by liganding of the hormone to in
16、tranuclear TRs Plasma membrane-initiated actionsInitiated in the cytoplasmThe level of integrin receptorActivates ERK1/2 Local membrane actions on ion transport systems三.TH signaling in cardiac remodelingMyocardial ischemia hemodynamic overload cardiac hypertrophycardiac dilatation and failurefetal
17、gene transcriptional programming,cardiac hypertrophyThe fetal-like re-programming no longer suffices to support cardiac structure and functionCompensatory mechanisms细胞分化和器官形态改变涉及此过程1.TH signaling a playeror bystander?Maturation of the myocardium Maturation of the myocardium depends on increasing TH
18、depends on increasing TH signalingsignalingTH can TH can promote organ morphogenesis promote organ morphogenesis by by integrating metabolism,cellular integrating metabolism,cellular growth and shape,cellular function growth and shape,cellular function and response to stressand response to stressTH
19、signaling in TH signaling in cardiac remodeling cardiac remodeling A player 2.TH signaling alterations in the course of post-ischemic remodelingmyocardial infarctionCoronary ligation post-ischemic remodeling 创造心急缺血重塑条件 TH-TRs变化的衡量及变化情况TH levels in plasmaD3 activityTRs expressionT3 levels in plasma b
20、e lower within a weekand remained abnormal after 4 weeksHigh activity of D3 both in rats and mouse model TR1 receptor downregulated independentlyTR1 expression was up-regulatedTH signaling can be implicated in the response to ischemia both in normal and pathological myocardium.3.TH signaling and pos
21、t-ischemic remodeling in co-morbiditieshypothyroidismeffect1.increases the tolerance to acute ischemiareperfusion2.abolishes the ischemic preconditioning effect3.accelerates cardiac remodeling after myocardial infarction4.looses the ability to develop compensatory hypertrophy 糖尿病 TRa1 and TRb1 recep
22、tors 表达下调tissue hypothyroidism 心肌梗死TR 1-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organ morphogenesisTR only expression after the end of fetal lifeand remained abnormal after 4 weeksLong-term pretreatment with THIncrease tolerance of ischemia/reperfusion injurysuppressed activation of the isc
23、hemiareperfusion p38 MAPKIn the course of cardiac remodelingorgan morphogenesisThe role of THin cardiac remodelingdisplay congenital hypothyroidism，repression of T3 target genesKey mediators of pathological growth：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T3 levels in plasma be lower within a weekprotein ki
24、nase C(PKC)TR2-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TR 1-a molecular switch to postnatal lifeInflammatory response?TR 1 function in heartInitiated in the cytoplasmPE administration4.TH signaling in the non-ischemic pathological heart心脏肥大诱因心脏肥大诱因TH SignalingTH Signalingeffectseffects右心室超负荷压力D3 activity increase
25、Tissue hypothrodismD2 activity increaseAlter expression patterns of Pathological hypertrophy主动脉缩窄Down-regulation of TRsTissue hypothrodism四 .TH s function in the cardiac remodeling Prevent and/or reverses contractile dysfunctionIncrease tolerance of ischemia/reperfusion injury Convert pathological t
26、o physiological hypertrophyTH TH functionfunctionRegulating the expression of contractice Regulating the expression of contractice proteinsproteins1.TH 阻止或者反转心肌梗死后的收缩功能障碍TH treatment prevented the induction of-MHCthe ratio of SERCA/PLB increasedreversed the fetal pattern of myosin isoform expression
27、 regulating novel pathways related to cardiac regulating novel pathways related to cardiac contractilitycontractilityTH treatment protein kinase C(PKC)heat shock protein 70(HSP70)TH optimizes cardiac geometryTH optimizes cardiac geometryTH treatment induce distinct changes in left ventricular chambe
28、r geometry in a time-dependent mannerNormalizes wall stress by increaing cardiac mass TH induces favorable changes in cardiac geometryactivation of p38 MAPK,PI3K/Akt/mTOR signalingTRs changesCell growth activation of p44 ERK signaling Cell shape changes圆形-椭圆形射血分数增加 TH controls collagen synthesis TH
29、controls collagen synthesisTHinhibits the pro-a1 collagen promoter activitydown-regulates the collagen type I biosynthesisnormalized the increased collagen type I gene expression TH induces angiogenesis TH induces angiogenesisa thyroid analog treatmentSome angiogenic growth factors elevated transcri
30、ption of several angiogenesis-relevant genes action of TH is both non-genomic and genomicTH seems to mediate angiogenesis via its TR receptor4 TH：mechanisms of actionThe distinct function of TR isoforms has been identifiedA playerIn the course of cardiac remodelingT3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
31、变量分析中是评价NYHA的唯一参数changes in cardiac geometrylow TH levelsand remained abnormal after 4 weeks压力低于T4组，胶原蛋白量增加suppressed activation of the ischemiareperfusion p38 MAPKconserved in mammalscardiac remodelingIn the course of cardiac remodelingTH treatment压力低于T4组，胶原蛋白量增加collagen type I biosynthesisPostnata
32、l life受T3依赖的核监管蛋白的调节cardiac dilatation and failureSome angiogenic growth2.TH increases tolerance of the myocardium to ischemia/reperfusion injuryComplex intracellular signaling underlies the cellular response to ischemiaA delicate balance between pro-death and survival pathways exists and determines
33、 the fate of the stressed cellThis signaling can be manipulated either at pre-ischemia level or at reperfusionTH mimics preconditioning effectTH mimics preconditioning effect TH treatment preserves ischemic preconditioning effect while hypothyroidism abolishes the ischemic preconditioning responseTH
34、s cardioprotection function in the ischemia-reperfusion injuryAcute pretreatment with THLong-term pretreatment with THEven the dobutamine detrimental effect on reperfusion injury can be reversed by T4 pretreatmentTHTH心脏保护功能机制PKC:a potential key playerHeat shock proteins:critical end-effectors氧化还原调控信
35、号TH 抑制再灌注损失TH诱导线粒体生物合成PKC:a potential key playerTH treatment PKC过表达和磷酸化HSP27的磷酸化suppressed activation of the ischemiareperfusion p38 MAPK心肌保护Heat shock proteins:critical end-Heat shock proteins:critical end-effectorseffectorsTH treatment HSP27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TH treatment in
36、duce distinct changes in left ventricular chamber geometry in a time-dependent manneractivation of p38 MAPK,display congenital hypothyroidism，repression of T3 target genesIn the heart,TR only function in the hyperthyroid state,and mediate TH-induced angiogenesisTH induces favorable changes用儿茶酚胺刺激肾上腺
37、素受体可以导致心脏肥大与凋亡，导致不良的心脏重塑TR 1-a molecular switch to postnatal lifePlasma membrane-initiated actionsTR 1 TRde-differentiationPostnatal lifePE administration创造心急缺血重塑条件TH treatmentPGC1a 表达增加Increase tolerance of ischemia/reperfusion injuryorgan morphogenesisHSP27的过表达，转运和磷酸化TR 1 TR效果：心脏和运动表现改善，射血分数增加，心脏输
38、出增加，心肺功能参数改善氧化还原调控信号Long TH treatmentMDA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P38MAPK信号通路来改善缺血后的心室功能恢复TH 诱导线粒体生物合成T3左心室边缘梗死区HIF-1a，mtTFA and PGC1a 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TH also has been shown to increase myocardial mitochondrial mass,mitochondrial respiration,oxidat
39、ive phosphorylation(OXPHOS),enzyme activities,mitochondrial protein synthesis(by stimulation in a T3-dependent manner),cytochrome,phospholipid and mtDNA content.In addition,TH can modulate cardiac mitochondrial protein-import apparatus 3.TH can convert pathological to physiological hypertrophy myoca
40、rdial infarction induced pathological hypertrophy model TH treatment changes in cardiac geometryimproved EF%圆形-椭圆形 Aortic constriction-induced pathological hypertrophy model T4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，也不会发展成为心肌衰竭，胶原蛋白浓度降低，spontaneously hypertensive h
41、eart failure(SHHF)modelTreat with three different TH doses from 20 to21 months of age对照组低剂量TH组中剂量TH组高剂量TH组-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4.TH and signaling of the unloaded heartUnload heartspaceflightmicrogravity心脏辅助设备(LVAD)植入末期心脏衰竭病人time-dependent depressions of C
42、a2+handling and myocyte contractilityTH treatment restorrestore e5.Clinical implications:protection versus functionT3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low TH levelstissue hypothyroidism tolerance of the post-ischemic myocardium to ischem
43、ia impaired cardiac function and increased mortalityButBut五.Clinical translation of TH effects1.TH treatment in heart failure 短期T4治疗 慢性心脏衰竭组别组别人数人数治疗方式治疗方式实验组10T4 100ug/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 短期T3治疗 心肌缺血和非心肌缺血膨胀综合症组别组别人数人数治疗方式治疗方式实验组10T3 3天对照组10安慰剂 3天效果：T3增加，无副作用，心率下
44、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 中期T4治疗 组别组别人数人数治疗方式治疗方式实验组10T4 3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TR 1-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TH signaling alterations
45、 in the course of post-ischemic remodelingThyroid hormonedepends on increasing TH signalingT3 levels in plasma be lower within a weekfetal gene transcriptional programming,PE administration4 TH：mechanisms of actionspaceflightTR 1 TRactivation of p38 MAPK,THs cardioprotection function in the ischemia
46、-reperfusion injuryHomo-receptorinitiated by liganding of the hormone to intranuclear TRsThe role of THin cardiac remodeling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组别人数人数治疗方式治疗方式效果效果实验组22T4 1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 NYN
47、A-期心脏充血衰竭患者组别组别人数人数治疗方式治疗方式实验组57DITPA 3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2.TH treatment in the setting of controlled ischemiareperfusionT3治疗 冠动脉搭桥手术病人组别组别人数人数治疗方式治疗方式效果效果实验组4T3 7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Study 1Study 2Study 2组别组别人数人数效果效果T
48、363GIK157T3+GIK60安慰剂组160conclusionTH promotes cell growth and differentiation and as such has pleiotropic effects on the heartTH controls cellular function and metabolism,cell growth and shape and cellular response to stress through distinct intracellular signaling pathwaysTH can reverse and/or prev
49、ent cardiac remodelingBackgrounds1.Cardiac remodelingMyocardial ischemia hemodynamic overloadstructural and functional changes in the myocardium2.New facts about Cardiac remodeling cell differentiationde-differentiation organ morphogenesismechanisms implicated in cardiac remodeling一.Cardiac remodeli
50、ng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Myocardial ischemiahemodynamic overloadcardiac hypertrophy cardiac dilatation and failure心肌梗死myocardial infarctionCardiac remodeling Cardiac remodeling -The distinct function of TR isoforms has been identified1.TR1.TR的功能的功能TR only expression after the end of fetal li
