甲状腺激素在心脏重塑中的前景

1、会计学1甲状腺激素在心脏重塑中的前景甲状腺激素在心脏重塑中的前景第1页/共56页1.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第2页/共56页3.n

2、atures paradigms of tissue remodeling/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 mammals第3页/共56页4.TH has attracted little attention in the context of cardiac dis

3、easethe acceleration of heart rhythmlow T3 state, 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 remodeling第4页/共56页1.Cardiac

4、remodeling2.Thyroid hormone 3.TH signaling in cardiac remodeling4.TH s function in the cardiac remodeling 5. Clinical translation of TH effectscontent第5页/共56页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 infarct

5、ionCardiac remodeling -第6页/共56页TH简介TH受体TH受体的不同功能TH的作用方式第7页/共56页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thyronamines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. 甲状腺激素简介第8页/共56页2. TH receptors (TRs) The transcriptional activity of TRs is regulated a

6、t 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第9页/共56页 The distinct function of TR isoforms has been identified1.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 hy

7、perthyroid state ,and mediate TH-induced angiogenesis 2.TR 的功能的功能TR 1-通过控制心率，适应性产热应激反应，食物吸收等方式保持在体内的平衡，并控制由DNA损伤诱导的组织修复第10页/共56页3.TR 1 function in heart In the heart , preferential coupling of TR1 to -MHC . TR 1- a molecular switch to postnatal life发育时期发育时期TR 1 表达状表达状态态TR 1结合状态结合状态TR 1状态状态原因原因对发育的对发

8、育的影响影响Fetal 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 life ！第11页/共56页a fetal transcriptional gene re-programmingthe developmental consequences of TH depletion are attenuated display congenital hypothyroidism ，repressio

9、n 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 mutations第12页/共56页In the course of cardiac 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

10、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第13页/共56页 PE administration Neuro-endocrine 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Increased expression of TRa1Altered expression of MHC有TH，无TH第14页/共56页Inflammatory response ?TNF-TNF-closely associated with cardiac dysfuncti

11、on 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 response第15页/共56页ERK and/or mTOR signaling in PE-induced changes in TRa1 expression in nucleusthere is now evidence that alterations in THsignaling during car

12、diac remodeling can be also attributed in micro-RNA 208第16页/共56页第17页/共56页4 TH：mechanisms of action initiated by liganding of the hormone to intranuclear TRs Plasma membrane-initiated actionsInitiated in the cytoplasmThe level of integrin receptorActivates ERK1/2 Local membrane actions on ion transpo

13、rt systems第18页/共56页Myocardial ischemia hemodynamic overload cardiac hypertrophycardiac dilatation and failurefetal 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.

14、TH signaling a playeror bystander?第19页/共56页Maturation of the myocardium depends on increasing TH signalingTH can promote organ morphogenesis by integrating metabolism, cellular growth and shape, cellular function and response to stressTH signaling in cardiac remodeling A player 第20页/共56页myocardial i

15、nfarctionCoronary 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 be lower within a weekand remained abnormal after 4 weeksHigh activity of D3 both in rats and mouse model TR1 receptor downregulated independentlyTR1 express

16、ion was up-regulated第21页/共56页TH signaling can be implicated in the response to ischemia both in normal and pathological myocardium.3. TH signaling and post-ischemic remodeling in co-morbiditieshypothyroidismeffect1. increases the tolerance to acute ischemiareperfusion2. abolishes the ischemic precon

17、ditioning effect3. accelerates cardiac remodeling after myocardial infarction4. looses the ability to develop compensatory hypertrophy 糖尿病 TRa1 and TRb1 receptors 表达下调tissue hypothyroidism 心肌梗死第22页/共56页4.TH signaling in the non-ischemic pathological heart心脏肥大诱因心脏肥大诱因TH Signalingeffects右心室超负荷压力D3 act

18、ivity increaseTissue hypothrodismD2 activity increaseAlter expression patterns of Pathological hypertrophy主动脉缩窄Down-regulation of TRsTissue hypothrodism第23页/共56页Prevent and/or reverses contractile dysfunctionIncrease tolerance of ischemia/reperfusion injury Convert pathological to physiological hype

19、rtrophyTH function第24页/共56页1. 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 regulating novel pathways related to cardiac contractilityTH treatment protein kinase C (PKC) heat shock protein 70 (

20、HSP70)第25页/共56页第26页/共56页 TH optimizes cardiac geometryTH treatment induce distinct changes in left ventricular chamber 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 signalingTR

21、s changesCell growth activation of p44 ERK signaling Cell shape changes圆形-椭圆形射血分数增加第27页/共56页 TH controls collagen synthesisTHinhibits the pro-a1 collagen promoter activitydown-regulates the collagen type I biosynthesisnormalized the increased collagen type I gene expression第28页/共56页 TH induces angio

22、genesisa thyroid analog treatmentSome angiogenic growth factors elevated transcription of several angiogenesis-relevant genes action of TH is both non-genomic and genomicTH seems to mediate angiogenesis via its TR receptor第29页/共56页第30页/共56页第31页/共56页2.TH increases tolerance of the myocardium to ische

23、mia/reperfusion injuryComplex intracellular signaling underlies the cellular response to ischemiaA delicate balance between pro-death and survival pathways exists and determines the fate of the stressed cellThis signaling can be manipulated either at pre-ischemia level or at reperfusion第32页/共56页THs

24、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 pretreatment第33页/共56页PKC: a potential key playerHeat shock proteins: critical end-effectors氧化还原调控信号TH

25、 抑制再灌注损失TH诱导线粒体生物合成第34页/共56页TH 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-effectorsTH 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第35页/共56页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

26、灌注诱导的P38MAPK信号通路来改善缺血后的心室功能恢复第36页/共56页第37页/共56页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, oxidative phosphorylation (OXPHOS), enzyme activities, mitochondrial protein synthes

27、is (by stimulation in a T3-dependent manner), cytochrome, phospholipid and mtDNA content.In addition, TH can modulate cardiac mitochondrial protein-import apparatus 第38页/共56页 myocardial infarction induced pathological hypertrophy model TH treatment changes in cardiac geometryimproved EF% 圆形-椭圆形 Aort

28、ic 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，冠动脉血流量第39页/共56页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 heart 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-

29、 - 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，即趋于椭圆第40页/共56页Unload heartspaceflightmicrogravity心脏辅助设备(LVAD) 植入末期心脏衰竭病人time-dependent depressions of Ca2+ handling and myocyte contractilityTH treatment restore第41页/共56页T3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

30、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 ischemia impaired cardiac function and increased mortalityBut第42页/共56页1. 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

31、脏输出增加，心肺功能参数改善第43页/共56页 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，工作量不变第44页/共56页 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第45页/共56页 低剂量T4 治疗 难治性心率衰竭和正常甲状腺病态综合

32、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 NYNA-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有拟甲状腺功能第46页/共56页T3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

33、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 1第47页/共56页Study 2组别组别人数人数效果效果T363GIK157T3+GIK60安慰剂组160第48页/共56页第49页/共56页1.Cardiac remodelingMyocardial ischemia hemodynamic overloadstructural and functional changes in the myocardium2.New facts about Cardiac remodeling cell differentiationde-differentiation organ m

34、orphogenesismechanisms implicated in cardiac remodeling第50页/共56页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 -第51页/共56页 The distinct function of TR isoforms has been identified1.TR的

35、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 angiogenesis 2.TR 的功能的功能TR 1-通过控制心率，适应性产热应激反应，食物吸收等方式保持在体内的平衡，并控制由DNA损伤诱导的组织修复第52页/共56页3.TR 1 function in heart In the heart , preferential coupling o