甲狀腺激素在心臟重塑中的前景

1、會計學1甲狀腺激素在心臟重塑中的前景甲狀腺激素在心臟重塑中的前景第1頁/共56頁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頁/共56頁3.n

2、atures paradigms of tissue remodeling/regeneration- 兩棲動物變態(tài)a delicate balance between cell apoptosis, proliferation and differentiation existsthe transcriptional gene program regulated by thyroid hormone(TH) conserved in mammals第3頁/共56頁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沒有受到關(guān)注用于心臟疾病的治療recent experimental and clinical research has provided new insights into the role of TH in cardiac remodelingThe role of THin cardiac remodeling第4頁/共56頁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頁/共56頁由于心急缺血或者血液壓力超負荷而導致的心臟形態(tài)結(jié)構(gòu)，功能的變化Myocardial ischemiahemodynamic overloadcardiac hypertrophy cardiac dilatation and failure心肌梗死m(xù)yocardial infarct

5、ionCardiac remodeling -第6頁/共56頁TH簡介TH受體TH受體的不同功能TH的作用方式第7頁/共56頁甲狀腺激素甲狀腺激素組成-甲狀腺素（T4）和3，5，3-三碘甲腺原氨酸（3）運輸-被動的，親脂性的，被動的，載體和能量依賴的 代謝T4T3去碘化酶D2T4去碘化酶D1rT3T3去碘化酶D3T2T3去羧化酶thyronamines作用于線粒體作用于細胞膜受體-TRs T3結(jié)合TH受體啟動TH信號1. 甲狀腺激素簡介第8頁/共56頁2. TH receptors (TRs) The transcriptional activity of TRs is regulated a

6、t multiple levels1.T3的調(diào)節(jié)2.T3靶基因啟動子上的應(yīng)答因子調(diào)節(jié)3.受生長和組織依賴的TR異構(gòu)體的調(diào)節(jié)4.受T3依賴的核監(jiān)管蛋白的調(diào)節(jié)5.受磷酸化作用的調(diào)節(jié)第9頁/共56頁 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-在耳膜和視網(wǎng)膜發(fā)育，下丘腦垂體的負反饋調(diào)節(jié)有重要作用 TR1-在肝膽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-通過控制心率，適應(yīng)性產(chǎn)熱應(yīng)激反應(yīng)，食物吸收等方式保持在體內(nèi)的平衡，并控制由DNA損傷誘導的組織修復第10頁/共56頁3.TR 1 function in heart In the heart , preferential coupling of TR1 to -MHC . TR 1- a molecular switch to postnatal life發(fā)育時期發(fā)育時期TR 1 表達狀表達狀態(tài)態(tài)TR 1結(jié)合狀態(tài)結(jié)合狀態(tài)TR 1狀態(tài)狀態(tài)原因原因?qū)Πl(fā)育的對發(fā)

8、育的影響影響Fetal lifeTR 1 TR apo-receptorTHD1TH-D3TH濃度低轉(zhuǎn)錄抑制胎兒發(fā)育Postnatal lifeTR 1 TR Homo-receptorTH濃度增加促進細胞分化A molecular swith to postnatal life ！第11頁/共56頁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頁/共56頁In the course of cardiac remodeling補償期TRa1 過表達且為未受體結(jié)合狀態(tài)誘導生長，抑制T3的正調(diào)控基

10、因心臟衰竭期TRa1表達下降甲狀腺機能減退心臟萎縮，腔擴張，血流受損，動脈及功能損失心肌肥大第13頁/共56頁 PE administration Neuro-endocrine systems ?腎上腺素A1腎上腺素用兒茶酚胺刺激腎上腺素受體可以導致心臟肥大與凋亡，導致不良的心臟重塑a1-adrenergic 增加Increased expression of TRa1Altered expression of MHC有TH，無TH第14頁/共56頁Inflammatory response ?TNF-TNF-closely associated with cardiac dysfuncti

11、on in animals and patients with heart failureTNF- treatmentTR表達下調(diào)TR表達不變TR1 may be regulated rather by progrowth stimuli than the inflammatory response第15頁/共56頁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頁/共56頁第17頁/共56頁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頁/共56頁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細胞分化和器官形態(tài)改變涉及此過程1.

14、TH signaling a playeror bystander?第19頁/共56頁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頁/共56頁myocardial i

15、nfarctionCoronary ligation post-ischemic remodeling 創(chuàng)造心急缺血重塑條件 TH-TRs變化的衡量及變化情況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頁/共56頁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 表達下調(diào)tissue hypothyroidism 心肌梗死第22頁/共56頁4.TH signaling in the non-ischemic pathological heart心臟肥大誘因心臟肥大誘因TH Signalingeffects右心室超負荷壓力D3 act

18、ivity increaseTissue hypothrodismD2 activity increaseAlter expression patterns of Pathological hypertrophy主動脈縮窄Down-regulation of TRsTissue hypothrodism第23頁/共56頁Prevent and/or reverses contractile dysfunctionIncrease tolerance of ischemia/reperfusion injury Convert pathological to physiological hype

19、rtrophyTH function第24頁/共56頁1. TH 阻止或者反轉(zhuǎn)心肌梗死后的收縮功能障礙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頁/共56頁第26頁/共56頁 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圓形-橢圓形射血分數(shù)增加第27頁/共56頁 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頁/共56頁 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頁/共56頁第30頁/共56頁第31頁/共56頁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頁/共56頁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頁/共56頁PKC: a potential key playerHeat shock proteins: critical end-effectors氧化還原調(diào)控信號TH

25、 抑制再灌注損失TH誘導線粒體生物合成第34頁/共56頁TH treatment PKC過表達和磷酸化HSP27的磷酸化suppressed activation of the ischemiareperfusion p38 MAPK心肌保護Heat shock proteins: critical end-effectorsTH treatment HSP27的過表達，轉(zhuǎn)運和磷酸化HSP70的過表達保持細胞骨架的完整性增加對缺血再灌注的承受力第35頁/共56頁Long TH treatmentMDA水平高氧壓增大于心肌保護分子相協(xié)調(diào)心肌承受增加TH 限制再灌注損傷T3通過抑制促凋亡的由缺血再

26、灌注誘導的P38MAPK信號通路來改善缺血后的心室功能恢復第36頁/共56頁第37頁/共56頁T3左心室邊緣梗死區(qū)HIF-1a ，mtTFA and PGC1a 表達增加線粒體DNA轉(zhuǎn)錄和生物合成增加保護細胞不死亡關(guān)于線粒體DNA轉(zhuǎn)錄和合成的因子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頁/共56頁 myocardial infarction induced pathological hypertrophy model TH treatment changes in cardiac geometryimproved EF% 圓形-橢圓形 Aort

28、ic constriction-induced pathological hypertrophy model T4組對照組壓力負荷增大，膠原蛋白量低壓力低于T4組，膠原蛋白量增加T3處理恢復毛細血管密度，冠動脈血流量第39頁/共56頁T4 處理壓力增大，但是不會引起腔和心肌的僵硬，也不會發(fā)展成為心肌衰竭，膠原蛋白濃度降低， spontaneously hypertensive heart failure (SHHF) modelTreat with three different TH doses from 20 to21 months of age對照組低劑量TH組中劑量TH組高劑量TH組-

29、 - 肌球蛋白量均減少左心室大小功能不變甲亢，心室壓力減小，心室形狀變化趨向橢圓甲亢（重量增加，心率增加） ，直徑/壁厚 減小，即趨于橢圓第40頁/共56頁Unload heartspaceflightmicrogravity心臟輔助設(shè)備(LVAD) 植入末期心臟衰竭病人time-dependent depressions of Ca2+ handling and myocyte contractilityTH treatment restore第41頁/共56頁T3可用于評價患有心肌充血衰竭病人的心肌功能障礙（NYHA），并且在多變量分析中是評價NYHA的唯一參數(shù)T3總量也與擴張型心肌病人的

30、最大耗氧量有關(guān)低T3水平似乎是獨立增加心肌衰竭病人死亡率的危險因素low TH levelstissue hypothyroidism tolerance of the post-ischemic myocardium to ischemia impaired cardiac function and increased mortalityBut第42頁/共56頁1. TH treatment in heart failure 短期T4治療 慢性心臟衰竭組別組別人數(shù)人數(shù)治療方式治療方式實驗組10T4 100ug/day對照組10安慰劑100ug/day效果：心臟和運動表現(xiàn)改善，射血分數(shù)增加，心

31、臟輸出增加，心肺功能參數(shù)改善第43頁/共56頁 短期T3治療 心肌缺血和非心肌缺血膨脹綜合癥組別組別人數(shù)人數(shù)治療方式治療方式實驗組10T3 3天對照組10安慰劑 3天效果：T3增加，無副作用，心率下降，一些神經(jīng)激素濃度下降，左心室容積和博出量增加，工作量不變第44頁/共56頁 中期T4治療 組別組別人數(shù)人數(shù)治療方式治療方式實驗組10T4 3月對照組10安慰劑 3月效果：無甲亢癥狀，心臟功能改善（射血分數(shù)增加，心臟輸出增加），心臟擴張尺寸，全身血管阻力減小，多巴酚丁胺輸入是心臟輸出和心率也都有改善，在運動高峰時心臟輸出有增加第45頁/共56頁 低劑量T4 治療 難治性心率衰竭和正常甲狀腺病態(tài)綜合

32、癥組別組別人數(shù)人數(shù)治療方式治療方式效果效果實驗組22T4 1月無死亡，無心率不齊發(fā)生，BNP,射血分數(shù)，心臟功能提升，無甲狀腺毒癥對照組32安慰劑 1月5人死于心率不齊，27人BNP和射血分數(shù)，及心臟功能不變 TH類似物治療 NYNA-期心臟充血衰竭患者組別組別人數(shù)人數(shù)治療方式治療方式實驗組57DITPA 3月對照組29安慰劑 3月由于病人對藥物的耐受性差，實驗提前終止TH類似物的耐受性差，掩蓋了對充血性心臟衰竭的具體效果，但一些參數(shù)顯示，DITPA有擬甲狀腺功能第46頁/共56頁T3治療 冠動脈搭橋手術(shù)病人組別組別人數(shù)人數(shù)治療方式治療方式效果效果實驗組4T3 7天 125ug/day手術(shù)前后

33、心臟指數(shù)增加，平均肌力要求下降對照組4安慰劑 3月無變化Study 1第47頁/共56頁Study 2組別組別人數(shù)人數(shù)效果效果T363GIK157T3+GIK60安慰劑組160第48頁/共56頁第49頁/共56頁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頁/共56頁由于心急缺血或者血液壓力超負荷而導致的心臟形態(tài)結(jié)構(gòu)，功能的變化Myocardial ischemiahemodynamic overloadcardiac hypertrophy cardiac dilatation and failure心肌梗死m(xù)yocardial infarctionCardiac remodeling -第51頁/共56頁 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-在耳膜和視網(wǎng)膜發(fā)育，下丘腦垂體的負反饋調(diào)節(jié)有重要作用 TR1-在肝膽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-通過控制心率，適應(yīng)性產(chǎn)熱應(yīng)激反應(yīng)，食物吸收等方式保持在體內(nèi)的平衡，并控制由DNA損傷誘導的組織修復第52頁/共56頁3.TR 1 function in heart In the heart , preferential coupling o