The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy.
The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy.
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DOI：
10.1371/journal.pone.0002642
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发表时间：
2008-07-09
期刊：
影响因子：
3.7
通讯作者：
Seidman JG
中科院分区：
文献类型：
--
作者：
Ahmad F;Banerjee SK;Lage ML;Huang XN;Smith SH;Saba S;Rager J;Conner DA;Janczewski AM;Tobita K;Tinney JP;Moskowitz IP;Perez-Atayde AR;Keller BB;Mathier MA;Shroff SG;Seidman CE;Seidman JG
肥厚型(HCM)和扩张型(DCM)心肌病是由肌瘤蛋白突变引起的，包括心肌肌钙蛋白T(cTnT，TNNT2)。我们确定了TNNT2突变是否通过改变cTnT的功能或数量而导致心肌病；扩张型心肌病的严重程度是否与突变型和野生型cTnT的比例有关；扩张型心肌病是否存在钙脱敏；以及cTnT的缺失是否损害了早期胚胎心脏的发生。我们去除Tnnt2以产生杂合子Tnnt2+/−小鼠，然后杂交产生纯合子缺失的Tnnt2−/−胚胎。我们还获得了过表达野生型(TGWT)和DCM突变体(TGK210Δ)Tnnt2的转基因小鼠。杂交产生的小鼠缺乏Tnnt2等位基因，但携带野生型(Tnnt2+/−/Tgwt)或突变型(Tnnt2+/−/TGK210Δ)转基因。与野生型相比，TnNT2+/−小鼠的转录水平显著降低(0.82±0.06vs.1.00±0.12个任意单位；p = 0.025)，但蛋白质水平(1.01±0.20vs.1.00±0.13个任意单位；p = 0.44)无明显变化。TnNT2+/−小鼠心脏形态、质量、左室舒张末期内径、短轴缩短率均正常。此外，TnNT2+/−/TGK210Δ小鼠有严重的扩张性心肌梗死，而TGK210Δ小鼠只有轻微的扩张性心肌梗死(FS18±4vs.29±7%；p<；0.01)。Tnnt2+/−/TGK210Δ小鼠中突变型和野生型TnNT2转录本的比例高于TGK210Δ小鼠(2.42±0.08，p = 0.03)。Tnnt2+/−/TGK210Δ肌表现出钙离子脱敏作用( = 为5.34±0.08vs.5.58±0.03，肌节长度为1.9µm，p<；0.01)，但最大作用力无明显差异。第9.5天Tnnt2−/−胚胎正常心脏呈环状，但室壁变薄，大量心包积液，心脏无收缩，肌节严重紊乱。缺乏一个Tnnt2等位基因会导致转录的轻微缺陷，但不会导致蛋白质的缺失，从而导致正常的心脏表型。DCM是由一种突变蛋白的功能异常引起的，该突变蛋白与心肌细胞钙脱敏有关。DCM的严重程度取决于突变型和野生型Tnnt2转录本的比例。CTnT对肌节的形成是必不可少的，但正常的胚胎心脏环路是没有收缩活动的。
Hypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. We ablated Tnnt2 to produce heterozygous Tnnt2 +/− mice, and crossbreeding produced homozygous null Tnnt2 −/− embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2 +/−/TGWT) or mutant (Tnnt2 +/−/TGK210Δ) transgenes. Tnnt2 +/− mice relative to wildtype had significantly reduced transcript (0.82±0.06[SD] vs. 1.00±0.12 arbitrary units; p = 0.025), but not protein (1.01±0.20 vs. 1.00±0.13 arbitrary units; p = 0.44). Tnnt2 +/− mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2 +/−/TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18±4 vs. 29±7%; p<0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2 +/−/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2 +/−/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34±0.08 vs. 5.58±0.03 at sarcomere length 1.9 µm, p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2 −/− embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity.
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影响因子：
4.8
作者：
Mirza, M;Marston, S;Watkins, H
通讯作者：
Watkins, H
影响因子：
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作者：
Montgomery, DE;Tardiff, JC;Chandra, M
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作者：
FYRBERG, E;FYRBERG, CC;SAVILLE, DL
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SAVILLE, DL
影响因子：
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作者：
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通讯作者：
Stewart, AFR
DOI：
10.1152/ajpheart.00733.2004
发表时间：
2005-10-01
影响因子：
4.8
作者：
Saba, S;Janczewski, AM;London, B
通讯作者：
London, B