Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization.
Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization.
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DOI：
10.1371/journal.pone.0167681
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ahmad F
中科院分区：
文献类型：
--
作者：
Ramratnam M;Salama G;Sharma RK;Wang DW;Smith SH;Banerjee SK;Huang XN;Gifford LM;Pruce ML;Gabris BE;Saba S;Shroff SG;Ahmad F
大部分导致遗传性扩张型心肌病（DCM）的机制的研究已经在体外系统中进行了重建。基因工程小鼠模型提供了在体内解剖这些机制的机会。我们建立了Tnnt 2中常染色体显性Arg 141 Trp（R141 W）突变的基因靶向敲入小鼠模型，该突变首次在DCM人类家族中描述。突变（Tnnt 2 R141 W/+）杂合子小鼠重现了人类表型，出现左心室扩张和收缩力降低。转基因过量表达野生型Tnnt 2 mRNA转录本可减弱Tnnt 2 R141 W/+小鼠的表型，并存在基因剂量效应。雄性小鼠的存活率低于雌性小鼠。对来自Tnnt 2 R141 W/+心脏的皮肤纤维的生物力学研究显示，相对于野生型心脏，pCa 50（产生50%最大力所需的-log[Ca 2 +]）显著降低，表明Ca 2+脱敏。Langendorff灌注Tnnt 2 R141 W/+心脏的光学标测研究显示舒张期和收缩期峰值细胞内Ca 2+（[Ca 2 +]i）显著增加，收缩期[Ca 2 +]i升高和舒张期[Ca 2 +]i下降延长。灌注Tnnt 2 R141 W/+心脏在窦性心律下具有较慢的固有频率，并且对异丙肾上腺素的反应降低了峰值心率。与野生型小鼠相比，Tnnt 2 R141 W/+小鼠心脏磷酸化受磷蛋白减少。然而，将Tnnt 2 R141 W/+小鼠与受磷蛋白敲除（Pln-/-）小鼠杂交，其表现出增加的Ca 2+瞬变和收缩性，对DCM表型没有影响。我们得出结论，Tnnt 2 R141 W突变导致Ca 2+脱敏，小鼠通过增加Ca 2+瞬时振幅来适应，这损害了Ca 2+处理动力学、代谢和对β-肾上腺素能激活的反应。
Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 (-log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i), and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/-) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to β-adrenergic activation.
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影响因子：
3.7
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
通讯作者：
Seidman JG
DOI：
10.1152/ajpheart.00431.2002
发表时间：
2003-02-01
影响因子：
4.8
作者：
London, B;Baker, LC;Salama, G
通讯作者：
Salama, G
DOI：
10.1152/ajpheart.00528.2014
发表时间：
2015-04-15
影响因子：
4.8
作者：
Gollapudi, Sampath K.;Tardiff, Jil C.;Chandra, Murali
通讯作者：
Chandra, Murali
影响因子：
3.4
作者：
Adhikari, BB;Regnier, M;Martyn, DA
通讯作者：
Martyn, DA
影响因子：
9.7
作者：
Dyer, Emma C.;Jacques, Adam M.;Marston, Steven B.
通讯作者：
Marston, Steven B.