Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models
Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models
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DOI：
10.1152/ajpheart.01143.2008
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发表时间：
2009-08-01
影响因子：
4.8
通讯作者：
Tardiff, Jil C.
中科院分区：
文献类型：
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作者：
Guinto, Pia J.;Haim, Todd E.;Tardiff, Jil C.
Guinto PJ，Haim TE，Dowell-Martino CC，Sibinga N，Tardiff JC.钙稳态的时间和突变特异性改变差异决定了小鼠模型中cTnT相关心肌病的进展Am J Physiol Heart Circ Physiol 297：H614-H626，2009。首次发表于2009年6月5日; doi：10.1152/ajpheart.01143.2008。心肌肌钙蛋白T（cTnT）的自然发生突变导致家族性肥厚型心肌病的临床亚型。为了确定细丝突变和心血管表型之间的机制联系，我们已经产生并表征了几种携带cTnT突变的转基因小鼠模型。我们解决了两个中心问题，关于以前观察到的变化，肌细胞力学和Ca 2+稳态：1）他们的特点是所有严重的cTnT突变，和2）他们是主要的（早期）或次要（晚期）组件的肌细胞反应？成年左心室肌细胞分离自2月龄和6月龄的转基因小鼠，其在残基92处携带错义突变，侧接TNT 1 NH 2末端尾部结构域。R92 L和R92 W心肌细胞的结果显示，在2个月时收缩和舒张指数发生突变特异性改变，6个月时有所改善。Ca 2+动力学的改变与机械数据保持一致，其中R92 L和R92 W在早期时间点表现出严重的舒张功能障碍，并随着年龄的增加而改善。在基线cTnI磷酸化改变的背景下，Ca 2+动力学的正常调节表明R92 L优先在肌丝水平上的致病机制。R92 W小鼠中Ca 2+处理蛋白的定量揭示了一种协同补偿机制，涉及受磷蛋白的Ser 16和Thr 17磷酸化增加，有助于改善细胞力学和Ca 2+稳态的时间起始。因此，cTnT在TNT 1结构域中的独立突变导致原发性突变特异性效应和肌细胞力学、Ca 2+动力学和Ca 2+稳态改变的不同时间发作，这些复杂机制可能导致cTnT相关家族性肥厚型心肌病突变的临床变异性。
Guinto PJ, Haim TE, Dowell-Martino CC, Sibinga N, Tardiff JC. Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models. Am J Physiol Heart Circ Physiol 297: H614-H626, 2009. First published June 5, 2009; doi:10.1152/ajpheart.01143.2008.-Naturally occurring mutations in cardiac troponin T (cTnT) result in a clinical subset of familial hypertrophic cardiomyopathy. To determine the mechanistic links between thin-filament mutations and cardiovascular phenotypes, we have generated and characterized several transgenic mouse models carrying cTnT mutations. We address two central questions regarding the previously observed changes in myocellular mechanics and Ca2+ homeostasis: 1) are they characteristic of all severe cTnT mutations, and 2) are they primary (early) or secondary (late) components of the myocellular response? Adult left ventricular myocytes were isolated from 2-and 6-mo-old transgenic mice carrying missense mutations at residue 92, flanking the TNT1 NH2-terminal tail domain. Results from R92L and R92W myocytes showed mutation-specific alterations in contraction and relaxation indexes at 2 mo with improvements by 6 mo. Alterations in Ca2+ kinetics remained consistent with mechanical data in which R92L and R92W exhibited severe diastolic impairments at the early time point that improved with increasing age. A normal regulation of Ca2+ kinetics in the context of an altered baseline cTnI phosphorylation suggested a pathogenic mechanism at the myofilament level taking precedence for R92L. The quantitation of Ca2+ handling proteins in R92W mice revealed a synergistic compensatory mechanism involving an increased Ser16 and Thr17 phosphorylation of phospholamban, contributing to the temporal onset of improved cellular mechanics and Ca2+ homeostasis. Therefore, independent cTnT mutations in the TNT1 domain result in primary mutation-specific effects and a differential temporal onset of altered myocellular mechanics, Ca2+ kinetics, and Ca2+ homeostasis, complex mechanisms which may contribute to the clinical variability in cTnT-related familial hypertrophic cardiomyopathy mutations.