Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy
Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy
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DOI：
10.1152/ajpheart.00107.2013
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发表时间：
2013-08-01
影响因子：
4.8
通讯作者：
Szczesna-Cordary, Danuta
中科院分区：
文献类型：
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作者：
Kazmierczak, Katarzyna;Paulino, Ellena C.;Szczesna-Cordary, Danuta
在体外和体内使用先前产生的转基因（Tg）小鼠表达A57 G-ELC突变体与野生型（WT）的人心脏ELC和重组A57 G或WT蛋白交换的猪心肌条，评估了家族性肥厚型心肌病A57 G（丙氨酸到甘氨酸）突变在肌球蛋白心室必需轻链（ELC）中的功能后果。与Tg-WT相比，在突变体制剂中观察到力的Ca 2+敏感性显著增加（Δ pCa（50）等于0.1），并且每个肌肉横截面的最大力降低了1.3倍。此外，在Tg-A57 G与Tg-WT条中监测到响应于拉伸的被动张力的显著增加，表明突变诱导的心肌硬度。一致地，Tg-A57 G小鼠的心脏表现出高水平的纤维化和肥大，表现为增加的心脏重量-体重比和减少的细胞核数量，表明Tg-A57 G相对于Tg-WT肌细胞的二维尺寸增加。超声心动图检查显示Tg-A57 G小鼠的离心性肥大表型，左心室（LV）腔尺寸增加，而LV后壁/前壁厚度无变化。有创血流动力学数据显示收缩末期弹性显著增加，由压力-容积关系的斜率定义，表明突变诱导的心肌收缩力增加。我们的研究结果表明，A57 G等位基因引起疾病的离散调制肌丝功能，增加Ca 2+的敏感性，并降低最大张力，其次是代偿性肥大和增强收缩力。这些和其他促成因素，如增加心肌硬度和纤维化最有可能激活心肌病信号通路，导致病理性心脏重塑。
The functional consequences of the familial hypertrophic cardiomyopathy A57G (alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G- or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca2+ sensitivity of force (Delta pCa(50) congruent to 0.1) and an similar to 1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca2+ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling.