Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia.
Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia.
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DOI：
10.1007/s00395-020-00818-8
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发表时间：
2020-09-10
影响因子：
9.5
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中科院分区：
文献类型：
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暗蛋白是一个巨大的模块化蛋白家族，在横纹肌中起着关键的结构和调节作用。obscurin的免疫球蛋白结构域58/59（Ig 58/59）介导与肌肉结构和功能的基本调节剂的结合，包括经典肌联蛋白、肌联蛋白的较小剪接变体（称为novex-3）和受磷蛋白（PLN）。重要的是，位于模糊蛋白-Ig 58/59区域内的影响与titins和/或PLN结合的错义突变与人类肌病的发展有关。为了阐明该区域的病理生理学作用，我们产生了组成型缺失小鼠模型Obscn-Δ Ig 58/59，其表达缺乏Ig 58/59的obscurin，并确定了在急性应激条件下和通过衰老的生理过程中这种操作对心脏形态和功能的影响。我们的研究表明，年轻的Obscn-Δ Ig 58/59小鼠对急性β-肾上腺素能应激敏感。此外，久坐的Obscn-Δ Ig 58/59小鼠随着年龄的增长发生左心室肥大，进而发展为扩张、收缩功能障碍、心房扩大和心律失常，雄性比雌性受影响更大。在心室心肌细胞中的实验揭示了与主要Ca 2+循环蛋白（包括PLN、SERCA 2和RyR 2）的表达和/或磷酸化水平变化相关的Ca 2+循环改变。总之，我们的工作表明，obscurin-Ig 58/59是心脏中的一个重要调节模块，其缺失导致年龄和性别依赖性心脏重塑，心室扩张和心律失常，由于钙离子循环失调。
Obscurin comprises a family of giant modular proteins that play key structural and regulatory roles in striated muscles. Immunoglobulin domains 58/59 (Ig58/59) of obscurin mediate binding to essential modulators of muscle structure and function, including canonical titin, a smaller splice variant of titin, termed novex-3, and phospholamban (PLN). Importantly, missense mutations localized within the obscurin-Ig58/59 region that affect binding to titins and/or PLN have been linked to the development of myopathy in humans. To elucidate the pathophysiological role of this region, we generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59, and determined the consequences of this manipulation on cardiac morphology and function under conditions of acute stress and through the physiological process of aging. Our studies show that young Obscn-ΔIg58/59 mice are susceptible to acute β-adrenergic stress. Moreover, sedentary Obscn-ΔIg58/59 mice develop left ventricular hypertrophy that progresses to dilation, contractile impairment, atrial enlargement, and arrhythmia as a function of aging with males being more affected than females. Experiments in ventricular cardiomyocytes revealed altered Ca2+ cycling associated with changes in the expression and/or phosphorylation levels of major Ca2+ cycling proteins, including PLN, SERCA2, and RyR2. Taken together, our work demonstrates that obscurin-Ig58/59 is an essential regulatory module in the heart and its deletion leads to age- and sex-dependent cardiac remodeling, ventricular dilation, and arrhythmia due to deregulated Ca2+ cycling.
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影响因子：
--
作者：
Feng Y;Cheng J;Wei B;Wang Y
通讯作者：
Wang Y
DOI：
10.1016/j.jacbts.2016.12.002
发表时间：
2017-03
期刊：
JACC. Basic to translational science
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DOI：
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发表时间：
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影响因子：
3.1
作者：
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通讯作者：
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