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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Mice with cardiac-restricted overexpression of Myozap are sensitized to biomechanical stress and develop a protein-aggregate-associated cardiomyopathy
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Mice with cardiac-restricted overexpression of Myozap are sensitized to biomechanical stress and develop a protein-aggregate-associated cardiomyopathy

机译：心脏受限的Myozap过度表达的小鼠对生物力学应激敏感并发展出蛋白质聚集相关的心肌病

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摘要

The intercalated disc (ID) is a major component of the cell-cell contact structures of cardiomyocytes and has been recognized as a hot spot for cardiomyopathy. We have previously identified Myozap as a novel cardiac-enriched ID protein, which interacts with several other ID proteins and is involved in RhoA/SRF signaling in vitro. To now study its potential role in vivo we generated a mouse model with cardiac overexpression of Myozap. Transgenic (Tg) mice developed cardiomyopathy with hypertrophy and LV dilation. Consistently, these mice displayed upregulation of the hypertrophy-associated and SRF-dependent gene expression. Pressure overload (transverse aortic constriction, TAC) caused exaggerated cardiac hypertrophy, further loss of contractility and LV dilation. Similarly, a physiological stimulus (voluntary running) also led to significant LV dysfunction. On the ultrastruc-tural level, Myozap-Tg mouse hearts exhibited massive protein aggregates composed of Myozap, desmoplakin and other ID proteins. This aggregate-associated pathology closely resembled the alterations observed in desmin-related cardiomyopathy. Interestingly, desmin was not detectable in the aggregates, yet was largely displaced from the ID. Molecular analyses revealed induction of autophagy and dysregulation of the unfolded protein response (LJPR), associated with apoptosis. Taken together, cardiac overexpression of Myozap leads to cardiomyopathy, mediated, at least in part by induction of Rho-dependent SRF signaling in vivo. Surprisingly, this phenotype was also accompanied by protein aggregates in cardiomyocytes, UPR alteration, accelerated autophagy and apoptosis. Thus, this mouse model may also offer additional insight into the pathogenesis of protein-aggregate-associated cardiomyopathies and represents a new candidate gene itself.
机译：嵌入盘（ID）是心肌细胞的细胞间接触结构的主要组成部分，已被认为是心肌病的热点。我们之前已将Myozap确定为一种新型的富含心脏的ID蛋白，它与其他几种ID蛋白相互作用，并参与体外RhoA / SRF信号传导。现在要研究其在体内的潜在作用，我们构建了具有Myozap心脏过度表达的小鼠模型。转基因（Tg）小鼠发展为心肌肥大和左心室扩张。一致地，这些小鼠表现出肥大相关和SRF依赖基因表达的上调。压力超负荷（主动脉横向狭窄，TAC）导致心脏肥大，进一步的收缩力丧失和左室扩张。同样，生理刺激（自愿跑步）也导致严重的左室功能障碍。在超结构水平上，Myozap-Tg小鼠心脏显示出由Myozap，桥粒斑蛋白和其他ID蛋白组成的大量蛋白质聚集体。这种聚集体相关的病理学非常类似于在结蛋白相关性心肌病中观察到的变化。有趣的是，在集合体中无法检测到结蛋白，但很大程度上已脱离了ID。分子分析显示诱导自噬和与细胞凋亡相关的未折叠蛋白应答（LJPR）失调。两者合计，Myozap的心脏过度表达导致心肌病，至少部分地通过体内诱导Rho依赖性SRF信号传导来介导。令人惊讶的是，该表型还伴有心肌细胞中的蛋白质聚集，UPR改变，加速的自噬和凋亡。因此，这种小鼠模型也可能提供蛋白质聚集相关心肌病发病机制的其他见解，并代表一个新的候选基因本身。

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