Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death
Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death
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心脏特异性消融导致严重的扩张型心肌病并导致过早死亡
DOI：
10.1093/hmg/ddn400
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发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
Chen, Ju
中科院分区：
文献类型：
--
作者：
Zheng, Ming;Cheng, Hongqiang;Chen, Ju
累积的数据表明，细胞骨架蛋白的改变/缺陷与心肌病和心力衰竭的进展之间存在联系，尽管这种联系的分子基础尚不清楚。Cypher/ZASP是位于肌节Z线的细胞骨架蛋白。其编码基因的突变已在孤立性左心室心肌致密化不全、扩张型心肌病（DCM）和肥厚型心肌病患者中被鉴定。为了探索Cypher在心肌中的作用，并更好地理解Cypher突变导致心肌病的分子机制，我们利用条件性方法敲除Cypher，特别是在发育中或成年心肌中。心脏特异性Cypher基因敲除（CKO）小鼠发展为严重形式的DCM，心肌细胞超微结构破坏，心脏功能下降，最终导致23周龄前死亡。在诱导型心脏特异性CKO小鼠中观察到类似的表型，其中Cypher在成年心肌中特异性消融。在两种心脏特异性CKO模型中，ERK和Stat 3信号通路均增强。最后，我们证明了Cypher的PDZ结构域的C-末端区域的钙肌蛋白-1和myotilin内的Z-线的特异性结合。总之，我们的研究表明：（i）Cypher通过与其他Z线蛋白的蛋白质-蛋白质相互作用在维持成人心脏结构和心脏功能方面发挥关键作用，（ii）Cypher的心肌消融导致DCM伴过早死亡，（iii）特定信号传导通路参与Cypher mu介导的心脏功能障碍，并可能共同促进心力衰竭的进展。
Accumulating data suggest a link between alterations/deficiencies in cytoskeletal proteins and the progression of cardiomyopathy and heart failure, although the molecular basis for this link remains unclear. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line. Mutations in its encoding gene have been identified in patients with isolated non-compaction of the left ventricular myocardium, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy. To explore the role of Cypher in myocardium and to better understand molecular mechanisms by which mutations in cypher cause cardiomyopathy, we utilized a conditional approach to knockout Cypher, specially in either developing or adult myocardium. Cardiac-specific Cypher knockout (CKO) mice developed a severe form of DCM with disrupted cardiomyocyte ultrastructure and decreased cardiac function, which eventually led to death before 23 weeks of age. A similar phenotype was observed in inducible cardiac-specific CKO mice in which Cypher was specifically ablated in adult myocardium. In both cardiac-specific CKO models, ERK and Stat3 signaling pathways were augmented. Finally, we demonstrate the specific binding of Cypher's PDZ domain to the C-terminal region of both calsarcin-1 and myotilin within the Z-line. In conclusion, our studies suggest that (i) Cypher plays a pivotal role in maintaining adult cardiac structure and cardiac function through protein-protein interactions with other Z-line proteins, (ii) myocardial ablation of Cypher results in DCM with premature death and (iii) specific signaling pathways participate in Cypher mutant-mediated dysfunction of the heart, and may in concert facilitate the progression to heart failure.