首页> 外文期刊>American Journal of Physiology >Disruption of cardiac Ena-VASP protein localization in intercalated disks causes dilated cardiomyopathy.
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Disruption of cardiac Ena-VASP protein localization in intercalated disks causes dilated cardiomyopathy.

机译:插入盘中心脏Ena-VASP蛋白定位的破坏会引起扩张型心肌病。

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摘要

Vasodilator-stimulated phosphoprotein (VASP) and mammalian enabled (Mena) are actin cytoskeleton and signaling modulators. Ena-VASP proteins share an identical domain organization with an NH2-terminal Ena VASP homology (EVH1) domain, which mediates the binding of these proteins to FPPPP-motif containing partners such as zyxin and vinculin. VASP and Mena are abundantly expressed in the heart. However, previous studies showed that disruption by gene targeting of VASP or Mena genes in mice did not reveal any cardiac phenotype, whereas mice lacking both VASP and Mena died during embryonic development. To determine the in vivo function of Ena-VASP proteins in the heart, we used a dominant negative strategy with cardiac-specific expression of the VASP-EVH1 domain. Transgenic mice with cardiac myocyte-restricted, alpha-myosin heavy chain promoter-directed expression of the VASP-EVH1 domain were generated. Overexpression of the EVH1 domain resulted in specific displacement of both VASP and Mena from cardiac intercalated disks. VASP-EVH1 transgenic mice developed dilated cardiomyopathy with myocyte hypertrophy and bradycardia, which resulted in early postnatal lethality in mice with high levels of transgene expression. The results demonstrate that Ena-VASP proteins may play an important role in intercalated disk function at the interface between cardiac myocytes.
机译:血管舒张剂刺激的磷蛋白(VASP)和具有哺乳动物功能的(Mena)是肌动蛋白的细胞骨架和信号传导调节剂。 Ena-VASP蛋白与NH2末端Ena VASP同源性(EVH1)域共享相同的域结构,该域介导这些蛋白与包含FPPPP-基序的伴侣(如zyxin和vinculin)的结合。 VASP和Mena在心脏中大量表达。但是,先前的研究表明,通过对VASP或Mena基因进行基因靶向破坏小鼠并没有发现任何心脏表型,而同时缺乏VASP和Mena的小鼠则在胚胎发育过程中死亡。为了确定Ena-VASP蛋白在心脏中的体内功能,我们使用了占主导地位的阴性策略,即VASP-EVH1域的心脏特异性表达。产生了具有心肌细胞限制性,α-肌球蛋白重链启动子指导的VASP-EVH1域表达的转基因小鼠。 EVH1结构域的过表达导致VASP和Mena从心脏插层盘中发生特定移位。 VASP-EVH1转基因小鼠发展成扩张型心肌病,并伴有心肌细胞肥大和心动过缓,从而导致转基因表达水平高的小鼠在出生后具有早期致死性。结果表明,Ena-VASP蛋白可能在心肌细胞之间界面的盘功能中起重要作用。

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