Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity
Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity
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DOI：
10.1172/jci31240
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发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
Kuwahara, Koichiro;Pipes, Gordon C. Teg;Olson, Eric N.
细胞骨架蛋白与心肌病的发病机制有关，但细胞骨架如何影响与不良心脏重塑相关的转录改变仍不清楚。横纹肌Rho信号激活因子（STARS）是一种肌特异性肌动蛋白结合蛋白，定位于Z盘，通过诱导肌心蛋白相关的SRF共激活因子MRTF-A和-B的核转位激活血清反应因子依赖性（SRF依赖性）转录。我们发现，STARS的表达上调，在小鼠模型的心脏肥大和失败的人类心脏。STARS启动子的保守区含有肌细胞增强因子2（MEF 2）的必需结合位点，MEF 2是一种应激反应性转录激活因子，可介导STARS的心脏表达，进而激活SRF靶基因。心脏中STARS的强制过表达使心脏对压力超负荷和钙调磷酸酶信号传导敏感，导致响应于这些肥大刺激的心脏功能过度恶化。这些发现表明，STARS通过充当MEF 2和SRF之间的细胞骨架中介来调节心脏对应激信号的反应。
Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor-2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.