Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy
Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy
复制标题
DOI：
10.1242/jcs.067165
复制
发表时间：
2010-07-15
影响因子：
4
通讯作者：
Jing, Qing
中科院分区：
文献类型：
--
作者：
Li, Qing;Song, Xiao-Wei;Jing, Qing
MicroRNA 参与心脏肥大的多个方面，包括心脏生长、传导和纤维化。然而，它们在这一病理过程中对心肌细胞细胞骨架的调节作用尚不清楚。在这里，通过 microRNA 微阵列和小 RNA 文库测序，我们表明 microRNA-1 (miR-1) 是人类心脏中最丰富的 microRNA。通过应用生物信息学靶点预测，细胞骨架调节蛋白twinfilin-1被确定为miR-1的潜在靶点。 miR-1的过表达不仅降低了含有twinfilin-1 mRNA 3'非翻译区的报告基因的荧光素酶活性，而且抑制了twinfilin-1的内源蛋白表达，表明twinfilin-1是miR-1的直接靶标。在大鼠肥大的左心室和去氧肾上腺素诱导的肥大心肌细胞中，miR-1显着下调，相应地，twinfilin-1的蛋白水平增加。此外，肥大心肌细胞中miR-1的过度表达会减小细胞大小并减弱肥大标记物的表达，而心肌细胞中miR-1的沉默会导致肥大表型。相应地，twinfilin-1 过度表达促进心肌细胞肥大。综上所述，我们的结果表明，细胞骨架调节蛋白 twinfilin-1 是 miR-1 的一个新靶点，肥大刺激导致 miR-1 的减少会诱导 twinfilin-1 的上调，进而通过调节心脏细胞骨架引起肥大。
MicroRNAs are involved in several aspects of cardiac hypertrophy, including cardiac growth, conduction, and fibrosis. However, their effects on the regulation of the cardiomyocyte cytoskeleton in this pathological process are not known. Here, with microRNA microarray and small RNA library sequencing, we show that microRNA-1 (miR-1) is the most abundant microRNA in the human heart. By applying bioinformatic target prediction, a cytoskeleton regulatory protein twinfilin-1 was identified as a potential target of miR-1. Overexpression of miR-1 not only reduced the luciferase activity of the reporter containing the 3' untranslated region of twinfilin-1 mRNA, but also suppressed the endogenous protein expression of twinfilin-1, indicating that twinfilin-1 is a direct target of miR-1. miR-1 was substantially downregulated in the rat hypertrophic left ventricle and phenylephrine-induced hypertrophic cardiomyocytes, and accordingly, the protein level of twinfilin-1 was increased. Furthermore, overexpression of miR-1 in hypertrophic cardiomyocytes reduced the cell size and attenuated the expression of hypertrophic markers, whereas silencing of miR-1 in cardiomyocytes resulted in the hypertrophic phenotype. In accordance, twinfilin-1 overexpression promoted cardiomyocyte hypertrophy. Taken together, our results demonstrate that the cytoskeleton regulatory protein twinfilin-1 is a novel target of miR-1, and that reduction of miR-1 by hypertrophic stimuli induces the upregulation of twinfilin-1, which in turn evokes hypertrophy through the regulation of cardiac cytoskeleton.