Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, NJ 07103, USA.
Circ Res. 2011 Feb 4;108(3):305-13. doi: 10.1161/CIRCRESAHA.110.228437. Epub 2010 Dec 23.
Thioredoxin (Trx)1 inhibits pathological cardiac hypertrophy. MicroRNAs (miRNAs) are small noncoding RNAs that downregulate posttranscriptional expression of target molecules.
We investigated the role of miRNAs in mediating the antihypertrophic effect of Trx1 on angiotensin II (Ang II)-induced cardiac hypertrophy.
Microarray analyses of mature rodent microRNAs and quantitative RT-PCR/Northern blot analyses showed that Trx1 upregulates members of the let-7 family, including miR-98, in the heart and the cardiomyocytes therein. Adenovirus-mediated expression of miR-98 in cardiomyocytes reduced cell size both at baseline and in response to Ang II. Knockdown of miR-98, and of other members of the let-7 family, augmented Ang II-induced cardiac hypertrophy, and attenuated Trx1-mediated inhibition of Ang II-induced cardiac hypertrophy, suggesting that endogenous miR-98/let-7 mediates the antihypertrophic effect of Trx1. Cyclin D2 is one of the predicted targets of miR-98. Ang II significantly upregulated cyclin D2, which in turn plays an essential role in mediating Ang II-induced cardiac hypertrophy, whereas overexpression of Trx1 inhibited Ang II-induced upregulation of cyclin D2. miR-98 decreased both expression of cyclin D2 and the activity of a cyclin D2 3'UTR luciferase reporter, suggesting that both Trx1 and miR-98 negatively regulate cyclin D2. Overexpression of cyclin D2 attenuated the suppression of Ang II-induced cardiac hypertrophy by miR-98, suggesting that the antihypertrophic actions of miR-98 are mediated in part by downregulation of cyclin D2.
These results suggest that Trx1 upregulates expression of the let-7 family, including miR-98, which in turn inhibits cardiac hypertrophy, in part through downregulation of cyclin D2.
硫氧还蛋白 1（Trx）1 可抑制病理性心肌肥厚。微小 RNA（miRNA）是一种可下调靶分子转录后表达的小型非编码 RNA。
我们研究了 miRNA 在介导 Trx1 对抗血管紧张素 II（Ang II）诱导的心肌肥厚的抗肥厚作用中的作用。
成熟啮齿动物 miRNA 的微阵列分析和定量 RT-PCR/Northern 印迹分析表明，Trx1 在心脏及其心肌细胞中上调 let-7 家族成员，包括 miR-98。心肌细胞中 miR-98 的腺病毒表达在基础状态和 Ang II 反应中均降低细胞大小。miR-98 和 let-7 家族其他成员的敲低增强了 Ang II 诱导的心肌肥厚，并减弱了 Trx1 介导的 Ang II 诱导的心肌肥厚抑制作用，表明内源性 miR-98/let-7 介导了 Trx1 的抗肥厚作用。细胞周期蛋白 D2 是 miR-98 的预测靶标之一。Ang II 显著上调细胞周期蛋白 D2，这反过来在介导 Ang II 诱导的心肌肥厚中起关键作用，而 Trx1 的过表达抑制 Ang II 诱导的细胞周期蛋白 D2 上调。miR-98 降低细胞周期蛋白 D2 的表达和细胞周期蛋白 D2 3'UTR 荧光素酶报告基因的活性，表明 Trx1 和 miR-98 均负调控细胞周期蛋白 D2。细胞周期蛋白 D2 的过表达减弱了 miR-98 对 Ang II 诱导的心肌肥厚的抑制作用，表明 miR-98 的抗肥厚作用部分通过下调细胞周期蛋白 D2 介导。
这些结果表明，Trx1 上调包括 miR-98 在内的 let-7 家族的表达，而 miR-98 又通过下调 cyclin D2 来抑制心肌肥厚。
