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一种新的微小RNA调节因子miR-672通过抑制JUN表达减轻心肌肥厚。

A new miRNA regulator, miR-672, reduces cardiac hypertrophy by inhibiting JUN expression.

作者信息

Lu Yili, Wu Fangli

机构信息

Department of Pediatrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.

Key Laboratory of Plant Secondary Metabolism and Regulation of Zhejiang Province, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.

出版信息

Gene. 2018 Mar 30;648:21-30. doi: 10.1016/j.gene.2018.01.047. Epub 2018 Jan 12.

Abstract

Cardiac hypertrophy is one of the initial symptoms of many heart diseases. We found that miR-672-5p may participate in the regulation of heart disease development in mouse, but the association between miR-672-5p and cardiac hypertrophy remains unclear. In the present study, we found that the abundance of miR-672-5p decreased in hypertrophic cardiomyocytes induced by phenylephrine, angiotensin II (Ang II) and insulin-like growth factor 1. Putative target genes of miR-672-5p were identified using four pipelines, miRWalk, miRanda, RNA22 and Targetscan, and a total of 834 genes were predicted by all four pipelines. Among these target genes, 98 were associated with the development of heart disease. PPI networks showed that the Jun proto-oncogene product (JUN), a subunit of the AP-1 transcription factor, had the highest node degree, and it was defined as the hub gene of the PPI networks. Luciferase assays showed that miR-672-5p bound to the 3' UTR of the JUN gene and decreased luciferase activity, indicating that JUN is a target of miR-672-5p. Finally, we found that increasing the abundance of miR-672-5p in cardiomyocytes controlled the relative cell area in Ang II-stimulated hypertrophic cardiomyocytes. Correspondingly, the abundance of JUN, a target of miR-672-5p, was decreased in hypertrophic cardiomyocytes on both mRNA and protein levels, implying that miR-672-5p had suppressive effects on cardiac hypertrophy through regulating the expression of Jun in cardiomyocytes.

摘要

心脏肥大是许多心脏病的初始症状之一。我们发现miR-672-5p可能参与小鼠心脏病发展的调控,但miR-672-5p与心脏肥大之间的关联仍不清楚。在本研究中,我们发现苯肾上腺素、血管紧张素II(Ang II)和胰岛素样生长因子1诱导的肥大心肌细胞中miR-672-5p丰度降低。使用miRWalk、miRanda、RNA22和Targetscan这四个程序鉴定了miR-672-5p的潜在靶基因,所有这四个程序共预测出834个基因。在这些靶基因中,98个与心脏病发展相关。蛋白质-蛋白质相互作用(PPI)网络显示,AP-1转录因子的一个亚基原癌基因Jun产物(JUN)具有最高的节点度,并被定义为PPI网络的枢纽基因。荧光素酶检测显示,miR-672-5p与JUN基因的3'非翻译区(UTR)结合并降低荧光素酶活性,表明JUN是miR-672-5p的一个靶标。最后,我们发现在心肌细胞中增加miR-672-5p的丰度可控制Ang II刺激的肥大心肌细胞中的相对细胞面积。相应地,miR-672-5p的靶标JUN在肥大心肌细胞中的mRNA和蛋白质水平均降低,这意味着miR-672-5p通过调节心肌细胞中Jun的表达对心脏肥大具有抑制作用。

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