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靶向EZH1和EZH2有助于miR-214-3p在心肌成纤维细胞中抑制纤维化相关基因。

Targeting EZH1 and EZH2 contributes to the suppression of fibrosis-associated genes by miR-214-3p in cardiac myofibroblasts.

作者信息

Zhu Wen-Si, Tang Chun-Mei, Xiao Zhen, Zhu Jie-Ning, Lin Qiu-Xiong, Fu Yong-Heng, Hu Zhi-Qin, Zhang Zhuo, Yang Min, Zheng Xi-Long, Wu Shu-Lin, Shan Zhi-Xin

机构信息

Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangzhou, China.

Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

出版信息

Oncotarget. 2016 Nov 29;7(48):78331-78342. doi: 10.18632/oncotarget.13048.

DOI:10.18632/oncotarget.13048
PMID:27823969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5346642/
Abstract

The role of microRNA-214-3p (miR-214-3p) in cardiac fibrosis was not well illustrated. The present study aimed to investigate the expression and potential target of miR-214-3p in angiotensin II (Ang-II)-induced cardiac fibrosis. MiR-214-3p was markedly decreased in the fibrotic myocardium of a mouse Ang-II infusion model, but was upregulated in Ang-II-treated mouse myofibroblasts. Cardiac fibrosis was shown attenuated in Ang-II-infused mice received tail vein injection of miR-214-3p agomir. Consistently, miR-214-3p inhibited the expression of Col1a1 and Col3a1 in mouse myofibroblasts in vitro. MiR-214-3p could bind the 3'-UTRs of enhancer of zeste homolog 1 (EZH1) and -2, and suppressed EZH1 and -2 expressions at the transcriptional level. Functionally, miR-214-3p mimic, in parallel to EZH1 siRNA and EZH2 siRNA, could enhance peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and inhibited the expression of Col1a1 and Col3a1 in myofibroblasts. In addition, enforced expression of EZH1 and -2, and knockdown of PPAR-γ resulted in the increase of Col1a1 and Col3a1 in myofibroblasts. Moreover, the NF-κB signal pathway was verified to mediate Ang-II-induced miR-214-3p expression in myofibroblasts. Taken together, our results revealed that EZH1 and -2 were novel targets of miR-214-3p, and miR-214-3p might be one potential miRNA for the prevention of cardiac fibrosis.

摘要

微小RNA-214-3p（miR-214-3p）在心脏纤维化中的作用尚未得到充分阐明。本研究旨在探讨miR-214-3p在血管紧张素II（Ang-II）诱导的心脏纤维化中的表达及潜在靶点。在小鼠Ang-II输注模型的纤维化心肌中，miR-214-3p明显降低，但在Ang-II处理的小鼠成肌纤维细胞中上调。尾静脉注射miR-214-3p激动剂的Ang-II输注小鼠的心脏纤维化减轻。同样，miR-214-3p在体外抑制小鼠成肌纤维细胞中Col1a1和Col3a1的表达。miR-214-3p可与zeste同源物增强子1（EZH1）和-2的3'-UTR结合，并在转录水平抑制EZH1和-2的表达。在功能上，miR-214-3p模拟物与EZH1 siRNA和EZH2 siRNA一样，可增强过氧化物酶体增殖物激活受体-γ（PPAR-γ）的表达，并抑制成肌纤维细胞中Col1a1和Col3a1的表达。此外，EZH1和-2的过表达以及PPAR-γ的敲低导致成肌纤维细胞中Col1a1和Col3a1增加。此外，核因子κB信号通路被证实介导Ang-II诱导的成肌纤维细胞中miR-214-3p的表达。综上所述，我们的结果表明EZH1和-2是miR-214-3p的新靶点，miR-214-3p可能是预防心脏纤维化的一种潜在微小RNA。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1615/5346642/9e1d498cf8a0/oncotarget-07-78331-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1615/5346642/9e1d498cf8a0/oncotarget-07-78331-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1615/5346642/00aa47db8f91/oncotarget-07-78331-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1615/5346642/b1c149fa1194/oncotarget-07-78331-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1615/5346642/9e1d498cf8a0/oncotarget-07-78331-g007.jpg

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