Long noncoding RNA Hotair facilitates retinal endothelial cell dysfunction in diabetic retinopathy

热空气 基因敲除 长非编码RNA 癌症研究 KLF2 细胞生物学 血管通透性 转录因子 视网膜 生物 下调和上调 细胞培养 内分泌学 生物化学 遗传学 基因
作者
Di Zhao,Yanyan Zhao,Jiao Wang,Lina Wu,Yanling Liu,Shuiying Zhao,Feng Guo,Xiaojun Ma,Shouxin Zhang,Zhizhen Li,Dongdong Meng,Lijun Xu,Lixia Zhang,Junqi Liu,Guijun Qin
出处
期刊:Clinical Science [Portland Press]
卷期号:134 (17): 2419-2434 被引量:36
标识
DOI:10.1042/cs20200694
摘要

Abstract Background: Retinal endothelial cell (REC) dysfunction induced by diabetes mellitus (DM) is an important pathological step of diabetic retinopathy (DR). Long noncoding RNAs (lncRNAs) have emerged as novel modulators in DR. The present study aimed to investigate the role and mechanism of lncRNA Hotair in regulating DM-induced REC dysfunction. Methods: The retinal vascular preparations and immunohistochemical staining assays were conducted to assess the role of Hotair in retinal vessel impairment in vivo. The EdU, transwell, cell permeability, CHIP, luciferase activity, RIP, RNA pull-down, and Co-IP assays were employed to investigate the underlying mechanism of Hotair-mediated REC dysfunction in vitro. Results: Hotair expression was significantly increased in diabetic retinas and high glucose (HG)-stimulated REC. Hotair knockdown inhibited the proliferation, invasion, migration, and permeability of HG-stimulated REC in vitro and reduced the retinal acellular capillaries and vascular leakage in vivo. Mechanistically, Hotair bound to LSD1 to inhibit VE-cadherin transcription by reducing the H3K4me3 level on its promoter and to facilitate transcription factor HIF1α-mediated transcriptional activation of VEGFA. Furthermore, LSD1 mediated the effects of Hotair on REC function under HG condition. Conclusion: The Hotair exerts its role in DR by binding to LSD1, decreasing VE-cadherin transcription, and increasing VEGFA transcription, leading to REC dysfunction. These findings revealed that Hotair is a potential therapeutic target of DR.
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