Meng, Yao, Wang, Yu, Shi, Yuan, Liu (2020) Knockdown of GAS5 Inhibits Atherosclerosis Progression via Reducing EZH2-Mediated ABCA1 Transcription in ApoE-/- Mice Molecular therapy. Nucleic acids 19() 84-96

Abstract

Atherosclerosis is a disorder occurring in the large arteries and the primary cause of heart diseases. Accumulating evidence has implicated long non-coding RNAs (lncRNAs) in atherosclerosis. This study aims to clarify the potential effects of lncRNA growth arrest-specific 5 (GAS5) on cholesterol reverse-transport and intracellular lipid accumulation in atherosclerosis. GAS5 was mainly localized in the nucleus and highly expressed in the human monocytic leukemia cell line (THP-1) macrophage-derived foam cells in coronary heart disease. Overexpressed GAS5 increased THP-1 macrophage lipid accumulation. Of note, GAS5 can inhibit the expression of ATP-binding cassette transporter A1 (ABCA1) by binding to enhancer of zeste homolog 2 (EZH2). Overexpression of EZH2 reduced cholesterol efflux and ABCA1 expression. EZH2 promoted triple methylation of lysine 27 (H3K27) in the ABCA1 promoter region. Subjected to overexpressed GAS5, overexpressed EZH2, or downregulated ABCA1, the Apolipoprotein E (ApoE)-/- mice with atherosclerosis showed increased total cholesterol (TC), free cholesterol (FC), cholesterol ester (CE), low-density lipoprotein (LDL) levels, aortic plaque, and lipid accumulation, accompanied by reduced high-density lipoprotein (HDL) level and cholesterol outflow. Altogether, knockdown of GAS5 can potentially promote reverse-transportation of cholesterol and inhibit intracellular lipid accumulation, ultimately preventing the progression of atherosclerosis via reducing EZH2-mediated transcriptional inhibition of ABCA1 by histone methylation. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

动脉粥样硬化是在大动脉中发生的疾病,是心脏病的主要原因。越来越多的证据表明动脉粥样硬化中存在长的非编码RNA(lncRNA)。这项研究旨在阐明lncRNA生长停滞特异性5(GAS5)对动脉粥样硬化中胆固醇逆向转运和细胞内脂质蓄积的潜在影响。 GAS5主要位于核中,并在冠心病的人单核细胞白血病细胞系(THP-1)巨噬细胞源性泡沫细胞中高表达。过表达的GAS5增加THP-1巨噬细胞脂质积累。值得注意的是,GAS5可以通过与zeste同系物2(EZH2)的增强子结合来抑制ATP结合盒转运蛋白A1(ABCA1)的表达。 EZH2的过表达降低胆固醇外流和ABCA1表达。 EZH2促进了ABCA1启动子区域中赖氨酸27(H3K27)的三甲基化。受到过表达的GAS5,过表达的EZH2或ABCA1的下调,伴有动脉粥样硬化的载脂蛋白E(ApoE)-/-小鼠显示总胆固醇(TC),游离胆固醇(FC),胆固醇酯(CE),低密度脂蛋白(LDL)升高)水平,主动脉斑块和脂质蓄积,并伴有高密度脂蛋白(HDL)水平降低和胆固醇流出。总之,敲低GAS5可能会促进胆固醇的逆向转运并抑制细胞内脂质的积累,最终通过减少EZH2介导的组蛋白甲基化对ABCA1的转录抑制作用,从而阻止动脉粥样硬化的发展。版权所有©2019作者。由Elsevier Inc.出版。保留所有权利。

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926212/pdf/
http://www.ncbi.nlm.nih.gov/pubmed/31830648
http://dx.doi.org/10.1016/j.omtn.2019.10.034

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