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      Knockdown of GAS5 Inhibits Atherosclerosis Progression via Reducing EZH2-Mediated ABCA1 Transcription in ApoE −/− Mice

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          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.

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          Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis

          Lei Chen, Wenjin Yang, Yijun Guo … (2017)
          Atherosclerosis is universally recognized as a chronic lipid-induced inflammation of the vessel wall. Oxidized low density lipoprotein (oxLDL) drives the onset of atherogenesis involving macrophages and endothelial cells (ECs). Our earlier work showed that expression of long noncoding RNA-growth arrest-specific 5 (lncRNA GAS5) was significantly increased in the plaque of atherosclerosis collected from patients and animal models. In this study, we found that knockdown of lncRNA GAS5 reduced the apoptosis of THP-1 cells treated with oxLDL. On the contrary, overexpression of lncRNA GAS5 significantly elevated the apoptosis of THP-1 cells after oxLDL stimulation. The expressions of apoptotic factors including Caspases were changed with lncRNA GAS5 levels. Moreover, lncRNA GAS5 was found in THP-1 derived-exosomes after oxLDL stimulation. Exosomes derived from lncRNA GAS5-overexpressing THP-1 cells enhanced the apoptosis of vascular endothelial cells after taking up these exosomes. However, exosomes shed by lncRNA GAS5 knocked-down THP-1 cells inhibited the apoptosis of endothelial cells. These findings reveal the function of lncRNA GAS5 in atherogenesis which regulates the apoptosis of macrophages and endothelial cells via exosomes and suggest that suppressing the lncRNA GAS5 might be an effective way for the therapy of atherosclerosis.
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            Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice.

            Andrew Platt, G Sorci, Brian Fulp … (2013)
            Reverse cholesterol transport (RCT) refers to the mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves peripheral tissues to reach plasma. We first used 2 models of disrupted lymphatic drainage from skin--1 surgical and the other genetic--to quantitatively track RCT following injection of [3H]-cholesterol-loaded macrophages upstream of blocked or absent lymphatic vessels. Macrophage RCT was markedly impaired in both models, even at sites with a leaky vasculature. Inhibited RCT was downstream of cholesterol efflux from macrophages, since macrophage efflux of a fluorescent cholesterol analog (BODIPY-cholesterol) was not altered by impaired lymphatic drainage. We next addressed whether RCT was mediated by lymphatic vessels from the aortic wall by loading the aortae of donor atherosclerotic Apoe-deficient mice with [2H]6-labeled cholesterol and surgically transplanting these aortae into recipient Apoe-deficient mice that were treated with anti-VEGFR3 antibody to block lymphatic regrowth or with control antibody to allow such regrowth. [2H]-Cholesterol was retained in aortae of anti-VEGFR3-treated mice. Thus, the lymphatic vessel route is critical for RCT from multiple tissues, including the aortic wall. These results suggest that supporting lymphatic transport function may facilitate cholesterol clearance in therapies aimed at reversing atherosclerosis.
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              Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression.

              Lin Zhu, Pei Xu (2013)
              Long noncoding RNAs (lncRNAs) are key regulators of diverse biological processes such as transcriptional regulation, cell growth and differentiation. Previous studies have demonstrated that the lncRNA-ANCR (anti-differentiation ncRNA) is required to maintain the undifferentiated cell state within the epidermis. However, little is known about whether ANCR regulates osteoblast differentiation. In this study, we found that the ANCR expression level is significantly decreased during hFOB1.19 cell differentiation. ANCR-siRNA blocks the expression of endogenous ANCR, resulting in osteoblast differentiation, whereas ANCR overexpression is sufficient to inhibit osteoblast differentiation. We further demonstrated that ANCR is associated with enhancer of zeste homolog 2 (EZH2) and that this association results in the inhibition of both Runx2 expression and subsequent osteoblast differentiation. These data suggest that ANCR is an essential mediator of osteoblast differentiation, thus offering a new target for the development of therapeutic agents to treat bone diseases. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Jian Liu
                Journal
                Journal ID (nlm-ta): Mol Ther Nucleic Acids
                Journal ID (iso-abbrev): Mol Ther Nucleic Acids
                Title: Molecular Therapy. Nucleic Acids
                Publisher: American Society of Gene & Cell Therapy
                ISSN (Electronic): 2162-2531
                Publication date PMC-release: 12 November 2019
                Publication date Collection: 06 March 2020
                Publication date (Electronic): 12 November 2019
                Volume: 19
                Pages: 84-96
                Affiliations
                [1 ]Department of Cardiovascular Surgery, Shanghai General Hospital, Shanghai 200080, P.R. China
                Author notes
                [∗ ]Corresponding author Jian Liu, Department of Cardiovascular Surgery, Shanghai General Hospital, No. 100, Haining Road, Hongkou District, Shanghai 200080, P.R. China. swalk0721@ 123456163.com
                Article
                Publisher ID: S2162-2531(19)30344-0
                DOI: 10.1016/j.omtn.2019.10.034
                PMC ID: 6926212
                PubMed ID: 31830648
                SO-VID: 49b21f93-5053-4ccb-b5eb-93118b4654ff
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 24 February 2019
                Date accepted : 29 October 2019
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular medicine
                Keywords: atherosclerosis,long non-coding rna,gas5,abca1,ezh2,thp-1 macrophage,cholesterol,epigenetics
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: atherosclerosis, long non-coding rna, gas5, abca1, ezh2, thp-1 macrophage, cholesterol, epigenetics

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