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

Meng, Xiangdong; Yao, Hua-Hong; Wang, Limin; Yu, Min; Shi, Sheng; Yuan, Zihao; Liu, Jian

doi:10.1016/j.omtn.2019.10.034

Cited by 70 publications

(81 citation statements)

References 41 publications

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“…Of the mechanisms that have been described, pathway included ABCA1/ABCG1 was widely studied. [16][17][18][19] As far as we know, cholesterol efflux transport relies on some specific proteins, such as ABCA1 and ABCG1, which has been regarded as gatekeeper for mediating tissue cholesterol. 20 ABCA1 and ABCG1 present additional activities during enhancing process of reverse cholesterol transport in vivo.…”

Section: Introductionmentioning

confidence: 99%

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

Hang

Peng

Xiang

et al. 2020

DDDT

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These authors contributed equally to this workObjective: This study was to investigate the mechanism of inflammatory pathology modification induced by ox-LDL in endothelial cells. Methodology: In this study, we firstly investigated the efflux of cholesterol of endothelial cells under the treatment of ox-LDL, and cell proliferation, ROS production, cell apoptosis was measured. Further, proteins of ASK1, NLRP3 inflammasomes and endoplasmic reticulum stress response were detected. Afterwards, ASK1 inhibitor (GS-4997) or endoplasmic reticulum stress (ERS) inhibitor (4-PBA) was used to measure the performance of endothelial cells. Results: In this study, endothelial cells were treated with ox-LDLs alone or in combination with a GS-4997 or 4-PBA. Results showed that ox-LDLs attenuated the efflux of cholesterol from endothelial cells in a dose-dependent manner. Ox-LDLs inhibited the proliferation of endothelial cells, and induced their apoptosis and production of reactive oxygen species (ROS). Additionally, ox-LDLs upregulated the levels of phosphorylated ASK1, ERS-related proteins (chop, p-PERK, GRP78, and p-IRE-1), and inflammation-associated proteins (NLRP3, IL-1β, and caspase 1) in endothelial cells. Moreover, we proved that GS-4997 could partly reverse ox-LDL-mediated cell proliferation, apoptosis, ROS production, and inflammation in endothelial cells, and increase cholesterol efflux. We also found that 4-PBA could attenuate the effects of ox-LDLs on endothelial cell cholesterol efflux, proliferation, apoptosis, ROS production, and inflammation. Conclusion: Our results suggest that cholesterol efflux from endothelial cells is reduced by ox-LDLs, and these reductions in cholesterol efflux are accompanied by increased NLRP3 inflammasome signaling, ASK1 and higher levels of endoplasmic reticulum stress. Our results suggest this axis as potential targets for treating atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

Hang

Peng

Xiang

et al. 2020

DDDT

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“…ApoE-/-mice with overexpression of GAS5 or EZH2 showed increased total cholesterol, free cholesterol, cholesterol ester, low-density lipoprotein levels, aortic plaque, and lipid accumulation, accompanied by reduced HDL levels and cholesterol outflow. These data suggest GAS5 as a promising target to restore cholesterol homeostasis and inhibit atherosclerotic plaque formation in patients [86].…”

Section: Reverse Cholesterol Transport -Abca1 and Abcg1 Regulationmentioning

confidence: 84%

“…Macrophage-expressed lncRNAs can also have detrimental effects on foam cell formation through the inhibition of ABCA1. In the study by Meng et al [86], the lncRNA growth arrest-specific 5 (GAS5) was highly expressed in the THP-1 macrophage-derived foam cells and localized primarily to the nucleus. The overexpression of GAS5 facilitated lipid accumulation and foam cell formation.…”

Section: Reverse Cholesterol Transport -Abca1 and Abcg1 Regulationmentioning

confidence: 99%

Macrophage Long Non-Coding RNAs in Pathogenesis of Cardiovascular Disease

Wysoczynski

Kim

Moore

et al. 2020

ncRNA

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Chronic inflammation is inextricably linked to cardiovascular disease (CVD). Macrophages themselves play important roles in atherosclerosis, as well as acute and chronic heart failure. Although the role of macrophages in CVD pathophysiology is well-recognized, little is known regarding the precise mechanisms influencing their function in these contexts. Long non-coding RNAs (lncRNAs) have emerged as significant regulators of macrophage function; as such, there is rising interest in understanding how these nucleic acids influence macrophage signaling, cell fate decisions, and activity in health and disease. In this review, we summarize current knowledge regarding lncRNAs in directing various aspects of macrophage function in CVD. These include foam cell formation, Toll-like receptor (TLR) and NF-kβ signaling, and macrophage phenotype switching. This review will provide a comprehensive understanding concerning previous, ongoing, and future studies of lncRNAs in macrophage functions and their importance in CVD.

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“…A recent study showed that lncRNA GAS5 was mainly localized in the nucleus and highly expressed in THP-1 macrophage-derived foam cells in coronary heart disease. The knockdown of GAS5 increased cholesterol efflux and inhibited intracellular lipid accumulation in THP-1 macrophage-derived foam cells and homozygous apolipoprotein E (ApoE) knockout mice by reducing the EZH2-mediated transcriptional inhibition of ABCA1 by histone methylation (66). The overexpression of RP-833A20.1 in THP-1 macrophages may also decrease cholesterol efflux.…”

Section: Role Of Lncrnas In Lipid Effluxmentioning

confidence: 99%

“…Lipid disorders cause lipoprotein accumulation within middle and large artery walls, thus triggering atherosclerosis (155). Several lncRNAs are involved in lipid metabolism-related disorders through the regulation of lipid synthesis, reverse cholesterol transport, and bile acid excretion (63,66). The formation of macrophage foam cells, which play central roles in the initiation and progression of atherosclerotic plaques, has been shown to be closely related to DYNLRB2-2, MeXis, and RP5-833A20.1 (63,64,67).…”

Section: Atherosclerosismentioning

confidence: 99%

Regulation of Glucose and Lipid Metabolism by Long Non-coding RNAs: Facts and Research Progress

et al. 2020

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Long non-coding RNAs (lncRNAs) are a type of non-coding RNA with a length that exceeds 200 nucleotides. Previous studies have shown that lncRNAs play an important role in the pathogenesis of various diseases. Research in both animal models and humans has begun to unravel the profound complexity of lncRNAs and demonstrated that lncRNAs exert direct effects on glucose and lipid metabolism both in vivo and in vitro. Such research has elucidated the regulatory role of lncRNAs in glucose and lipid metabolism in human disease. lncRNAs mediate glucose and lipid metabolism under physiological and pathological conditions and contribute to various metabolism disorders. This review provides an update on our understanding of the regulatory role of lncRNAs in glucose and lipid metabolism in various diseases. As our understanding of the function of lncRNAs improves, the future is promising for the development of new diagnostic biomarkers that utilize lncRNAs and treatments that target lncRNAs to improve clinical outcomes.

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

Cited by 70 publications

References 41 publications

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

Macrophage Long Non-Coding RNAs in Pathogenesis of Cardiovascular Disease

Regulation of Glucose and Lipid Metabolism by Long Non-coding RNAs: Facts and Research Progress

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