ABCA1-Super Enhancer RNA Promotes Cholesterol Efflux, Reduces Macrophage-Mediated Inflammation and Atherosclerosis

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC: Basic to Translational Science Pub Date : 2024-12-01 DOI:10.1016/j.jacbts.2024.08.005

Jing Wang PhD , Qianqian Xiao MD , Yuwei Cai MD , Man Wang MD , Chen Chen MD , Luyun Wang MD, PhD , Ruiying Ma MD , Yanyan Cao PhD , Yan Wang MD, PhD , Hu Ding MD, PhD , Dao Wen Wang MD, PhD

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引用次数: 0

Abstract

We describe a previously uncharacterized ATP-binding cassette A1 super enhancer RNA (ABCA1-seRNA)-mediated cholesterol efflux. In addition, it promoted macrophage inflammatory cytokine release, and was causally correlated with coronary artery disease severity. Mechanistically, ABCA1-seRNA upregulated cholesterol efflux by interacting with mediator complex subunit 23 and recruiting retinoid X receptor-alpha and liver X receptor-alpha to promote ABCA1 transcription in a cis manner. Meanwhile, ABCA1-seRNA induced P65 ubiquitination degradation, and thereby repressed the macrophage inflammatory response. Consistently, overexpression of ABCA1-seRNA in ApoE^−/− mice decreased plasma lipids, cytokines, and atherosclerotic plaques. These findings indicate ABCA1-seRNA is a critical epigenetic regulator that maintains cholesterol homeostasis and modulates inflammation, thus promising a therapeutic target for atherosclerotic cardiovascular diseases.

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abca1 -超级增强子RNA促进胆固醇外流，减少巨噬细胞介导的炎症和动脉粥样硬化。

我们描述了一种以前未被表征的atp结合盒A1超增强子RNA （ABCA1-seRNA）介导的胆固醇外溢。此外，它促进巨噬细胞炎症细胞因子的释放，并与冠状动脉疾病的严重程度有因果关系。机制上，ABCA1- serna通过与中介复合物亚基23相互作用，募集类维生素a X受体- α和肝X受体- α，顺式促进ABCA1转录，从而上调胆固醇外排。同时，ABCA1-seRNA诱导P65泛素化降解，从而抑制巨噬细胞的炎症反应。一致地，ApoE-/-小鼠中ABCA1-seRNA的过度表达降低了血浆脂质、细胞因子和动脉粥样硬化斑块。这些发现表明，ABCA1-seRNA是维持胆固醇稳态和调节炎症的关键表观遗传调节因子，因此有望成为动脉粥样硬化性心血管疾病的治疗靶点。

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.