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

  • JACC Basic Transl Sci. 2024 Oct 9;9(12):1388-1405. doi: 10.1016/j.jacbts.2024.08.005.
Jing Wang  1  2 ,  Qianqian Xiao  1  2 ,  Yuwei Cai  1  2 ,  Man Wang  1  2 ,  Chen Chen  1  2 ,  Luyun Wang  1  2 ,  Ruiying Ma  1 ,  Yanyan Cao  1  2 ,  Yan Wang  1  2 ,  Hu Ding  1  2 ,  Dao Wen Wang  1  2
Affiliations
  • 1. Division of Cardiology, Departments of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 2. Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
PMID: 39822602 DOI: 10.1016/j.jacbts.2024.08.005
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.

Keywords
ABCA1; ABCA1-seRNA; atherosclerotic cardiovascular disease (ASCVD); cholesterol; inflammation; macrophage; super-enhancer.
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