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

Overview

Journal JACC Basic Transl Sci

Date 2025 Jan 17

PMID 39822602

Authors

Jing Wang

Qianqian Xiao

Yuwei Cai

Man Wang

Chen Chen

Luyun Wang

Ruiying Ma

Yanyan Cao

Yan Wang

Hu Ding

Dao Wen Wang

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Application Strategies of Super-Enhancer RNA in Cardiovascular Diseases.

He Y, Cai Y, Cao Y, Wang Y, Wang J, Ding H Biomedicines. 2025; 13(1).

PMID: 39857701 PMC: 11762524. DOI: 10.3390/biomedicines13010117.

Knowing Your ABCs: Macrophage ABCA1-Mediated Cholesterol Efflux as a Therapeutic Target in Atherosclerotic Cardiovascular Disease.

Karpouzas G, Ronda N JACC Basic Transl Sci. 2025; 9(12):1406-1408.

PMID: 39822603 PMC: 11733745. DOI: 10.1016/j.jacbts.2024.09.008.

References

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M . An atlas of active enhancers across human cell types and tissues. Nature. 2014; 507(7493):455-461. PMC: 5215096. DOI: 10.1038/nature12787. View

Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N . Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007; 117(4):e25-146. DOI: 10.1161/CIRCULATIONAHA.107.187998. View

Zannis V, Fotakis P, Koukos G, Kardassis D, Ehnholm C, Jauhiainen M . HDL biogenesis, remodeling, and catabolism. Handb Exp Pharmacol. 2014; 224:53-111. DOI: 10.1007/978-3-319-09665-0_2. View

Bauersachs R, Zeymer U, Briere J, Marre C, Bowrin K, Huelsebeck M . Burden of Coronary Artery Disease and Peripheral Artery Disease: A Literature Review. Cardiovasc Ther. 2020; 2019:8295054. PMC: 7024142. DOI: 10.1155/2019/8295054. View

Whyte W, Orlando D, Hnisz D, Abraham B, Lin C, Kagey M . Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013; 153(2):307-19. PMC: 3653129. DOI: 10.1016/j.cell.2013.03.035. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Liang Z, Li G, Wang Z, Djekidel M, Li Y, Qian M . BL-Hi-C is an efficient and sensitive approach for capturing structural and regulatory chromatin interactions. Nat Commun. 2017; 8(1):1622. PMC: 5696378. DOI: 10.1038/s41467-017-01754-3. View

Westerterp M, Fotakis P, Ouimet M, Bochem A, Zhang H, Molusky M . Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis. Circulation. 2018; 138(9):898-912. PMC: 6160368. DOI: 10.1161/CIRCULATIONAHA.117.032636. View

Hu Y, Guo F, Xu Y, Li P, Lu Z, McVey D . Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXN. J Clin Invest. 2018; 129(3):1115-1128. PMC: 6391138. DOI: 10.1172/JCI98230. View

10.

Back M, Yurdagul Jr A, Tabas I, Oorni K, Kovanen P . Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019; 16(7):389-406. PMC: 6727648. DOI: 10.1038/s41569-019-0169-2. View

11.

Mach F, Baigent C, Catapano A, Koskinas K, Casula M, Badimon L . 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019; 41(1):111-188. DOI: 10.1093/eurheartj/ehz455. View

12.

Stadhouders R, Kolovos P, Brouwer R, Zuin J, van den Heuvel A, Kockx C . Multiplexed chromosome conformation capture sequencing for rapid genome-scale high-resolution detection of long-range chromatin interactions. Nat Protoc. 2013; 8(3):509-24. DOI: 10.1038/nprot.2013.018. View

13.

Chen C, Zhou D, Gu Y, Wang C, Zhang M, Lin X . SEA version 3.0: a comprehensive extension and update of the Super-Enhancer archive. Nucleic Acids Res. 2019; 48(D1):D198-D203. PMC: 7145603. DOI: 10.1093/nar/gkz1028. View

14.

Li W, Notani D, Rosenfeld M . Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat Rev Genet. 2016; 17(4):207-23. DOI: 10.1038/nrg.2016.4. View

15.

Willer C, Schmidt E, Sengupta S, Peloso G, Gustafsson S, Kanoni S . Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45(11):1274-1283. PMC: 3838666. DOI: 10.1038/ng.2797. View

16.

Wang G, Balamotis M, Stevens J, Yamaguchi Y, Handa H, Berk A . Mediator requirement for both recruitment and postrecruitment steps in transcription initiation. Mol Cell. 2005; 17(5):683-94. DOI: 10.1016/j.molcel.2005.02.010. View

17.

Baigent C, Keech A, Kearney P, Blackwell L, Buck G, Pollicino C . Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366(9493):1267-78. DOI: 10.1016/S0140-6736(05)67394-1. View

18.

Sanson M, Distel E, Fisher E . HDL induces the expression of the M2 macrophage markers arginase 1 and Fizz-1 in a STAT6-dependent process. PLoS One. 2013; 8(8):e74676. PMC: 3749183. DOI: 10.1371/journal.pone.0074676. View

19.

Fang S, Zhang L, Guo J, Niu Y, Wu Y, Li H . NONCODEV5: a comprehensive annotation database for long non-coding RNAs. Nucleic Acids Res. 2017; 46(D1):D308-D314. PMC: 5753287. DOI: 10.1093/nar/gkx1107. View

20.

Mouton A, Li X, Hall M, Hall J . Obesity, Hypertension, and Cardiac Dysfunction: Novel Roles of Immunometabolism in Macrophage Activation and Inflammation. Circ Res. 2020; 126(6):789-806. PMC: 7255054. DOI: 10.1161/CIRCRESAHA.119.312321. View