Endothelial c-REL orchestrates atherosclerosis at regions of disturbed flow through crosstalk with TXNIP-p38 and non-canonical NF-κB pathways


Tardajos Ayllon, B, Bowden, N, Souilhol, C, Darwish, H, Tian, S, Duckworth, C ORCID: 0000-0001-7971-3561, Pritchard, DM ORCID: 0000-0001-7971-3561, Xu, S ORCID: 0000-0002-5488-5217, Sayers, J, Francis, S et al (show 3 more authors) (2025) Endothelial c-REL orchestrates atherosclerosis at regions of disturbed flow through crosstalk with TXNIP-p38 and non-canonical NF-κB pathways Cardiovascular Research, 121 (5). pp. 748-759. ISSN 0008-6363, 1755-3245

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Abstract

Aims Atherosclerosis initiation at sites of disturbed blood flow involves heightened inflammation coupled to excessive endothelial cell (EC) proliferation. Here, we unveil the pivotal role of c-REL, a member of the NF-κB transcription factor family, in orchestrating these processes by driving dual pathological inflammatory and cell cycle pathways. Methods and results Analysis of cultured EC and murine models revealed enrichment and activation of c-REL at atherosusceptible sites experiencing disturbed flow. Transcriptome analysis, extensively validated in vitro and in vivo, demonstrates that endothelial c-REL drives inflammation via a TXNIP-p38 MAP kinase signalling pathway and enhances proliferation through a non-canonical NFKB2-p21 pathway. Consistent with its pivotal role in EC pathology, genetic deletion of c-Rel in EC significantly reduces plaque burden in hypercholesterolaemic mice. Conclusion These findings underscore the fundamental role of c-REL in endothelial responses to disturbed flow and highlight therapeutic targeting of endothelial c-REL as a potential strategy for atherosclerosis treatment.

Item Type: Article
Uncontrolled Keywords: Cells, Cultured, Endothelial Cells, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Disease Models, Animal, p38 Mitogen-Activated Protein Kinases, Carrier Proteins, NF-kappa B, Proto-Oncogene Proteins c-rel, Signal Transduction, Cell Proliferation, Regional Blood Flow, Male, Atherosclerosis, Thioredoxins, Plaque, Atherosclerotic, Human Umbilical Vein Endothelial Cells, Mice, Knockout, ApoE
Divisions: Faculty of Health & Life Sciences
Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 26 Mar 2025 10:20
Last Modified: 24 Jan 2026 05:10
DOI: 10.1093/cvr/cvaf024
Open Access URL: https://doi.org/10.1093/cvr/cvaf024
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3191025
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