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

Tardajos Ayllon, Blanca; Bowden, Neil; Souilhol, Celine; Darwish, Hazem; Tian, Siyu; Duckworth, Carrie; Pritchard, David Mark; Xu, Suowen; Sayers, Jon; Francis, Sheila; Serbanovic-Canic, Jovana; Oakley, Fiona; Evans, Paul Charles

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

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TARDAJOS AYLLON, Blanca, BOWDEN, Neil, SOUILHOL, Celine, DARWISH, Hazem, TIAN, Siyu, DUCKWORTH, Carrie, PRITCHARD, David Mark, XU, Suowen, SAYERS, Jon, FRANCIS, Sheila, SERBANOVIC-CANIC, Jovana, OAKLEY, Fiona and EVANS, Paul Charles (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), 748-759. [Article]

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36818:1177427

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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.

More Information

Official URL:

https://academic.oup.com/cardiovascres/article/121...

Open Access URL:

https://academic.oup.com/cardiovascres/article-pdf...

Open Access Version:

Published version

Uncontrolled Keywords:

1102 Cardiorespiratory Medicine and Haematology; Cardiovascular System & Hematology; 3201 Cardiovascular medicine and haematology

Page Range:

748-759

Identifiers