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Tribbles 3 deficiency promotes atherosclerotic fibrous cap thickening and macrophage-mediated extracellular matrix remodelling

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journal contribution
posted on 2023-06-23, 15:46 authored by Laura Martinez-Campesino, Klaudia Kocsy, Jaime Canedo, Jessica M Johnston, Charlotte E Moss, Simon A Johnston, Stephen Hamby, Alison H Goodall, Jessica Redgrave, Sheila E Francis, Endre Kiss-Toth, Heather L Wilson
Tribbles 3 (TRIB3) modulates lipid and glucose metabolism, macrophage lipid uptake, with a gain-of-function variant associated with increased cardiovascular risk. Here we set out to examine the role of this pseudokinase in atherosclerotic plaque development. Human endarterectomy atherosclerotic tissue specimens analysed by immunofluorescence showed upregulated TRIB3 in unstable plaques and an enrichment in unstable regions of stable plaques. Atherosclerosis was induced in full body Trib3KO and Trib3WT littermate mice by injecting mPCSK9 expressing adeno-associated virus and western diet feeding for 12 weeks. Trib3KO mice showed expanded visceral adipose depot while circulatory lipid levels remained unaltered compared to wildtype mice. Trib3KO mice aortae showed a reduced plaque development and improved plaque stability, with increased fibrous cap thickness and collagen content, which was accompanied by increased macrophage content. Analysis of both mouse and human macrophages with reduced TRIB3 expression showed elongated morphology, increased actin expression and altered regulation of genes involved in extracellular matrix remodelling. In summary, TRIB3 controls plaque development and may be atherogenic in vivo. Loss of TRIB3 increases fibrous cap thickness via altered metalloproteinase expression in macrophages, thus inhibiting collagen and elastic fibre degradation, suggesting a role for TRIB3 in the formation of unstable plaques.

History

Citation

Martinez-Campesino L, Kocsy K, Cañedo J, Johnston JM, Moss CE, Johnston SA, Hamby S, Goodall AH, Redgrave J, Francis SE, Kiss-Toth E and Wilson HL (2022) Tribbles 3 deficiency promotes atherosclerotic fibrous cap thickening and macrophage-mediated extracellular matrix remodelling. Front. Cardiovasc. Med. 9:948461. doi: 10.3389/fcvm.2022.948461

Author affiliation

Department of Cardiovascular Sciences and Leicester NIHR Biomedical Research Centre

Version

  • VoR (Version of Record)

Published in

FRONTIERS IN CARDIOVASCULAR MEDICINE

Volume

9

Pagination

948461

Publisher

FRONTIERS MEDIA SA

issn

2297-055X

eissn

2297-055X

Acceptance date

2022-08-02

Copyright date

2022

Available date

2023-06-23

Language

English