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- Title
Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.
- Authors
Martinez-Campanario, M. C.; Cortés, Marlies; Moreno-Lanceta, Alazne; Han, Lu; Ninfali, Chiara; Domínguez, Verónica; Andrés-Manzano, María J.; Farràs, Marta; Esteve-Codina, Anna; Enrich, Carlos; Díaz-Crespo, Francisco J.; Pintado, Belén; Escolà-Gil, Joan C.; García de Frutos, Pablo; Andrés, Vicente; Melgar-Lesmes, Pedro; Postigo, Antonio
- Abstract
Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis. Accumulation of lipid-laden macrophages in the arterial wall is a critical step in atherosclerosis. Here, the authors show that downregulation of Zeb1 in macrophages promotes lipid accumulation and atherosclerotic plaque formation while its restoration with macrophage-targeted nanoparticles reverses these effects.
- Subjects
ATHEROSCLEROTIC plaque; FOAM cells; MYELOID cells; LOW density lipoproteins; DOWNREGULATION
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43896-7