Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation

M. C. Martinez-Campanario, Marlies Cortés, Alazne Moreno-Lanceta, Lu Han, Chiara Ninfali, Verónica Domínguez, María J. Andrés-Manzano, Marta Farràs, Anna Esteve-Codina, Carlos Enrich, Francisco J. Díaz-Crespo, Belén Pintado, Joan C. Escolà-Gil, Pablo García de Frutos, Vicente Andrés, Pedro Melgar-Lesmes and Antonio Postigo ()
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M. C. Martinez-Campanario: Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS
Marlies Cortés: Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS
Alazne Moreno-Lanceta: University of Barcelona School of Medicine
Lu Han: Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS
Chiara Ninfali: Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS
Verónica Domínguez: Transgenesis Facility, National Center of Biotechnology (CNB) and Center for Molecular Biology Severo Ochoa (UAM-CBMSO), Spanish National Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco
María J. Andrés-Manzano: Group of Molecular and Genetic Cardiovascular Pathophysiology, Spanish National Center for Cardiovascular Research (CNIC)
Marta Farràs: University Autonomous of Barcelona
Anna Esteve-Codina: National Center for Genomics Analysis (CNAG)
Carlos Enrich: University of Barcelona School of Medicine
Francisco J. Díaz-Crespo: Hospital General Universitario Gregorio Marañón
Belén Pintado: Transgenesis Facility, National Center of Biotechnology (CNB) and Center for Molecular Biology Severo Ochoa (UAM-CBMSO), Spanish National Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco
Joan C. Escolà-Gil: University Autonomous of Barcelona
Pablo García de Frutos: Center for Biomedical, Research Network in Cardiovascular Diseases (CIBERCV), Carlos III Health Institute
Vicente Andrés: Group of Molecular and Genetic Cardiovascular Pathophysiology, Spanish National Center for Cardiovascular Research (CNIC)
Pedro Melgar-Lesmes: University of Barcelona School of Medicine
Antonio Postigo: Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43896-7

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