Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation

Nat Commun. 2023 Dec 14;14(1):8316. doi: 10.1038/s41467-023-43896-7.

M C Martinez-Campanario ¹, Marlies Cortés ^# ¹, Alazne Moreno-Lanceta ^# ², Lu Han ¹, Chiara Ninfali ¹, Verónica Domínguez ³, María J Andrés-Manzano ⁴ ⁵, Marta Farràs ⁶ ⁷, Anna Esteve-Codina ⁸, Carlos Enrich ² ⁹, Francisco J Díaz-Crespo ¹⁰, Belén Pintado ³, Joan C Escolà-Gil ⁶ ⁷, Pablo García de Frutos ⁵ ¹¹ ¹², Vicente Andrés ⁴ ⁵, Pedro Melgar-Lesmes ² ¹³ ¹⁴ ¹⁵, Antonio Postigo ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1 Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain.
2 Department of Biomedicine, University of Barcelona School of Medicine, 08036, Barcelona, Spain.
3 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, 28049, Madrid, Spain.
4 Group of Molecular and Genetic Cardiovascular Pathophysiology, Spanish National Center for Cardiovascular Research (CNIC), 28029, Madrid, Spain.
5 Center for Biomedical, Research Network in Cardiovascular Diseases (CIBERCV), Carlos III Health Institute, 28029, Madrid, Spain.
6 Department of Biochemistry and Molecular Biology, Institute of Biomedical Research Sant Pau, University Autonomous of Barcelona, 08041, Barcelona, Spain.
7 Center for Biomedical Research Network in Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute, 28029, Madrid, Spain.
8 National Center for Genomics Analysis (CNAG), 08028, Barcelona, Spain.
9 Group of signal transduction, intracellular compartments and cancer, IDIBAPS, 08036, Barcelona, Spain.
10 Department of Pathology, Hospital General Universitario Gregorio Marañón, 28007, Madrid, Spain.
11 Department Of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036, Barcelona, Spain.
12 Group of Hemotherapy and Hemostasis, IDIBAPS, 08036, Barcelona, Spain.
13 Department of Biochemistry and Molecular Genetics, Hospital Clínic, 08036, Barcelona, Spain.
14 Center for Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III Health Institute, 28029, Madrid, Spain.
15 Institute for Medical Engineering & Science, Massachusetts Institute of Technology (MIT), Cambridge, MA, 02139, USA.
16 Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain. idib412@recerca.clinic.cat.
17 Center for Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III Health Institute, 28029, Madrid, Spain. idib412@recerca.clinic.cat.
18 Molecular Targets Program, Division of Oncology, Department of Medicine, J.G. Brown Cancer Center, Louisville, KY, 40202, USA. idib412@recerca.clinic.cat.
19 ICREA, 08010, Barcelona, Spain. idib412@recerca.clinic.cat.
# Contributed equally.

PMID: 38097578 DOI: 10.1038/s41467-023-43896-7

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 (Zeb1^WT/apoE^KO), male mice with Zeb1 ablation in their myeloid cells (Zeb1^∆M/apoE^KO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient Cholesterol efflux. Zeb1^∆M/apoE^KO mice display more pronounced systemic metabolic alterations than Zeb1^WT/apoE^KO 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/apoE^KO 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.

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