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Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.

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.

SUBMITTER: Martinez-Campanario MC

PROVIDER: S-EPMC10721632 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.

Martinez-Campanario M C MC Cortés Marlies M Moreno-Lanceta Alazne A Han Lu L Ninfali Chiara C Domínguez Verónica V Andrés-Manzano María J MJ Farràs Marta M Esteve-Codina Anna A Enrich Carlos C Díaz-Crespo Francisco J FJ Pintado Belén B Escolà-Gil Joan C JC García de Frutos Pablo P Andrés Vicente V Melgar-Lesmes Pedro P Postigo Antonio A

Nature communications 20231214 1

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 h ...[more]

PMID: 38097578

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Project description:Background and aimsAtherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development.MethodsTRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2(-/-) and ApoE(-/-) mice. ApoE(-/-) mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell (SMC) content by histomorphometry, and aortic gene expression by RT-qPCR.ResultsThe plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE(-/-) mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and SMC contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor α, TNFα), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice expressed markedly reduced levels of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing-Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17).ConclusionsTRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases.

Dataset Information

Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.

Publications

Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.

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