Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation
Por:
Martinez-Campanario, MC, Cortés, M, Moreno-Lanceta, A, Han, L, Ninfali, C, Domínguez, V, Andrés-Manzano, MJ, Farràs, M, Esteve-Codina, A, Enrich, C, Diaz-Crespo, FJ, Pintado, B, Escolà-Gil, JC, de Frutos, PG, Andrés, V, Melgar-Lesmes, P, Postigo, A
Publicada:
14 dic 2023
Resumen:
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 increment M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1 increment 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 increment 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 increment 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.
Filiaciones:
Martinez-Campanario, MC:
IDIBAPS, Grp Gene Regulat Stem Cells Cell Plast Differentia, Barcelona 08036, Spain
Cortés, M:
IDIBAPS, Grp Gene Regulat Stem Cells Cell Plast Differentia, Barcelona 08036, Spain
Moreno-Lanceta, A:
Univ Barcelona, Sch Med, Dept Biomed, Barcelona 08036, Spain
Han, L:
IDIBAPS, Grp Gene Regulat Stem Cells Cell Plast Differentia, Barcelona 08036, Spain
Ninfali, C:
IDIBAPS, Grp Gene Regulat Stem Cells Cell Plast Differentia, Barcelona 08036, Spain
Domínguez, V:
Natl Ctr Biotechnol CNB, Transgenesis Facil, Madrid, Spain
CSIC, Ctr Mol Biol Severo Ochoa UAM CBMSO, Madrid 28049, Spain
Autonomous Univ Madrid UAM, Madrid 28049, Spain
Andrés-Manzano, MJ:
Spanish Natl Ctr Cardiovasc Res CNIC, Grp Mol & Genet Cardiovasc Pathophysiol, Madrid 28029, Spain
Res Network Cardiovasc Dis CIBERCV, Carlos III Health Inst, Ctr Biomed, Madrid 28029, Spain
Farràs, M:
Univ Autonomous Barcelona, Inst Biomed Res St Pau, Dept Biochem & Mol Biol, Barcelona 08041, Spain
Carlos III Hlth Inst, Ctr Biomed Res Network Diabet & Associated Metab D, Madrid 28029, Spain
Esteve-Codina, A:
Natl Ctr Genom Anal CNAG, Barcelona 08028, Spain
Enrich, C:
Univ Barcelona, Sch Med, Dept Biomed, Barcelona 08036, Spain
Grp Signal Transduct Intracellular Compartments &, IDIBAPS, Immunol Unit, Barcelona 08036, Spain
Diaz-Crespo, FJ:
Hosp Gen Univ Gregorio Maranon, Dept Pathol, Madrid 28007, Spain
Pintado, B:
Natl Ctr Biotechnol CNB, Transgenesis Facil, Madrid, Spain
CSIC, Ctr Mol Biol Severo Ochoa UAM CBMSO, Madrid 28049, Spain
Autonomous Univ Madrid UAM, Madrid 28049, Spain
Escolà-Gil, JC:
Univ Autonomous Barcelona, Inst Biomed Res St Pau, Dept Biochem & Mol Biol, Barcelona 08041, Spain
Carlos III Hlth Inst, Ctr Biomed Res Network Diabet & Associated Metab D, Madrid 28029, Spain
de Frutos, PG:
Autonomous Univ Madrid UAM, Madrid 28049, Spain
Grp Signal Transduct Intracellular Compartments &, IDIBAPS, Immunol Unit, Barcelona 08036, Spain
Hosp Gen Univ Gregorio Maranon, Dept Pathol, Madrid 28007, Spain
Andrés, V:
Spanish Natl Ctr Cardiovasc Res CNIC, Grp Mol & Genet Cardiovasc Pathophysiol, Madrid 28029, Spain
Res Network Cardiovasc Dis CIBERCV, Carlos III Health Inst, Ctr Biomed, Madrid 28029, Spain
Melgar-Lesmes, P:
Univ Barcelona, Sch Med, Dept Biomed, Barcelona 08036, Spain
Hosp Clin Barcelona, Dept Biochem & Mol Genet, Barcelona 08036, Spain
Carlos III Hlth Inst, Ctr Biomed Res Network Gastrointestinal & Liver Di, Madrid 28029, Spain
MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA
Postigo, A:
IDIBAPS, Grp Gene Regulat Stem Cells Cell Plast Differentia, Barcelona 08036, Spain
Carlos III Hlth Inst, Ctr Biomed Res Network Gastrointestinal & Liver Di, Madrid 28029, Spain
JG Brown Canc Ctr, Dept Med, Mol Targets Program, Div Oncol, Louisville, KY 40202 USA
ICREA, Barcelona 08010, Spain
CSIC, Inst Biomed Res Barcelona IIBB, Dept Cell Death & Proliferat, Barcelona 08036, Spain
Grp Hemotherapy & Hemostasis, IDIBAPS, Barcelona 08036, Spain
gold
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