ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression

Binod Aryal, Noemi Rotllan, Elisa Araldi, Cristina M. Ramírez, Shun He, Benjamin G. Chousterman, Ashley M. Fenn, Amarylis Wanschel, Julio Madrigal-Matute, Nikhil Warrier, Jose L. Martín-Ventura, Filip K. Swirski, Yajaira Suárez () and Carlos Fernández-Hernando ()
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Binod Aryal: Vascular Biology and Therapeutics Program, Yale University School of Medicine
Noemi Rotllan: Vascular Biology and Therapeutics Program, Yale University School of Medicine
Elisa Araldi: Vascular Biology and Therapeutics Program, Yale University School of Medicine
Cristina M. Ramírez: Vascular Biology and Therapeutics Program, Yale University School of Medicine
Shun He: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School
Benjamin G. Chousterman: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School
Ashley M. Fenn: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School
Amarylis Wanschel: New York University School of Medicine
Julio Madrigal-Matute: New York University School of Medicine
Nikhil Warrier: New York University School of Medicine
Jose L. Martín-Ventura: Vascular Research Lab, IIS-Fundación Jimenez-Díaz, Universidad Autónoma de Madrid
Filip K. Swirski: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School
Yajaira Suárez: Vascular Biology and Therapeutics Program, Yale University School of Medicine
Carlos Fernández-Hernando: Vascular Biology and Therapeutics Program, Yale University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it’s absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.

Date: 2016
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DOI: 10.1038/ncomms12313

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