title: ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression.
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.
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Binod
authors.initials: B
authors.lastname: Aryal
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Araldi
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Chousterman
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Fenn
authors.affiliation: Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Amarylis
authors.initials: A
authors.lastname: Wanschel
authors.affiliation: Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.affiliation: Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Warrier
authors.affiliation: Vascular Research Lab, IIS-Fundación Jimenez-Díaz, Universidad Autónoma de Madrid, Madrid 28040, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Martín-Ventura
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D000075803:Angiopoietin-Like Protein 4 / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D005487:Foam Cells / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007964:Leukocytosis / Q000150:complications / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000150:complications / Q000378:metabolism / Q000473:pathology
chemical_list: D000075803:Angiopoietin-Like Protein 4