1. Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels
- Author
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Menno Hoekstra, Illiana Meurs, Giovanna Chimini, Theo J.C. Van Berkel, Vivian de Waard, Miranda Van Eck, Ruud Out, Yanan Wang, Kim L. L. Habets, Johan Kuiper, Reeni B. Hildebrand, Division of Biopharmaceutics, Universiteit Leiden [Leiden], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
MESH: Spleen ,030204 cardiovascular system & hematology ,MESH: Mice, Knockout ,MESH: Atherosclerosis ,Leukocyte Count ,Mice ,chemistry.chemical_compound ,MESH: Cholesterol ,0302 clinical medicine ,MESH: Animals ,MESH: Bone Marrow Transplantation ,ATP Binding Cassette Transporter, Subfamily G, Member 1 ,Bone Marrow Transplantation ,Foam cell ,Mice, Knockout ,0303 health sciences ,biology ,MESH: Hypercholesterolemia ,MESH: Lipoproteins ,Cholesterol ,medicine.anatomical_structure ,MESH: ATP-Binding Cassette Transporters ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,ATP Binding Cassette Transporter 1 ,medicine.medical_specialty ,MESH: Foam Cells ,Lipoproteins ,Hypercholesterolemia ,MESH: Diet, Atherogenic ,Lesion ,03 medical and health sciences ,Peritoneal cavity ,Internal medicine ,medicine ,Animals ,MESH: Mice ,030304 developmental biology ,Atherosclerosis ,Transplantation ,Disease Models, Animal ,Endocrinology ,Receptors, LDL ,chemistry ,MESH: Receptors, LDL ,MESH: Leukocyte Count ,ABCA1 ,LDL receptor ,biology.protein ,Diet, Atherogenic ,ATP-Binding Cassette Transporters ,Bone marrow ,MESH: Disease Models, Animal ,Spleen ,Foam Cells - Abstract
Objective— The purpose of this study was to evaluate the effect of the combined deletion of ABCA1 and ABCG1 expression in macrophages on foam cell formation and atherosclerosis. Methods and Results— LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/ABCG1 double KO (dKO) mice. Plasma cholesterol levels after 6 weeks of Western-type diet (WTD) feeding were significantly lower in dKO transplanted mice than ABCA1 KO, ABCG1 KO, and control transplanted animals. Extreme foam cell formation was present in macrophages of various tissues and the peritoneal cavity of dKO transplanted animals. Furthermore, severe hypoplasia of the thymus and a significant decrease in CD4-positive T cells in blood was observed. Despite relatively low plasma cholesterol levels dKO transplanted animals developed lesion sizes of 156±19×10 3 μm 2 after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226±30×10 3 μm 2 ; P 3 μm 2 ) and WT transplanted mice (112±15×10 3 μm 2 ). Conclusions— Macrophage ABCA1 and ABCG1 play a crucial role in the prevention of macrophage foam cell formation, whereas combined deletion only modestly influences atherosclerosis which is associated with an attenuated increase in WTD-induced plasma cholesterol and decreased proinflammatory CD4-positive T cell counts.
- Published
- 2008