Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow–Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet

Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein. Objective: The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis. Methods and Results: Low-density lipoprotein receptor knockout (LDLr KO) mice were transplanted with bone marrow from ABCA1/SR-BI double knockout mice, the respective single knockouts, or wild-type littermates. Serum cholesterol levels were lower in ABCA1/SR-BI double knockout transplanted animals, as compared to the single knockout and wild-type transplanted animals on Western-type diet. Despite the lower serum cholesterol levels, massive foam cell formation was found in macrophages from spleen and the peritoneal cavity. Interestingly, ABCA1/SR-BI double knockout transplanted animals also showed a major increase in proinflammatory KC (murine interleukin-8) and interleukin-12p40 levels in the circulation. Furthermore, after 10 weeks of Western-type diet feeding, atherosclerotic lesion development in the aortic root was more extensive in the LDLr KO mice reconstituted with ABCA1/SR-BI double knockout bone marrow. Conclusions: Deletion of ABCA1 and SR-BI in bone marrow–derived cells enhances in vivo macrophage foam cell formation and atherosclerotic lesion development in LDLr KO mice on Western diet, indicating that under high dietary lipid conditions, both macrophage ABCA1 and SR-BI contribute significantly to cholesterol homeostasis in the macrophage in vivo and are essential for reducing the risk for atherosclerosis.

[1]  A. Tall,et al.  ATP-Binding Cassette Transporters and HDL Suppress Hematopoietic Stem Cell Proliferation , 2010, Science.

[2]  D. Rader,et al.  Pathways by Which Reconstituted High-Density Lipoprotein Mobilizes Free Cholesterol From Whole Body and From Macrophages , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[3]  C. Mineo,et al.  Signaling by the High-Affinity HDL Receptor Scavenger Receptor B Type I , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[4]  B. De Geest,et al.  Critical role of scavenger receptor-BI-expressing bone marrow-derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer. , 2009, Blood.

[5]  A. von Eckardstein,et al.  Lipidation of apolipoprotein A-I by ATP-binding cassette transporter (ABC) A1 generates an interaction partner for ABCG1 but not for scavenger receptor BI. , 2008, Biochimica et biophysica acta.

[6]  K. Node,et al.  Interleukin-8 as an independent predictor of long-term clinical outcome in patients with coronary artery disease. , 2008, International journal of cardiology.

[7]  F. Tacke,et al.  Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis , 2008, Circulation research.

[8]  I. Gelissen,et al.  Coexistence of Foam Cells and Hypocholesterolemia in Mice Lacking the ABC Transporters A1 and G1 , 2008, Circulation research.

[9]  A. Tall,et al.  Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. , 2007, The Journal of clinical investigation.

[10]  V. de Waard,et al.  Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[11]  D. Rader,et al.  The roles of different pathways in the release of cholesterol from macrophages Published, JLR Papers in Press, August 29, 2007. , 2007, Journal of Lipid Research.

[12]  D. Rader,et al.  Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. , 2007, The Journal of clinical investigation.

[13]  V. Videm,et al.  Multiple inflammatory markers in patients with significant coronary artery disease. , 2007, International journal of cardiology.

[14]  M. Linton,et al.  Severely altered cholesterol homeostasis in macrophages lacking apoE and SR-BI Published, JLR Papers in Press, February 13, 2007. , 2007, Journal of Lipid Research.

[15]  G. Getz,et al.  Lymphotoxin ß Receptor–Dependent Control of Lipid Homeostasis , 2007, Science.

[16]  H. McBride,et al.  Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathwayss⃞ Published, JLR Papers in Press, December 5, 2006. , 2007, Journal of Lipid Research.

[17]  D. Webb,et al.  25-Hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol upregulate interleukin-8 expression independently of Toll-like receptor 1, 2, 4 or 6 signalling in human macrophages , 2007, Free radical research.

[18]  A. Vaughan,et al.  ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL Published, JLR Papers in Press, August 10, 2006. , 2006, Journal of Lipid Research.

[19]  Andrew C. Li,et al.  Impaired Development of Atherosclerosis in Hyperlipidemic Ldlr−/− and ApoE−/− Mice Transplanted With Abcg1−/− Bone Marrow , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[20]  A. Tall,et al.  Decreased Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice Transplanted With Abcg1−/− Bone Marrow , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[21]  T. V. van Berkel,et al.  Macrophage ABCG1 Deletion Disrupts Lipid Homeostasis in Alveolar Macrophages and Moderately Influences Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[22]  K. Gaus,et al.  Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages , 2006, Current opinion in lipidology.

[23]  B. Coll,et al.  Manipulation of inflammation modulates hyperlipidemia in apolipoprotein E-deficient mice: a possible role for interleukin-6. , 2006, Cytokine.

[24]  M. Hayden,et al.  Macrophage ATP-Binding Cassette Transporter A1 Overexpression Inhibits Atherosclerotic Lesion Progression in Low-Density Lipoprotein Receptor Knockout Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[25]  R. Terkeltaub,et al.  Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. , 2006, The American journal of pathology.

[26]  I. Gelissen,et al.  ABCA1 and ABCG1 Synergize to Mediate Cholesterol Export to ApoA-I , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[27]  J. Renauld,et al.  Blockade of Interleukin-12 Function by Protein Vaccination Attenuates Atherosclerosis , 2005, Circulation.

[28]  T. V. van Berkel,et al.  Scavenger receptor BI and ATP-binding cassette transporter A1 in reverse cholesterol transport and atherosclerosis , 2005, Current opinion in lipidology.

[29]  R. Schwabe,et al.  Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. , 2005, The Journal of biological chemistry.

[30]  Paul T. Tarr,et al.  ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. , 2005, Cell metabolism.

[31]  T. V. van Berkel,et al.  Dual role for scavenger receptor class B, type I on bone marrow-derived cells in atherosclerotic lesion development. , 2004, The American journal of pathology.

[32]  M. Linton,et al.  Inactivation of Macrophage Scavenger Receptor Class B Type I Promotes Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice , 2003, Circulation.

[33]  P. Tipping,et al.  The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. , 2003, The American journal of pathology.

[34]  Scott D Covey,et al.  Scavenger Receptor Class B Type I–Mediated Protection Against Atherosclerosis in LDL Receptor–Negative Mice Involves Its Expression in Bone Marrow–Derived Cells , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[35]  Pascal J. Goldschmidt-Clermont,et al.  Aging, Progenitor Cell Exhaustion, and Atherosclerosis , 2003, Circulation.

[36]  Kazuo Haze,et al.  Neutrophil Infiltration of Culprit Lesions in Acute Coronary Syndromes , 2002, Circulation.

[37]  W. Fung-Leung,et al.  Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  O. Francone,et al.  Increased Atherosclerosis in Hyperlipidemic Mice With Inactivation of ABCA1 in Macrophages , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[39]  J. Kuiper,et al.  Attenuation of atherogenesis by systemic and local adenovirus‐mediated gene transfer of interleukin‐10 in LDLr ‐/‐ Mice , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  Steffen Jung,et al.  The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. , 2001, The Journal of clinical investigation.

[41]  G. Schmitz,et al.  ATP-Binding Cassette Transporter A1 (ABCA1) in Macrophages: A Dual Function in Inflammation and Lipid Metabolism? , 2000, Pathobiology.

[42]  G. Schmitz,et al.  ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Tzong-Shyuan Lee,et al.  The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[44]  R. Ross,et al.  Atherosclerosis is an inflammatory disease. , 1998, American heart journal.

[45]  R. Dean,et al.  Sterol Efflux Is Impaired from Macrophage Foam Cells Selectively Enriched with 7-Ketocholesterol* , 1996, The Journal of Biological Chemistry.

[46]  A. Tall,et al.  Interleukin 8 Is Induced by Cholesterol Loading of Macrophages and Expressed by Macrophage Foam Cells in Human Atheroma (*) , 1996, The Journal of Biological Chemistry.

[47]  B. Cronstein,et al.  Immunocomplexes stimulate different signalling events to chemoattractants in the neutrophil and regulate L-selectin and beta 2-integrin expression differently. , 1994, The Biochemical journal.

[48]  J. Schröder,et al.  Secretion of novel and homologous neutrophil-activating peptides by LPS-stimulated human endothelial cells. , 1989, Journal of immunology.

[49]  B. Dewald,et al.  A novel neutrophil-activating factor produced by human mononuclear phagocytes , 1988, The Journal of experimental medicine.

[50]  R. Williams,et al.  Quantitative assessment of atherosclerotic lesions in mice. , 1987, Atherosclerosis.

[51]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[52]  C. E. West,et al.  Separation of plasma lipoproteins by density-gradient ultracentrifugation. , 1975, Analytical biochemistry.

[53]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[54]  G. Getz,et al.  Lymphotoxin beta receptor-dependent control of lipid homeostasis. , 2007, Science.

[55]  R. Terkeltaub,et al.  Oxidized LDL induces monocytic cell expression of interleukin-8, a chemokine with T-lymphocyte chemotactic activity. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.