| ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis. | |
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MedLine Citation:
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PMID: 20431058 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Antiatherogenic effects of plasma high-density lipoprotein (HDL) include the ability to inhibit apoptosis of macrophage foam cells. The ATP-binding cassette transporters ABCA1 and ABCG1 have a major role in promoting cholesterol efflux from macrophages to apolipoprotein A-1 and HDL and are upregulated during the phagocytosis of apoptotic cells (efferocytosis). OBJECTIVE: The goal of this study was to determine the roles of ABCA1 and ABCG1 in preserving the viability of macrophages during efferocytosis. METHODS AND RESULTS: We show that despite similar clearance of apoptotic cells, peritoneal macrophages from Abca1(-/-)Abcg1(-/-), Abcg1(-/-), and, to a lesser extent, Abca1(-/-) mice are much more prone to apoptosis during efferocytosis compared to wild-type cells. Similar findings were observed following incubations with oxidized phospholipids, and the ability of HDL to protect against oxidized phospholipid-induced apoptosis was markedly reduced in Abca1(-/-)Abcg1(-/-) and Abcg1(-/-) cells. These effects were independent of any role of ABCA1 and ABCG1 in mediating oxidized phospholipid efflux but were reversed by cyclodextrin-mediated cholesterol efflux. The apoptotic response observed in Abca1(-/-)Abcg1(-/-) macrophages after oxidized phospholipid exposure or engulfment of apoptotic cells was dependent on an excessive oxidative burst secondary to enhanced assembly of NADPH oxidase (NOX)2 complexes, leading to sustained Jnk activation which turned on the apoptotic cell death program. Increased NOX2 assembly required Toll-like receptors 2/4 and MyD88 signaling, which are known to be enhanced in transporter deficient cells in a lipid raft-dependent fashion. CONCLUSIONS: We identified a new beneficial role of ABCA1, ABCG1 and HDL in dampening the oxidative burst and preserving viability of macrophages following exposure to oxidized phospholipids and/or apoptotic cells. |
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Authors:
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Laurent Yvan-Charvet; Tamara A Pagler; Tracie A Seimon; Edward Thorp; Carrie L Welch; Joseph L Witztum; Ira Tabas; Alan R Tall |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-04-29 |
Journal Detail:
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Title: Circulation research Volume: 106 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-25 Completed Date: 2010-07-21 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1861-9 Citation Subset: IM |
Affiliation:
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Division of Molecular Medicine, Department of Medicine, 630 W 168th St, Columbia University, New York, NY 10032, USA. ly2159@columbia.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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genetics,
physiology* Animals Apoptosis / physiology* Cell Survival / physiology Cells, Cultured Lipoproteins / genetics, physiology* Lipoproteins, HDL / physiology MAP Kinase Kinase 4 / physiology Macrophages, Peritoneal / cytology, physiology* Membrane Glycoproteins / physiology Mice Mice, Inbred C57BL Mice, Knockout Models, Animal Myeloid Differentiation Factor 88 / physiology NADPH Oxidase / physiology Oxidative Stress / physiology* Phagocytosis / physiology* Toll-Like Receptor 2 / physiology Toll-Like Receptor 4 / physiology |
| Grant Support | |
ID/Acronym/Agency:
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HL59541/HL/NHLBI NIH HHS; R01 HL075662-08/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABCG1 protein, mouse; 0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Lipoproteins; 0/Lipoproteins, HDL; 0/Membrane Glycoproteins; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/Tlr2 protein, mouse; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 2; 0/Toll-Like Receptor 4; EC 1.6.3.1/Cybb protein, mouse; EC 1.6.3.1/NADPH Oxidase; EC 2.7.12.2/MAP Kinase Kinase 4 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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