| Hemoglobin Directs Macrophage Differentiation and Prevents Foam Cell Formation in Human Atherosclerotic Plaques. | |
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MedLine Citation:
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PMID: 22154776 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVES: The purpose of this study was to examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis. BACKGROUND: Macrophage subsets are recognized in atherosclerosis, but the stimulus for and importance of differentiation programs remain unknown. METHODS: We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage. RESULTS: Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor-positive macrophages only when these cells contained Hb. Cultured human monocytes exposed to Hb:haptoglobin complexes, but not interleukin-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and up-regulation of ATP-binding cassette (ABC) transporters. M(Hb) demonstrated increased ferroportin expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of ferroportin using hepcidin increased ROS and inhibited ABCA1 expression and cholesterol efflux to apolipoprotein A-I, suggesting reduced ROS triggers these effects. Knockdown of liver X receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the antioxidant superoxide dismutase. Last, LXRα luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest that reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport. CONCLUSIONS: Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A decrease in macrophage intracellular iron plays an important role in this nonfoam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage reverse cholesterol transport. |
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Authors:
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Aloke V Finn; Masataka Nakano; Rohini Polavarapu; Vinit Karmali; Omar Saeed; Xiaoqing Zhao; Saami Yazdani; Fumiyuki Otsuka; Talina Davis; Anwer Habib; Jagat Narula; Frank D Kolodgie; Renu Virmani |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-7 |
Journal Detail:
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Title: Journal of the American College of Cardiology Volume: - ISSN: 1558-3597 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8301365 Medline TA: J Am Coll Cardiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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