| Heme Induces Heme Oxygenase 1 via Nrf2: Role in the Homeostatic Macrophage Response to Intraplaque Hemorrhage. | |
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MedLine Citation:
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PMID: 21868703 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVE: Intraplaque hemorrhage (IPH) is an important progression event in advanced atherosclerosis, in large part because of the delivery of prooxidant hemoglobin in erythrocytes. We have previously defined a novel macrophage phenotype (HA-mac) in human advanced plaques with IPH. These may be atheroprotective in view of raised heme oxygenase 1 (HO-1), CD163, and interleukin-10 expression and suppressed oxidative stress. METHODS AND RESULTS: We have used a combination of small interfering RNA and pharmacological reagents, protein analysis, and oxidative stress measurements to dissect the pathway leading to the development of this phenotype. We found that erythrocytes, hemoglobin, or purified heme similarly induced CD163 and suppressed HLA-DR and reactive oxygen species. HO-1 was required for the development of each of these features. Challenge of macrophages with purified heme provoked nuclear translocation of Nrf2, and Nrf2 small interfering RNA resulted in significant inhibition of the ability of heme to induce HO-1 protein. Furthermore, tert-butyl-hydroquinone, which activates Nrf2, upregulated CD163, suppressed HLA-DR, and induced interleukin-10, further supporting a role for Nrf2-mediated signaling. However, an inducible protein transactivator is also probably necessary, as heme-induced HO-1 mRNA expression was fully inhibited by the protein synthesis inhibitor cycloheximide. CONCLUSIONS: Our experiments define an Nrf2-mediated pathway by which heme induces a homeostatic macrophage response following IPH. |
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Authors:
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Joseph J Boyle; Michael Johns; Jonathan Lo; Alessandra Chiodini; Nicola Ambrose; Paul C Evans; Justin C Mason; Dorian O Haskard |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-25 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: - ISSN: 1524-4636 ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Cardiovascular Sciences, NHLI, Imperial College London, London, United Kingdom. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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