| FC2 Activating transcription factor 1 co-regulates iron, lipid and anti-inflammatory target genes to direct a novel atheroprotective human plaque macrophage subset. | |
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MedLine Citation:
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PMID: 20801788 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Rationale Monocytes entering tissues, including advanced atherosclerotic plaques, rapidly mature and adapt to their new microenvironment. Intraplaque haemorrhage promotes human atherosclerosis progression and destabilisation via a dual metabolic challenge: cholesterol-enriched erythrocyte membranes and haem-iron. In human coronary culprit lesions, we recently described a novel macrophage subset (M-haem) with atheroprotective properties (IL-10high HO1high CD163high HLADRlow MPOlow 8keto-Guanosinelow). Methodology We dissected the mechanism of M-haem differentiation by microarray, computational biology and gene manipulation in human primary macrophages and human coronary lesions. Results Microarray analysis showed that M-haem cells were distinct from conventional M1 or M2 subsets. Using computational biology, we identified a simple transcriptional network motif with activating transcription factor 1 (ATF1) as a hub co-inducing HO1, SOCS1 and NR1H2 (LXR-alpha). Silencing RNA experiments showed that ATF1 induction was required for haem to upregulate HO-1 SOCS1 and NR1H2. Luciferase analysis confirmed that ATF1 transcriptionally activated both HO-1 and LXR. Luciferase deletion mutants indicated that the key ATF1-site in the HO-1 enhancer was distal (-2.2 kb to -4.9 kb). Binding experiments showed that ATF1 bound to this sequence. ATF1 overexpression in human macrophages conferred the characteristics of M-haem cells, including co-induction of HO-1, NR1H2, resistance to foam cell formation, increased survival and antioxidant protection. Conclusions Our data define the molecular basis of the differentiation of M-haem, a novel atheroprotective macrophage subset. Our data indicate that redirection of macrophage phenotype in atherosclerosis progression is a modality appropriate for therapeutic development. |
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Authors:
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J J Boyle; M Johns; A T Nguyen; J Yu; L Game; D J Schaer; J C Mason; D O Haskard |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Heart (British Cardiac Society) Volume: 96 ISSN: 1468-201X ISO Abbreviation: Heart Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-08-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9602087 Medline TA: Heart Country: England |
Other Details:
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Languages: eng Pagination: e11 Citation Subset: AIM; IM |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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