| Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr mice. | |
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MedLine Citation:
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PMID: 17885686 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Accumulation of cholesteryl esters (CEs) in macrophage foam cells, central to atherosclerotic plaque formation, occurs as a result of imbalance between the cholesterol influx and efflux pathways. While the uptake, or influx, of modified lipoproteins is largely unregulated, extracellular acceptor-mediated free cholesterol (FC) efflux is rate limited by the intracellular hydrolysis of CE. We previously identified and cloned a neutral CE hydrolase (CEH) from human macrophages and demonstrated its role in cellular CE mobilization. In the present study, we examined the hypothesis that macrophage-specific overexpression of CEH in atherosclerosis-susceptible Ldlr(-/-) mice will result in reduction of diet-induced atherosclerosis. Transgenic mice overexpressing this CEH specifically in the macrophages (driven by scavenger receptor promoter/enhancer) were developed and crossed into the Ldlr(-/-) background (Ldlr(-/-)CEHTg mice). Macrophage-specific overexpression of CEH led to a significant reduction in the lesion area and cholesterol content of high-fat, high-cholesterol diet-induced atherosclerotic lesions. The lesions from Ldlr(-/-)CEHTg mice did not have increased FC, were less necrotic, and contained significantly higher numbers of viable macrophage foam cells. Higher CEH-mediated FC efflux resulted in enhanced flux of FC from macrophages to gall bladder bile and feces in vivo. These studies demonstrate that by enhancing cholesterol efflux and reverse cholesterol transport, macrophage-specific overexpression of CEH is antiatherogenic. |
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Authors:
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Bin Zhao; Jingmei Song; Woon N Chow; Richard W St Clair; Lawrence L Rudel; Shobha Ghosh |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 117 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 2007 Oct |
Date Detail:
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Created Date: 2007-10-02 Completed Date: 2007-11-27 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 2983-92 Citation Subset: AIM; IM |
Affiliation:
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Department of Internal Medicine and Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta / pathology Atherosclerosis / genetics, pathology* Cholesterol / blood, metabolism Cholesterol Esters / metabolism* Gene Expression Humans Macrophages, Peritoneal / enzymology* Mice Mice, Transgenic Necrosis / pathology Receptors, LDL / genetics Sterol Esterase / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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HL-069946/HL/NHLBI NIH HHS; P30 CA16059/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cholesterol Esters; 0/Receptors, LDL; 57-88-5/Cholesterol; EC 3.1.1.13/Sterol Esterase |
| Comments/Corrections | |
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