| Apolipoprotein E4 domain interaction accelerates diet-induced atherosclerosis in hypomorphic Arg-61 apoe mice. | |
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MedLine Citation:
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PMID: 22441102 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Apolipoprotein (apo) E4 is an established risk factor for atherosclerosis, but the structural components underlying this association remain unclear. ApoE4 is characterized by 2 biophysical properties: domain interaction and molten globule state. Substituting Arg-61 for Thr-61 in mouse apoE introduces domain interaction without molten globule state, allowing us to delineate potential proatherogenic effects of domain interaction in vivo. METHODS AND RESULTS: We studied atherosclerosis susceptibility of hypomorphic Apoe mice expressing either Thr-61 or Arg-61 apoE (ApoeT(h/h) or ApoeR(h/h)mice). On a chow diet, both mouse models were normolipidemic with similar levels of plasma apoE and lipoproteins. However, on a high-cholesterol diet, ApoeR(h/h) mice displayed increased levels of total plasma cholesterol and very-low-density lipoprotein as well as larger atherosclerotic plaques in the aortic root, arch, and descending aorta compared with ApoeT(h/h) mice. In addition, evidence of cellular dysfunction was identified in peritoneal ApoeR(h/h) macrophages which released lower amounts of apoE in culture medium and displayed increased expression of major histocompatibility complex class II molecules. CONCLUSIONS: These data indicate that domain interaction mediates proatherogenic effects of apoE4 in part by modulating lipoprotein metabolism and macrophage biology. Pharmaceutical targeting of domain interaction could lead to new treatments for atherosclerosis in apoE4 individuals. |
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Authors:
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Delphine Eberlé; Roy Y Kim; Fu Sang Luk; Nabora Soledad Reyes de Mochel; Nathalie Gaudreault; Victor R Olivas; Nikit Kumar; Jessica M Posada; Andrew C Birkeland; Joseph H Rapp; Robert L Raffai |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-03-22 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 32 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-04-20 Completed Date: 2012-07-10 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1116-23 Citation Subset: IM |
Affiliation:
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Department of Surgery, University of California San Francisco and VA Medical Center, San Francisco, CA 94121, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apolipoprotein E4 / biosynthesis, genetics* Atherosclerosis / etiology, genetics*, metabolism DNA / genetics* Diet, Atherogenic / adverse effects Disease Models, Animal Gene Expression Regulation* Genetic Predisposition to Disease* Macrophages, Peritoneal / metabolism, pathology Mice Mice, Inbred C57BL Mice, Knockout |
| Grant Support | |
ID/Acronym/Agency:
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HL089871/HL/NHLBI NIH HHS; R01 HL089871-01/HL/NHLBI NIH HHS; R01 HL089871-02S1/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Apolipoprotein E4; 9007-49-2/DNA |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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