| 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice. | |
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MedLine Citation:
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PMID: 20484557 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Intravenous administration of apolipoprotein (apo) A-I complexed with phospholipid has been shown to rapidly reduce plaque size in both animal models and humans. Short synthetic amphipathic peptides can mimic the antiatherogenic properties of apoA-I and have been proposed as alternative therapeutic agents. In this study, we investigated the atheroprotective effect of the 5A peptide, a bihelical amphipathic peptide that specifically effluxes cholesterol from cells by ATP-binding cassette transporter 1 (ABCA1). 5A stimulated a 3.5-fold increase in ABCA1-mediated efflux from cells and an additional 2.5-fold increase after complexing it with phospholipid (1:7 mol/mol). 5A-palmitoyl oleoyl phosphatidyl choline (POPC), but not free 5A, was also found to promote cholesterol efflux by ABCG1. When incubated with human serum, 5A-POPC bound primarily to high-density lipoprotein (HDL) but also to low-density lipoprotein (LDL) and promoted the transfer of cholesterol from LDL to HDL. Twenty-four hours after intravenous injection of 5A-POPC (30 mg/kg) into apoE-knockout (KO) mice, both the cholesterol (181%) and phospholipid (219%) content of HDL significantly increased. By an in vivo cholesterol isotope dilution study and monitoring of the flux of cholesterol from radiolabeled macrophages to stool, 5A-POPC treatment was observed to increase reverse cholesterol transport. In three separate studies, 5A when complexed with various phospholipids reduced aortic plaque surface area by 29 to 53% (n = 8 per group; p < 0.02) in apoE-KO mice. No signs of toxicity from the treatment were observed during these studies. In summary, 5A promotes cholesterol efflux both in vitro and in vivo and reduces atherosclerosis in apoE-KO mice, indicating that it may be a useful alternative to apoA-I for HDL therapy. |
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Authors:
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Marcelo J A Amar; Wilissa D'Souza; Scott Turner; Stephen Demosky; Denis Sviridov; John Stonik; Jayraz Luchoomun; Jason Voogt; Marc Hellerstein; Dmitri Sviridov; Alan T Remaley |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural Date: 2010-05-19 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 334 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-19 Completed Date: 2010-08-17 Revised Date: 2011-08-03 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 634-41 Citation Subset: IM |
Affiliation:
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Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ma90x@nih.gov |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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metabolism Animals Aorta / drug effects, pathology Apolipoprotein A-I / chemistry, physiology* Apolipoproteins E / genetics Atherosclerosis / drug therapy*, metabolism, pathology Biological Transport Cholesterol / metabolism* Female Humans Lipoproteins / metabolism Lipoproteins, HDL / blood Lipoproteins, LDL / blood Macrophages, Peritoneal / drug effects, metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Molecular Mimicry Peptides / chemistry, diagnostic use* Phosphatidylcholines / chemistry Rats Rats, Sprague-Dawley |
| Chemical | |
Reg. No./Substance:
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0/ABCG1 protein, mouse; 0/ATP-Binding Cassette Transporters; 0/Apolipoprotein A-I; 0/Apolipoproteins E; 0/Lipoproteins; 0/Lipoproteins, HDL; 0/Lipoproteins, LDL; 0/Peptides; 0/Phosphatidylcholines; 57-88-5/Cholesterol |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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