title: 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice.
abstract: 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.
authors.affiliation: 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
authors.forename: Marcelo J A
authors.initials: MJ
authors.lastname: Amar
authors.forename: Wilissa
authors.initials: W
authors.lastname: D'Souza
authors.forename: Scott
authors.initials: S
authors.lastname: Turner
authors.forename: Stephen
authors.initials: S
authors.lastname: Demosky
authors.forename: Denis
authors.initials: D
authors.lastname: Sviridov
authors.forename: John
authors.initials: J
authors.lastname: Stonik
authors.forename: Jayraz
authors.initials: J
authors.lastname: Luchoomun
authors.forename: Jason
authors.initials: J
authors.lastname: Voogt
authors.forename: Marc
authors.initials: M
authors.lastname: Hellerstein
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000502:physiology*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000613704:5A peptide; C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D036341:Intercellular Signaling Peptides and Proteins; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010455:Peptides; D010713:Phosphatidylcholines; D002784:Cholesterol