5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 334; no. 2; p. 634
• Main Authors: Amar, Marcelo J A, D'Souza, Wilissa, Turner, Scott, Demosky, Stephen, Sviridov, Denis, Stonik, John, Luchoomun, Jayraz, Voogt, Jason, Hellerstein, Marc, Sviridov, Dmitri, Remaley, Alan T
• Format: Journal Article
• Language: English
• Published: United States 01-08-2010
• Subjects: Animals; Aorta - drug effects; Aorta - pathology; Apolipoprotein A-I - chemistry; Apolipoprotein A-I - physiology; Apolipoproteins E - genetics; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - pathology; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - metabolism; Biological Transport; Cholesterol - metabolism; Female; Humans; In Vitro Techniques; Lipoproteins - metabolism; Lipoproteins, HDL - blood; Lipoproteins, LDL - blood; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Mimicry; Peptides - chemistry; Phosphatidylcholines - chemistry; Rats; Rats, Sprague-Dawley
• ISSN: 1521-0103
• DOI: 10.1124/jpet.110.167890

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.