Intravenous administration of apoA-I complexed with phospholipid has been shown to rapidly reduce plaque size in both animal models and in humans. Short synthetic amphipathic peptides can mimic the anti-atherogenic 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 bi-helical amphipathic peptide that specifically effluxes cholesterol from cells by the ABCA1 transporter. 5A stimulated a 3.5-fold increase in ABCA1 mediated efflux from cells and a further 2.5-fold increase after complexing it with phospholipid (5A:POPC [1:7 mol/mol]). 5A:POPC but not free 5A was also found to promote cholesterol efflux by ABCG1. When incubated with human serum, 5A-POPC primarily bound to HDL but also to LDL and promoted the transfer of cholesterol from LDL to HDL. 24 hours following IV injection of 5A-POPC (30 mg/kg) into apoE-KO mice, both the cholesterol (181%) and phospholipid (219%) content of HDL significantly increased. By an in vivo cholesterol isotope dilution study and by monitoring 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 29-53% (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.
- Received March 10, 2010.
- Revision received May 13, 2010.
- Accepted May 13, 2010.
- The American Society for Pharmacology and Experimental Therapeutics