Abstract 256: The ApoA-I Peptide Mimetic 5A Protects Against Atherosclerosis in ApoE Deficient Mice
Acute intravenous administration of an apoA-I phospholipid complex has been shown to rapidly reduce plaque size in humans. In addition, short synthetic amphipathic peptides have also been shown to reduce atherosclerosis in mice and are now being investigated in clinical trials. One possible mechanism for their atheroprotective effect is by enhancing reverse cholesterol transport but some apoA-I mimetic peptides have been shown to promote nonspecific cholesterol efflux independent of the ABCA1 transporter and to be potentially hemolytic. In this study, we investigated the use of the 5A peptide-lipid complex(DWLKAFYDKVAEKLKEAF - P -DWAKAAYDKAAEKAKEAA), which like apoA-I is specific for the ABCA1 transporter and is not hemolytic. IV injection of a 5A complex (5A Peptide:DPPC:Sphingomyelin [1:3.5:3.5]; 30 mg/kg) in C57Bl mice resulted in increased total plasma lipids (TC=38±5%, TG=295±33%, PL=56±5%, FC=141±18%, CE=-2±4%; n=4) and a 37% increase in HDL-C at 60 min after injection, which persisted for up to 24h and mimicked the pattern observed after injection of a apoA-I-lipid complex. FPLC analysis showed an increased level of smaller size HDL particles at 30 minutes after injection of the 5A complex which returned to a mature HDL particle size after 6h. Kinetic analysis revealed that the 5A complex had a 3-fold increase in FCR compared to apoA-I. In addition, the 5A complex enhanced delivery of cholesteryl ether to the liver by 137±47% over control after one hour. After 9 weeks of IP injections of 5A complex (three times a week; 30 mg peptide/kg) on 8 week-old ApoE deficient mice, the 5A group (n=4) developed 60% (p=0.02) less plaque surface coverage than the control group (saline IP; n=4). The treated and control mice showed a similar weight gain over the study and there was no apparent toxicity from the treatment. In summary, treatment with the 5A peptide led to athero-protective plasma changes, such as increased HDL-C and the generation of smaller pre-beta-like HDL, increased the delivery of CE to the liver and significantly reduced the development atherosclerosis in apoE deficient mice.