Abstract 5482: Reduction of Established Atherosclerosis in Hypercholesterolemic Mouse Models by ATI-5261: a Novel α-helix Peptide that Stimulates ABCA1 Cholesterol Efflux with High Efficiency

Abstract

Apolipoprotein(apo)s of HDL stimulate cholesterol efflux via the ATP-binding cassette transporter A1 (ABCA1), generating HDL and reversing the macrophage foam-cell phenotype. Despite these anti-atherogenic roles, the impact of specifically promoting ABCA1 cholesterol efflux on atherosclerosis development is largely unknown. Progress in this area has been hindered by a lack of synthetic agonists and/or apo mimetics optimized to mediate ABCA1 cholesterol efflux. The latter can be attributed, in part, to the fact that long segments of α-helical structure constituting the C-terminal (CT) domains of apoA-I and E are required to mediate ABCA1 cholesterol efflux efficiently. To begin to address these issues, we compressed the activity determinants of these CT helices into a single α-helix, creating a peptide (ATI-5261) that stimulates ABCA1 efflux with apo molar efficiency. Treatment of LDLr−/− mice made atherosclerotic by a high-fat western-diet (13 weeks) with ATI-5261 (30 mg/kg) ip on alternate days for 6 weeks reduced atherosclerosis by ~30%, as judged by lesion-area (Sudan IV) covering the aorta (7.9±2 vs.11.3±2.5% control, p=0.011), and the lipid-content (oil-red O) of aortic-sinus plaque (25±5.8 vs. 33±4.9% control, p=0.034). In similarly designed studies, ATI-5261 reduced atherosclerosis in apoE−/− mice by ~45% (lesion-area = 14±8 vs. 25±9% control, p=0.011; plaque lipid-content = 22±6 vs. 41±7% control, p=0.001). The minimum effective dose of ATI-5261 was 3 mg/kg in apoE−/− mice, consistent with the potent cholesterol efflux activity of the peptide. In both mouse models, ATI-5261 reduced atherosclerosis to the same extent as ATI-5261:POPC complexes (~7 nm). Single ip injection of ATI-5261 increased reverse cholesterol transport from macrophage foam-cells to feces for up to 48 h. To our knowledge, ATI-5261 is the first synthetic α-helix able to reduce atherosclerosis in mice having substantial plaque-lipid accumulation. This did not require peptide formulation with phospholipids and was achieved in the presence of vastly different lipoprotein profiles and plasma cholesterol concentrations. The data suggest that accelerating ABCA1 lipid-efflux may represent a viable approach to reduce atherosclerosis and stabilize vulnerable plaque.