Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties

Geoffrey D. Wool, Catherine A. Reardon, and Godfrey S. Getz

Pathology, University of Chicago, Chicago, IL 60637

Corresponding Author: getz{at}bsd.uchicago.edu

We hypothesize that apoA-I mimetic peptides better mimicking the punctuated a-helical repeats of full-length apoA-I are more anti-inflammatory and anti-atherogenic. This study compares a monomeric apoA-I mimetic helix to three different tandem helix peptides in vitro: 4F (18mer), 4F-proline-4F (37mer, Pro), 4F-alanine-4F (37mer, Ala), and 4F-KVEPLRA-4F (the human apoA-I 4/5 interhelical sequence (IHS), 43mer). All peptides cleared turbid lipid suspensions, with 4F being most effective. In contrast to lipid clearance, tandem peptides were more effective at remodeling mouse HDL. All four peptides displaced apoA-I and apoE from the HDL, leaving a larger particle containing apoA-II and peptide. Peptide-remodeled HDL particles show no deficit in ABCG1 cholesterol efflux despite the loss of the majority of apoA-I. Tandem peptides show greater ability to efflux cholesterol from lipid-loaded murine macrophages compared to 4F. While 4F inhibited oxidation of purified moLDL, the Ala tandem peptide increased oxidation. We compared several tandem 4F-based peptides with monomeric 4F in assays which correlated with suggested anti-inflammatory/anti-atherogenic pathways. Tandem 4F-based peptides, which better mimic full-length apoA-I, exceed monomeric 4F in HDL remodeling and cholesterol efflux but not LDL oxidation protection. In addition, apoA-I mimetic peptides may increase reverse cholesterol transport through both ABCA1 as well as ABCG1 pathways.

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