J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M700552-JLR200 on March 5, 2008

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Journal of Lipid Research, Vol. 49, 1268-1283, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

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

Geoffrey D. Wool, Catherine A. Reardon and Godfrey S. Getz1

The University of Chicago, Department of Pathology, Chicago, IL

This work was supported by the National Heart, Lung, and Blood Institute, Grant HL-68661. G.D.W. has received support from the National Institute of Child Health and Human Development, Grant HD-007009, Graduate Training in Growth and Development, the Francis L. Lederer Foundation Scholarship Fund, and an American Heart Association pre-doctoral fellowship.

Published, JLR Papers in Press, March 5, 2008.

1 To whom correspondence should be addressed. e-mail: getz{at}bsd.uchicago.edu

We hypothesize that apolipoprotein A-I (apoA-I) mimetic peptides better mimicking the punctuated {alpha}-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 (18 mer), 4F-proline-4F (37 mer, Pro), 4F-alanine-4F (37 mer, Ala), and 4F-KVEPLRA-4F [the human apoA-I 4/5 interhelical sequence (IHS), 43 mer]. 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 with 4F. Although 4F inhibited oxidation of purified mouse LDL, the Ala tandem peptide increased oxidation. We compared several tandem 4F-based peptides with monomeric 4F in assays that 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.

Supplementary key words synthetic peptides • 4F • cholesterol • metabolism • oxidation


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