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Journal of Lipid Research, Vol. 48, 1915-1923, September 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Review

Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides

G. M. Anantharamaiah^1,*, Vinod K. Mishra^*, David W. Garber^*, Geeta Datta^*, Shaila P. Handattu^*, Mayakonda N. Palgunachari^*, Manjula Chaddha^*, Mohamad Navab, Srinivasa T. Reddy, Jere P. Segrest^* and Alan M. Fogelman

^* Department of Medicine, Biochemistry, and Molecular Genetics and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294
Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095-1679

Published, JLR Papers in Press, June 14, 2007.

¹ To whom correspondence should be addressed. e-mail: ananth{at}uab.edu

Recently, attention has been focused on pharmacological treatments that increase HDL cholesterol to prevent coronary artery disease. Despite three decades of extensive research of human apolipoprotein A-I (apoA-I), the major protein component of HDL, the molecular basis for its antiatherogenic and anti-inflammatory functions remain elusive. Another protein component of HDL, apoA-II, has structural features similar to those of apoA-I but does not possess atheroprotective properties. To understand the molecular basis for the effectiveness of apoA-I, we used model synthetic peptides. We designed analogs of the class A amphipathic helical motif in apoA-I that is responsible for solubilizing phospholipids. None of these analogs has sequence homology to apoA-I, but all are similar in their lipid-associating structural motifs. Although all of these peptide analogs interact with phospholipids to form peptide:lipid complexes, the biological properties of these analogs are different. Physical-chemical and NMR studies of these peptides have enabled the delineation of structural requirements for atheroprotective and anti-inflammatory properties in these peptides. It has been shown that peptides that interact strongly with lipid acyl chains do not have antiatherogenic and anti-inflammatory properties. In contrast, peptides that associate close to the lipid head group (and hence do not interact strongly with the lipid acyl chain) are antiatherogenic and anti-inflammatory. Understanding the structure and function of apoA-I and HDL through studies of the amphipathic helix motif may lead to peptide-based therapies for inhibiting atherosclerosis and other related inflammatory lipid disorders.

Supplementary key words atherosclerosis • high density lipoprotein • hyperlipidemia • lipoproteins

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