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Journal of Lipid Research, Vol. 49, 2302-2311, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Anti-inflammatory apoA-I-mimetic peptides bind oxidized lipids with much higher affinity than human apoA-I^*

Brian J. Van Lenten^1,*, Alan C. Wagner^*, Chun-Ling Jung^*, Piotr Ruchala^*, Alan J. Waring^*, Robert I. Lehrer^*, Andrew D. Watson^*, Susan Hama^*, Mohamad Navab^*, G. M. Anantharamaiah and Alan M. Fogelman^*

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

^* This work was supported in part by US Public Health Service Grants HL-30568 and HL-34343 and the Laubisch, Castera, and M. K. Grey Funds at UCLA. MN, SH, GMA and AMF are principals in Bruin Pharma and AMF is an officer in Bruin Pharma.

Published, JLR Papers in Press, July 11, 2008.

¹ To whom correspondence should be addressed. e-mail: bvanlent{at}mednet.ucla.edu

4F is an anti-inflammatory, apolipoprotein A-I (apoA-I)-mimetic peptide that is active in vivo at nanomolar concentrations in the presence of a large molar excess of apoA-I. Physiologic concentrations (35 µM) of human apoA-I did not inhibit the production of LDL-induced monocyte chemotactic activity by human aortic endothelial cell cultures, but adding nanomolar concentrations of 4F in the presence of 35 µM apoA-I significantly reduced this inflammatory response. We analyzed lipid binding by surface plasmon resonance. The anti-inflammatory 4F peptide bound oxidized lipids with much higher affinity than did apoA-I. Initially, we examined the binding of PAPC (1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine) and observed that its oxidized products bound 4F with an affinity that was 4–6 orders of magnitude higher than that of apoA-I. This high binding affinity was confirmed in studies with defined lipids and phospholipids. 3F-2 and 3F¹⁴ are also amphipathic -helical octadecapeptides, but 3F-2 inhibits atherosclerosis in mice and 3F¹⁴ does not. Like 4F, 3F-2 also bound oxidized phospholipids with very high affinity, whereas 3F¹⁴ resembled apoA-I. The extraordinary ability of 4F to bind pro-inflammatory oxidized lipids probably accounts for its remarkable anti-inflammatory properties.

Supplementary key words atherosclerosis • apolipoprotein A-I • lipoproteins • oxidized phospholipids

Abbreviations: apoA-I, apolipoprotein A-I; HAEC, human aortic endothelial cell; MCP-1, monocyte chemoattractant protein-1; RU, resonance unit; SPR, surface plasmon resonance; SREBP, sterol-regulatory element binding protein

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