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

Brian J. Van Lenten, 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

Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1679

Corresponding Author: bvanlent{at}mednet.ucla.edu

4F is an anti-inflammatory, 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-1 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-1 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 alpha-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 likely accounts for its remarkable anti-inflammatory properties.

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