Anti-inflammatory apoA-I-mimetic peptides bind oxidized lipids with much higher affinity than human apoA-I.
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 ( approximately 35 microM) 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 approximately 35 microM 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 approximately 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 3F(14) are also amphipathic alpha-helical octadecapeptides, but 3F-2 inhibits atherosclerosis in mice and 3F(14) does not. Like 4F, 3F-2 also bound oxidized phospholipids with very high affinity, whereas 3F(14) resembled apoA-I. The extraordinary ability of 4F to bind pro-inflammatory oxidized lipids probably accounts for its remarkable anti-inflammatory properties.
Van Lenten
Brian J
BJ
Department of Medicine David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1679, USA. bvanlent@mednet.ucla.edu
Wagner
Alan C
AC
Jung
Chun-Ling
CL
Ruchala
Piotr
P
Waring
Alan J
AJ
Lehrer
Robert I
RI
Watson
Andrew D
AD
Hama
Susan
S
Navab
Mohamad
M
Anantharamaiah
G M
GM
Fogelman
Alan M
AM
D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology*; D018716:Molecular Mimicry / Q000502:physiology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology
C505693:APOA1 protein, human; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016632:Apolipoprotein A-I; C465468:D-4F peptide; D018836:Inflammation Mediators; C472885:L-4F peptide; D010455:Peptides; D010743:Phospholipids