The 5A apolipoprotein A-I mimetic peptide displays antiinflammatory and antioxidant properties in vivo and in vitro.
OBJECTIVE
The apolipoprotein (apo)A-I mimetic peptide 5A is highly specific for ATP-binding cassette transporter (ABC)A1-mediated cholesterol efflux. We investigated whether the 5A peptide shares other beneficial features of apoA-I, such as protection against inflammation and oxidation. Methods- New Zealand white rabbits received an infusion of apoA-I, reconstituted high-density lipoprotein (HDL) containing apoA-I ([A-I]rHDL), or the 5A peptide complexed with phospholipids (1-palmitoyl-2-linoleoyl phosphatidylcholine [PLPC]), before inserting a collar around the carotid artery. Human coronary artery endothelial cells (HCAECs) were incubated with (A-I)rHDL or 5A/PLPC before stimulation with tumor necrosis factor alpha. Results- ApoA-I, (A-I)rHDL, and 5A/PLPC reduced the collar-mediated increase in (1) endothelial expression of cell adhesion molecules vascular cell adhesion molecule-1 and intercellular adhesion molecule-1; (2) production, as well as the expression of the Nox4 catalytic subunits of the NADPH oxidase; and (3) infiltration of circulating neutrophils into the carotid intima-media. In HCAECs, both 5A/PLPC and (A-I)rHDL inhibited tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as the nuclear factor kappaB signaling cascade and production. The effects of the 5A/PLPC complex were no longer apparent in HCAECs knocked down for ABCA1.


CONCLUSIONS
Like apoA-I, the 5A peptide inhibits acute inflammation and oxidative stress in rabbit carotids and HCAECs. In vitro, the 5A peptide exerts these beneficial effects through interaction with ABCA1.
Tabet
Fatiha
F
Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia.
Remaley
Alan T
AT
Segaliny
Aude I
AI
Millet
Jonathan
J
Yan
Ling
L
Nakhla
Shirley
S
Barter
Philip J
PJ
Rye
Kerry-Anne
KA
Lambert
Gilles
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D018716:Molecular Mimicry; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D055815:Young Adult
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D010455:Peptides; D010713:Phosphatidylcholines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; C055402:1-palmitoyl-2-linoleoylphosphatidylcholine; D019255:NADPH Oxidases