Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Adult
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / pharmacology*
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Antioxidants / administration & dosage
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Antioxidants / metabolism
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Antioxidants / pharmacology*
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Apolipoprotein A-I / administration & dosage
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Apolipoprotein A-I / metabolism
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Apolipoprotein A-I / pharmacology*
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Carotid Arteries / drug effects*
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Carotid Arteries / metabolism
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Carotid Arteries / pathology
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Carotid Artery Diseases / drug therapy*
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Carotid Artery Diseases / metabolism
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Carotid Artery Diseases / pathology
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Cells, Cultured
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Disease Models, Animal
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism
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Gene Expression Regulation, Enzymologic / drug effects
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Humans
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Intercellular Adhesion Molecule-1 / metabolism
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Lipoproteins, HDL / metabolism
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Male
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Molecular Mimicry*
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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NF-kappa B / metabolism
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Neutrophil Infiltration / drug effects
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Peptides / administration & dosage
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Peptides / metabolism
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Peptides / pharmacology*
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Phosphatidylcholines / metabolism
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RNA Interference
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RNA, Messenger / metabolism
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Rabbits
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Recombinant Proteins / metabolism
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Signal Transduction / drug effects
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Superoxides / metabolism
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Time Factors
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Transfection
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Tumor Necrosis Factor-alpha / metabolism
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Vascular Cell Adhesion Molecule-1 / metabolism
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Young Adult
Substances
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ABCA1 protein, human
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters
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Anti-Inflammatory Agents
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Antioxidants
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Apolipoprotein A-I
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Lipoproteins, HDL
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NF-kappa B
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Peptides
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Phosphatidylcholines
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RNA, Messenger
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Superoxides
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Intercellular Adhesion Molecule-1
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1-palmitoyl-2-linoleoylphosphatidylcholine
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NADPH Oxidases