Published online before print April 14, 2005, doi: 10.1161/01.ATV.0000165694.39518.95
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© 2005 American Heart Association, Inc.
Brief Reviews |
Apolipoprotein A-I Mimetic Peptides
From the David Geffen School of Medicine at UCLA (M.N., S.T.R., S.H., G.H., V.R.G., N.Y., B.J.A., A.M.F.), Los Angeles, Calif; and the Department of Medicine (G.M.A., G.D., D.W.G.), Atherosclerosis Research Unit, University of Alabama, Birmingham.
Correspondence to Dr Mohamad Navab, Room 47-123 CHS, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte, Avenue, Los Angeles, CA 90095-1679. E-mail mnavab{at}mednet.ucla.edu
Series Editor: Daniel J. Rader
ATVB In Focus Novel Approaches to the Treatment of Dyslipidemia
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Despite identical amino acid composition, differences in class A amphipathic helical peptides caused by differences in the order of amino acids on the hydrophobic face results in substantial differences in antiinflammatory properties. One of these peptides is an apolipoprotein A-I (apoA-I) mimetic, D-4F. When given orally to mice and monkeys, D-4F caused the formation of pre-ß high-density lipoprotein (HDL), improved HDL-mediated cholesterol efflux, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. In apolipoprotein E (apoE)-null mice, D-4F increased reverse cholesterol transport from macrophages. Oral D-4F reduced atherosclerosis in apoE-null and low-density lipoprotein (LDL) receptor-null mice. In vitro when added to human plasma at nanomolar concentrations, D-4F caused the formation of pre-ß HDL, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. Physical-chemical properties and the ability of various class A amphipathic helical peptides to activate lecithin cholesterol acyltransferase (LCAT) in vitro did not predict biologic activity in vivo. In contrast, the use of cultured human artery wall cells in evaluating these peptides was more predictive of their efficacy in vivo. We conclude that the antiinflammatory properties of different class A amphipathic helical peptides depends on subtle differences in the configuration of the hydrophobic face of the peptides, which determines the ability of the peptides to sequester inflammatory lipids. These differences appear to be too subtle to predict efficacy based on physical-chemical properties alone. However, understanding these physical-chemical properties provides an explanation for the mechanism of action of the active peptides.
The antiinflammatory properties of different class A amphipathic helical peptides such as D-4F depend on subtle differences in the configuration of the hydrophobic face of the peptides that determine the ability of the peptides to sequester inflammatory lipids.
Key Words: HDL • apoA-I • peptide mimetics • D-4F • atherosclerosis • inflammation
Related Article:
Arterioscler. Thromb. Vasc. Biol. 2005 25: 1305-1306.
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