on June 14, 2004
Circulation. 2004
Published online before print June 14, 2004, doi: 10.1161/01.CIR.0000134275.90823.87
Published online before print June 14, 2004, doi: 10.1161/01.CIR.0000134275.90823.87
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© American Heart Association, Inc.
Basic Science Reports |
Oral D-4F Causes Formation of Pre-ß High-Density Lipoprotein and Improves High-Density Lipoprotein–Mediated Cholesterol Efflux and Reverse Cholesterol Transport From Macrophages in Apolipoprotein E–Null Mice
From the David Geffen School of Medicine at the University of California, Los Angeles (M.N., S.T.R., S.H., G.H., V.R.G., A.C.W., J.S.F., A.M.F.), and the Department of Medicine, Atherosclerosis Research Unit, University of Alabama, Birmingham (G.M.A., G.D., D.G.).
Correspondence to Mohamad Navab, PhD, Room 47-123 CHS, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail mnavab{at}mednet.ucla.edu
Received February 10, 2004; de novo received April 13, 2004; revision received April 13, 2004; accepted May 17, 2004.
Background— These studies were designed to determine the mechanism of action of an oral apolipoprotein (apo) A-I mimetic peptide, D-4F, which previously was shown to dramatically reduce atherosclerosis in mice.
Methods and Results— Twenty minutes after 500 µg of D-4F was given orally to apoE-null mice, small cholesterol-containing particles (CCPs) of 7 to 8 nm with pre-ß mobility and enriched in apoA-I and paraoxonase activity were found in plasma. Before D-4F, both mature HDL and the fast protein liquid chromatography fractions containing the CCPs were proinflammatory. Twenty minutes after oral D-4F, HDL and CCPs became antiinflammatory, and there was an increase in HDL-mediated cholesterol efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol transport from intraperitoneally injected cholesterol-loaded macrophages in vivo. In addition, oral D-4F significantly reduced lipoprotein lipid hydroperoxides (LOOH), except for pre-ß HDL fractions, in which LOOH increased.
Conclusions— The mechanism of action of oral D-4F in apoE-null mice involves rapid formation of CCPs, with pre-ß mobility enriched in apoA-I and paraoxonase activity. As a result, lipoprotein LOOH are reduced, HDL becomes antiinflammatory, and HDL-mediated cholesterol efflux and reverse cholesterol transport from macrophages are stimulated.
Key Words: cholesterol • lipoproteins • apolipoproteins
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