Published online before print June 16, 2005, doi: 10.1161/01.ATV.0000174589.70190.e2
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
An Oral ApoJ Peptide Renders HDL Antiinflammatory in Mice and Monkeys and Dramatically Reduces Atherosclerosis in Apolipoprotein E–Null Mice
From the David Geffen School of Medicine at UCLA (M.N., S.T.R., B.J.V.L., A.C.W., S.H., G.H., E.B., A.M.F.), Los Angeles, Calif; and the Department of Medicine (G.M.A., D.W.G., V.K.M., M.N.P.), Atherosclerosis Research Unit, University of Alabama at Birmingham.
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 Avenue, Los Angeles, California 90095-1679. E-mail mnavab{at}mednet.ucla.edu
Objective— To determine the properties of a peptide synthesized from D-amino acids corresponding to residues 113 to 122 in apolipoprotein (apo) J.
Methods and Results— In contrast to D-4F, D- [113–122]apoJ showed minimal self-association and helicity in the absence of lipids. D-4F increased the concentration of apoA-I with pre-ß mobility in apoE-null mice whereas D- [113–122]apoJ did not. After an oral dose D- [113–122]apoJ more slowly associated with lipoproteins and was cleared from plasma much more slowly than D-4F. D- [113–122]apoJ significantly improved the ability of plasma to promote cholesterol efflux and improved high-density lipoprotein (HDL) inflammatory properties for up to 48 hours after a single oral dose in apoE-null mice, whereas scrambled D- [113–122]apoJ did not. Oral administration of 125 µg/mouse/d of D- [113–122]apoJ reduced atherosclerosis in apoE-null mice (70.2% reduction in aortic root sinus lesion area, P=4.3x10–13; 70.5% reduction by en face analysis, P=1.5x10–6). In monkeys, oral D- [113–122]apoJ rapidly reduced lipoprotein lipid hydroperoxides (LOOH) and improved HDL inflammatory properties. Adding 250 ng/mL of D-[113–122]apoJ (but not scrambled D- [113–122]apoJ) to plasma in vitro reduced LOOH and increased paraoxonase activity.
Conclusions— Oral D- [113–122]apoJ significantly improves HDL inflammatory properties in mice and monkeys and inhibits lesion formation in apoE-null mice.
Oral D- [113–122]apoJ, a peptide synthesized from D-amino acids corresponding to residues 113 to 122 in apolipoprotein J, significantly improves HDL inflammatory properties in mice and monkeys and inhibits lesion formation in apoE-null mice.
Key Words: atherosclerosis • apolipoprotein J • high-density lipoproteins • lipoproteins • inflammation
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