on June 16, 2005
Published online before print June 16, 2005, doi: 10.1161/01.ATV.0000174589.70190.e2
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Submitted on February 24, 2005
Accepted on June 3, 2005
An Oral ApoJ Peptide Renders HDL Antiinflammatory in Mice and Monkeys and Dramatically Reduces Atherosclerosis in Apolipoprotein E-Null Mice
Mohamad Navab *;
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., 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.
* To whom correspondence should be addressed. 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-
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.
Key words: atherosclerosis • apolipoprotein J • high-density lipoproteins • lipoproteins • inflammation
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