An Oral ApoJ Peptide Renders HDL Antiinflammatory in Mice and Monkeys and Dramatically Reduces Atherosclerosis in Apolipoprotein E–Null Mice

Abstract

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-β 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 =4.3×10 ⁻¹³ ; 70.5% reduction by en face analysis, P =1.5×10 ⁻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.