An oral ApoJ peptide renders HDL antiinflammatory in mice and monkeys and dramatically reduces atherosclerosis in apolipoprotein E-null mice

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-beta 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 mu g/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 x 10(-13); 70.5% reduction by en face analysis, P = 1.5 x 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.