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.


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 microg/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.
Navab
Mohamad
M
David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1679, USA. mnavab@mednet.ucla.edu
Anantharamaiah
G M
GM
Reddy
Srinivasa T
ST
Van Lenten
Brian J
BJ
Wagner
Alan C
AC
Hama
Susan
S
Hough
Greg
G
Bachini
Eugene
E
Garber
David W
DW
Mishra
Vinod K
VK
Palgunachari
Mayakonda N
MN
Fogelman
Alan M
AM
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics*; D001158:Arteries / Q000166:cytology; D043303:Aryldialkylphosphatase / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D001798:Blood Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D051152:Clusterin / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D001798:Blood Proteins; D051152:Clusterin; C465468:D-4F peptide; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; D043303:Aryldialkylphosphatase