Potential clinical utility of high-density lipoprotein-mimetic peptides.
OBJECTIVE
To determine the potential clinical utility of high-density lipoprotein-mimetic peptides.


RESULTS
Oral administration of D-4F together with pravastatin caused lesion regression in old apoE null mice. Administration of D-4F to low-density lipoprotein receptor null mice fed a Western diet reduced the association of myeloperoxidase with apoA-I and reduced the 3-nitrotyrosine content of apoA-I. Oral D-4F improved arterial vasoreactivity independent of apoA-I. Mice genetically lacking apoA-I showed significant improvement in vasoreactivity but, in contrast to mice with apoA-I, did not demonstrate reduced arterial wall thickness after D-4F treatment. In a rat model of diabetes, D-4F administration induced heme oxygenase-1 and extracellular superoxide dismutase, prevented endothelial sloughing, and dramatically improved arterial vasoreactivity. A peptide with 10 D-amino acid residues taken from the sequence of apoJ rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and dramatically reduced atherosclerosis in apoE null mice. Oral administration of tetrapeptides synthesized from either L-amino acids or D-amino acids rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and reduced atherosclerosis in apoE null mice.


CONCLUSIONS
Peptides that sequester lipoprotein lipid hydroperoxides release a series of high-density lipoprotein-associated antioxidant enzymes such as paraoxonase from inhibition and protect apoA-I from oxidative damage that would impair cholesterol efflux.
Navab
Mohamad
M
David Geffen School of Medicine at UCLA, Los Angeles, California, USA. mnavab@mednet.ucla.edu
Anantharamaiah
G M
GM
Reddy
Srinivasa T
ST
Van Lenten
Brian J
BJ
Datta
Geeta
G
Garber
David
D
Fogelman
Alan M
AM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001053:Apolipoproteins / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; D010455:Peptides