EP 80317, a ligand of the CD36 scavenger receptor, protects apolipoprotein E-deficient mice from developing atherosclerotic lesions.
CD36, a type B scavenger receptor expressed on macrophages, appears to play a major role in fatty streak formation through scavenging oxidatively modified lipoproteins in the arterial wall. We tested the hypothesis that EP 80317, a novel CD36 ligand derived from the growth hormone (GH)-releasing peptide family but devoided of any GH releasing activity, exerts anti-atherosclerotic effects in apolipoprotein E-deficient (apoE-/-) mice fed an atherogenic diet from 6 wk of age. Daily subcutaneous injections of EP 80317 (300 microg/kg) or vehicle were initiated at 6, 10, 12, or 14 wk until death at 18 wk. En face analyses of the entire aortic tree revealed a striking reduction (up to 51%) of lesion areas in EP 80317-treated apoE-/- mice compared with controls. Chronic treatment with EP 80317 (12 wk) is also associated with a 30% decrease in total plasma cholesterol, suggesting potential effects of this drug on cholesterol metabolism at the intestine/hepatic levels. EP 80317 exerts both preventive and curative effects on atherosclerotic lesion progression that were shown to be reversible after cessation of treatment. At the macrophage level, EP 80317 reduced oxidized low density lipoproteins internalization and up-regulated genes involved in cholesterol efflux, including peroxisome proliferator-activated receptor gamma (PPARgamma), liver x receptor alpha (LXRalpha), and the ATP binding cassette (ABC) transporters ABCA1 and ABCG1, supporting a role in regulating peripheral cholesterol trafficking. Importantly, the effects of EP 80317 were shown to be CD36 dependent, inasmuch as no anti-atherosclerotic or hypocholesterolemic effects were observed in apoE/CD36 double-deficient mice. In addition, long-term treatment of apoE/CD36 double-deficient mice with EP 80317 did not modulate the expression of genes of the PPARgamma-LXRalpha-ABC transporters pathway. Our results suggest that EP 80317, as a CD36 ligand, might be a prototype for a novel class of anti-atherosclerotic agents.
Marleau
Sylvie
S
Faculty of Pharmacy and Department of Pharmacology, Faculty of Medicine, Université de Montréal, Québec, Canada.
Harb
Diala
D
Bujold
Kim
K
Avallone
Roberta
R
Iken
Khadija
K
Wang
Yanfei
Y
Demers
Annie
A
Sirois
Martin G
MG
Febbraio
Maria
M
Silverstein
Roy L
RL
Tremblay
André
A
Ong
Huy
H
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D001692:Biological Transport; D015153:Blotting, Western; D018955:CD36 Antigens / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D013006:Growth Hormone / Q000737:chemistry; D008024:Ligands; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D015233:Models, Statistical; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors; D010100:Oxygen / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; C468852:EP80317; D008024:Ligands; D008055:Lipids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D009842:Oligopeptides; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D010455:Peptides; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051117:Scavenger Receptors, Class A; C420120:gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide; D013006:Growth Hormone; D010100:Oxygen