1. EP 80317, a ligand of the CD36 scavenger receptor, protects apolipoprotein E-deficient mice from developing atherosclerotic lesions.
- Author
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Marleau S, Harb D, Bujold K, Avallone R, Iken K, Wang Y, Demers A, Sirois MG, Febbraio M, Silverstein RL, Tremblay A, and Ong H
- Subjects
- ATP Binding Cassette Transporter 1, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters metabolism, Animals, Aorta pathology, Atherosclerosis prevention & control, Biological Transport, Blotting, Western, Cholesterol, HDL metabolism, DNA-Binding Proteins metabolism, Growth Hormone chemistry, Lipid Metabolism, Lipids chemistry, Lipoproteins chemistry, Lipoproteins metabolism, Lipoproteins, LDL metabolism, Liver X Receptors, Macrophages metabolism, Macrophages, Peritoneal metabolism, Male, Mice, Mice, Transgenic, Models, Biological, Models, Statistical, Oligopeptides chemistry, Orphan Nuclear Receptors, Oxygen metabolism, PPAR gamma metabolism, Peptides chemistry, RNA, Messenger metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Scavenger Receptors, Class A metabolism, Signal Transduction, Time Factors, Up-Regulation, Apolipoproteins E genetics, Atherosclerosis genetics, Atherosclerosis pathology, CD36 Antigens metabolism, Ligands, Oligopeptides pharmacology
- Abstract
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.
- Published
- 2005
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