Faculty Collaboration Database

EP 80317, a ligand of the CD36 scavenger receptor, protects apolipoprotein E-deficient mice from developing atherosclerotic lesions. FASEB J 2005 Nov;19(13):1869-71

Date

08/27/2005

Pubmed ID

16123174

DOI

10.1096/fj.04-3253fje

Scopus ID

2-s2.0-27744467574 (requires institutional sign-in at Scopus site)   110 Citations

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.

Author List

Marleau S, Harb D, Bujold K, Avallone R, Iken K, Wang Y, Demers A, Sirois MG, Febbraio M, Silverstein RL, Tremblay A, Ong H

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ATP Binding Cassette Transporter 1
ATP-Binding Cassette Transporters
Animals
Aorta
Apolipoproteins E
Atherosclerosis
Biological Transport
Blotting, Western
CD36 Antigens
Cholesterol, HDL
DNA-Binding Proteins
Growth Hormone
Ligands
Lipid Metabolism
Lipids
Lipoproteins
Lipoproteins, LDL
Liver X Receptors
Macrophages
Macrophages, Peritoneal
Male
Mice
Mice, Transgenic
Models, Biological
Models, Statistical
Oligopeptides
Orphan Nuclear Receptors
Oxygen
PPAR gamma
Peptides
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Scavenger Receptors, Class A
Signal Transduction
Time Factors
Up-Regulation