EP80317, a selective ligand of the CD36 scavenger receptor, reduces 111In‐labeled macrophages trafficking to atherosclerotic lesions in apoE‐deficient mice

Abstract

Our recent studies have shown that long-term (12 weeks) treatment with growth hormone-releasing peptides (GHRPs), as ligands of the CD36 scavenger receptor, shows striking anti-atherosclerotic effects in apoE-deficient mice (apoE−/−) mice fed a high fat diet. Synthetic GHRPs such as hexarelin (Hex), in addition to binding CD36 on macrophages, also bind to the ghrelin receptor (GHS-R1a). In order to assess the relative contribution of these receptors to fatty streak formation, apoE−/− mice have been treated with ghrelin, the endogenous GHS-R1a ligand or with EP80317, a selective CD36 ligand. Long-term treatment with ghrelin failed to modulate the development of aortic lesions whereas EP80317 was associated with a 51% reduction of lesions. Importantly, the effects of GHRPs were shown to be CD36-dependent, no anti-atherosclerotic effects were observed in apoE/CD36 double-deficient mice. GHRP-treated mice received 111In-labeled macrophages and the aortic accumulation of labeled cells was assessed by radioactivity count of the aortic tree 48 hours later. Ghrelin failed to modulate 111In-labeled macrophages accumulation within lesions whereas treatment with EP 80317 was associated with a 31 ± 6 % reduction of macrophages trafficking to atherosclerotic lesions, suggesting a potential role of EP80317 in modulating the inflammatory component of atherosclerosis. Our results suggest that GHRPs might be prototypes for a novel class of anti-atherosclerotic agents.