Growth hormone-releasing peptides, CD36, and stimulation of cholesterol efflux: cyclooxygenase-2 is the link.

Atherosclerosis, a chronic inflammatory disease of the vasculature, is the primary cause of morbidity and mortality in industrialized countries. Endothelial dysfunction/ activation is a major initiating event in atherosclerosis, which leads to the recruitment of circulating monocytes, their differentiation into macrophages, and their subsequent transformation into lipid-loaded foam cells through the uptake of modified lipoproteins, particularly oxidized LDL (oxLDL). Foam cells play a key role in this disease by stimulating the production of inflammatory cytokines, chemokines, and reactive oxygen species at the vessel wall. Foam cell formation can be regarded as a balance between the uptake of modified lipoproteins, through scavenger receptors such as CD36, and the efflux of cholesterol, primarily via ATP-binding cassette transporters (ABC) A1 and G1. Several factors are known to control macrophage cholesterol uptake and efflux, including cytokines, bioactive peptides and activators of nuclear receptors, particularly peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors that regulate glucose and lipid homeostasis along with inflammatory responses, thereby representing excellent therapeutic targets for limiting atherosclerosis. PPARs are activated by several fatty acids and fatty acid-derived products along with synthetic agonists, including fibrates (PPARa) and thiazolidinediones (PPARg) used in the treatment of dyslipidaemia and type 2 diabetes, respectively. Activation of PPAR-a and -g inhibits foam cell formation by suppressing lipid uptake and storage and stimulating cholesterol trafficking and efflux. A major pathway for the PPARa/g-mediated cholesterol efflux involves the expression of liver-X-receptor (LXR)-a, which then induces the transcription of the ABCA1 gene. Bujold et al. provide insight into the mechanisms underlying the promotion of macrophage cholesterol efflux by a peptide ligand of CD36 through this PPAR-LXRa-ABCA1 pathway. The study relates to EP 80317, an analogue of growth hormone releasing-peptides (GHRPs), which stimulate growth hormone (GH) release via binding to the GH secretagogue-receptor 1a (GHS-R1a), a G protein-coupled receptor whose endogenous ligand is now recognized to be ghrelin. Several studies have shown that GHRPs have GH-independent cardioprotective properties, and the identification that they serve as ligands for CD36 suggested that interference with oxLDL binding might represent a potential mechanism. Subsequent studies showed that hexarelin, a synthetic GHRP, enhances macrophage cholesterol efflux and the expression of ABCA1 and ABCG1 genes through the activation of PPARg, and this requires its binding to both CD36 and GHS-R1a. To dissociate between the two receptor-binding activities, EP 80317, a GHRP analogue with CD36-binding activity but devoid of GHS-R1a interaction and GH-releasing activity, has been used in several studies in relation to atherosclerosis. Administration of EP 80317 was found to protect apolipoprotein E (apoE)deficient mice, but not apoE/CD36 double knockout mice, from developing atherosclerotic lesions through a reduction of oxLDL internalization and the activation of the PPARg-LXRa-ABCA1 pathway in macrophages. The current study describes the molecular mechanisms underlying the EP 80317-mediated cholesterol efflux. Using peritoneal macrophages from apoE-deficient mice along with the murine J774 cell line, which expresses low levels of apoE, the authors show that EP 80317 activates PPARg and stimulates cholesterol and phospholipid efflux in an ABCA1and ABCG1-dependent manner. More interestingly, using a combination of biochemical and pharmacological approaches, they demonstrate that EP 80317 mediates its actions through the activation of extracellular signalregulated kinase (ERK)1/2. This leads to increased expression of cyclooxygenase-2 (COX-2), which converts arachadonic acid to several bioactive lipids such as The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology. * Corresponding author. Tel/Fax: þ44 2920 876753. E-mail address: [email protected]