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

Extract

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).¹ 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.^1,2 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.^1,2 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).²

PPARs are ligand-activated transcription factors that regulate glucose and lipid homeostasis along with inflammatory responses, thereby representing excellent therapeutic targets for limiting atherosclerosis.^2,3 PPARs are activated by several fatty acids and fatty acid-derived products along with synthetic agonists, including fibrates (PPARα) and thiazolidinediones (PPARγ) used in the treatment of dyslipidaemia and type 2 diabetes, respectively.³ Activation of PPAR-α and -γ inhibits foam cell formation by suppressing lipid uptake and storage and stimulating cholesterol trafficking and efflux.³ A major pathway for the PPARα/γ-mediated cholesterol efflux involves the expression of liver-X-receptor (LXR)-α, which then induces the transcription of the ABCA1 gene.^3,4