The PPARδ agonist GW0742X reduces atherosclerosis in LDLR-/- mice

Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPAR delta) in the pathogenesis of atherosclerosis. Administration of synthetic PPAR delta agonists to obese rhesus monkeys elevates serum high-density lipoprotem (HDL) cholesterol as a result of increased reverse cholesterol transport whilst in vitro studies have suggested a role for PPAR delta in lipid uptake into macrophages. Recent studies have found that PPAR delta depletion from macrophages in LDL receptor (LDLR-/-) mice decreases lesion area via modulation of the inflammatory status of the macrophage, an effect also seen on pharmacological activation of PPAR delta in vitro. We demonstrate here that the PPAR delta agonist, GW0742X has potent anti-atherogenic activity in the LDLR-/- mouse, decreasing lesion area by up to 50%. Administration of GW0742X had no effect on total cholesterol, HDL or LDL cholesterol and modest effects on very low-density lipoprotein (VLDL). Treatment with GW0742X resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and intracellular adhesion moleculae 1 (ICAM-1) in the aortae of treated mice. In addition, GW0742X decreased tumour necrosis factor-alpha (TNF alpha) expression in peritoneal macrophages, aortae and adipose tissue in comparison with control animals. Changes in gene expression were reflected in decreased plasma levels of MCP-1. These observations support an atheroprotective effect of PPAR delta agonists in vivo. (c) 2004 Elsevier Ireland Ltd. All rights reserved.