The PPARδ agonist GW0742X reduces atherosclerosis in LDLR−/− mice
| Autor: | Claudette Mookherjee, Lisa Patel, Colin N. A. Palmer, Tracey L. Graham, Keith E. Suckling |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
Very low-density lipoprotein Arteriosclerosis Lipoproteins Biology GW0742 Eating Mice chemistry.chemical_compound Internal medicine medicine Animals PPAR delta Liver X receptor Aorta Inflammation Mice Knockout Cholesterol Macrophages Body Weight Reverse cholesterol transport Lipids Thiazoles Endocrinology Receptors LDL chemistry ABCA1 LDL receptor biology.protein lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine Biomarkers Lipoprotein |
| Zdroj: | Atherosclerosis. 181:29-37 |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/j.atherosclerosis.2004.12.028 |
| Popis: | Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPARdelta) in the pathogenesis of atherosclerosis. Administration of synthetic PPARdelta agonists to obese rhesus monkeys elevates serum high-density lipoprotein (HDL) cholesterol as a result of increased reverse cholesterol transport whilst in vitro studies have suggested a role for PPARdelta in lipid uptake into macrophages. Recent studies have found that PPARdelta 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 PPARdelta in vitro. We demonstrate here that the PPARdelta 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 (TNFalpha) 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 PPARdelta agonists in vivo. |
| Databáze: | OpenAIRE |
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