Lipid homeostasis and inflammation are key determinants in atherogenesis, exemplified by the requirement of lipid-laden, foam cell macrophages for atherosclerotic lesion formation. Although the nuclear receptor PPARδ has been implicated in both systemic lipid metabolism and macrophage inflammation, its role as a therapeutic target in vascular disease is unclear. We show here that orally active PPARδ agonists significantly reduce atherosclerosis in apoE-/- mice. Metabolic and gene expression studies reveal that PPARδ attenuates lesion progression through its HDL-raising effect and anti-inflammatory activity within the vessel wall, where it suppresses chemoattractant signaling by downregulation of chemokines. Activation of PPARδ also induces the expression of regulator of G protein signaling (RGS) genes, which are implicated in blocking the signal transduction of chemokine receptors. Consistent with this, PPARδ ligands repress monocyte transmigration and macrophage inflammatory responses elicited by atherogenic cytokines. These results reveal that PPARδ antagonizes multiple proinflammatory pathways and suggest PPARδ-selective drugs as candidate therapeutics for atherosclerosis.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Mar 18 2008|
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