Cyclooxygenase-2 Is Induced in Monocytes by Peroxisome Proliferator Activated Receptor γ and Oxidized Alkyl Phospholipids from Oxidized Low Density Lipoprotein

Low density lipoprotein (LDL) oxidation and monocyte infiltration of the vessel wall underlie atherogenesis. These cells express cyclooxygenase-2, but the way oxidized LDL stimulates cyclooxygenase-2 transcription is unknown. Oxidized LDL, oxidatively fragmented phospholipids isolated from oxidized LDL, a synthetic oxidized alkylphospholipid (azPC) that is a potent peroxisome proliferator activated receptor (PPAR) γ agonist, or the PPARγ agonist rosiglitazone all induced cyclooxygenase-2 expression and enhanced prostaglandin E2 (PGE2) secretion in primary human monocytes. The cyclooxygenase-2 inhibitor NS398 blocked PPARγ-induced PGE2 secretion. Phospholipase A1 and A2 digestion shows that oxidized alkylphospholipids, and not oxidized fatty acids, were the relevant agonists. The upstream PPAR-responsive element (PPRE) of cyclooxygenase-2 was required for induction of a luciferase reporter by oxidized phospholipids, azPC, and rosiglitazone, and a (COX-2 PPRE)3-luciferase reporter was responsive to these PPARγ agonists. Circulating human monocytes do not contain PPARγ, but PPARγ was induced rapidly (