PPARγ ligands induce prostaglandin production in vascular smooth muscle cells:: indomethacin acts as a peroxisome proliferator-activated receptor-γ antagonist

Peroxisome proliferator-activated receptor (PPAR)gamma and inducible cyclooxygenase-2 (COX-2) are expressed in atherosclerotic lesions, particularly in the intimal monocytic and vascular smooth muscle cells. We have therefore studied the interaction between PPAR. and inducible cyclo-oxygenase (COX-2) in rat aortic vascular smooth muscle cells (RASMC)s. The synthetic PPARgamma ligand rosiglitazone induced prostaglandin (PG) release from RASMCs, including that of PGD(2), the precursor of the putative endogenous PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2). Moreover, rosiglitazone both synergized with IL-1beta to further induce prostaglandin release and affected the expression of phospholipase A(2) and COX-2. Rosiglitazone-induced prostaglandin release was inhibited by the PPARgamma partial agonist GW0072 and the PPARgamma antagonist GW9662. Rosiglitazone also induced RASMC apoptosis, an effect not explained as an autocrine effect of the induced-prostanoids, but on arachidonic acid release, as cell death was unaffected by either the nonselective COX inhibitor piroxicam or the selective COX-2 inhibitor DFP, but by inhibitors of either secretory or cytosolic phospholipase A(2). In contrast, indomethacin, an alternative inhibitor of cyclooxygenase activity, inhibited both rosiglitazone-induced cell death, and rosiglitazone-induced PPAR reporter gene activation.