PPARgamma ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator-activated receptor-gamma 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 PPARgamma 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 PGD2, the precursor of the putative endogenous PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2. Moreover, rosiglitazone both synergized with IL-1beta to further induce prostaglandin release and affected the expression of phospholipase A2 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 A2. In contrast, indomethacin, an alternative inhibitor of cyclooxygenase activity, inhibited both rosiglitazone-induced cell death, and rosiglitazone-induced PPAR reporter gene activation.
Bishop-Bailey
David
D
Department of Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. d.bishop-bailey@qmul.ac.uk
Warner
Timothy D
TD
D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015533:Transcriptional Activation
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008024:Ligands; D011453:Prostaglandins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D007213:Indomethacin