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PPARγ ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator‐activated receptor‐γ antagonist
Author(s) -
Bishop-Bailey David,
Warner Timothy D.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1075fje
Subject(s) - rosiglitazone , phospholipase a2 , peroxisome proliferator activated receptor , prostaglandin , agonist , medicine , chemistry , endocrinology , cyclooxygenase , vascular smooth muscle , receptor , peroxisome , arachidonic acid , antagonist , pharmacology , biology , biochemistry , enzyme , smooth muscle
Peroxisome proliferator‐activated receptor (PPAR)γ 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 PPARγ and inducible cyclo‐oxygenase (COX‐2) in rat aortic vascular smooth muscle cells (RASMC)s. The synthetic PPARγ ligand rosiglitazone induced prostaglandin (PG) release from RASMCs, including that of PGD 2 , the precursor of the putative endogenous PPARγ ligand 15‐deoxy‐A 12,14 ‐prostaglandin J 2 . Moreover, rosiglitazone both synergized with IL‐1β to further induce prostaglandin release and affected the expression of phospholipase A 2 and COX‐2. Rosiglitazone‐induced prostaglandin release was inhibited by the PPARγ partial agonist GW0072 and the PPARγ 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.