Increased plasminogen activator inhibitor type I (PAI-1) levels are observed in endothelial cells stimulated by tumour necrosis factor alpha (TNF alpha). Thiazolidinediones (TZDs) may inhibit elevated endothelial cell PAI-1 accounting, in part, for the putative atheroprotective effects of TZDs. In an endothelial cell line, Rosiglitazone (RG) and Pioglitazone (PG) inhibited induction of PAI-1 by TNF alpha. The specific peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibitor, SR-202, failed to modulate this effect. RG also inhibited the effect of TNF alpha on a reporter gene construct harbouring the proximal PAI-1 promoter and PAI-1 mRNA in cells cotransfected with a dominant-negative PPAR-gamma construct. RG and PG attenuated TNF alpha-mediated induction of trans-acting factor(s) Nur77/Nurr1 and binding of nuclear proteins (NP) to the cis-acting element (NBRE). SR-202 failed to modulate these effects. The observations suggest TZDs inhibit TNF alpha-mediated PAI-1 induction independent of inducible PPAR gamma activation and this may involve in the modulation of Nur77/Nurr1 expression and NP binding to the PAI-1 NBRE. (c) 2005 Elsevier Inc. All rights reserved.