Thiazolidinediones inhibit TNFalpha induction of PAI-1 independent of PPARgamma activation

Biochem Biophys Res Commun. 2005 Aug 19;334(1):30-7. doi: 10.1016/j.bbrc.2005.06.055.


Increased plasminogen activator inhibitor type 1 (PAI-1) levels are observed in endothelial cells stimulated by tumour necrosis factor alpha (TNFalpha). 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 TNFalpha. The specific peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor, SR-202, failed to modulate this effect. RG also inhibited the effect of TNFalpha on a reporter gene construct harbouring the proximal PAI-1 promoter and PAI-1 mRNA in cells co-transfected with a dominant-negative PPARgamma construct. RG and PG attenuated TNFalpha-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 TNFalpha-mediated PAI-1 induction independent of inducible PPARgamma activation and this may involve in the modulation of Nur77/Nurr1 expression and NP binding to the PAI-1 NBRE.

MeSH terms

  • Cell Line
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Humans
  • PPAR gamma / metabolism*
  • Pioglitazone
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Rosiglitazone
  • Thiazolidinediones / pharmacology*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • PPAR gamma
  • Plasminogen Activator Inhibitor 1
  • Thiazolidinediones
  • Tumor Necrosis Factor-alpha
  • Rosiglitazone
  • Pioglitazone