Thiazolidinediones inhibit TNFalpha induction of PAI-1 independent of PPARgamma activation.
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.
Liu
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HB
Australian Centre for Blood Diseases, Monash University, 6th Floor Burnet Tower, 89 Commercial Road, Prahran 3181, Melbourne, Victoria, Australia.
Hu
Y S
YS
Medcalf
R L
RL
Simpson
R W
RW
Dear
A E
AE
D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D000077205:Pioglitazone