PPAR gamma-independent thiazolidinedione-mediated inhibition of NUR77 expression in vascular endothelial cells

The thiazolidinediones (TZDs) have been reported to reduce atherogenesis in preclinical models and atherosclerosis in clinical trials in pre-diabetic and diabetic patients. Although peroxisome proliferator-activated receptor gamma (PPAR gamma)-mediated effects on gene expression have been thought responsible for this effect, a complete understanding of the molecular mechanisms responsible remains to be fully elucidated. We have previously reported PPAR gamma-independent modulation of NUR77 (also known as Nr4a1), an orphan nuclear receptor deemed important in the atherogenic process, in association with TZD-mediated inhibition of tumour necrosis factor alpha (TNF alpha) induction of plasminogen activator inhibitor type 1 expression. Here, we report NUR77 mRNA expression is increased in human vascular endothelial cells (HUVEC) stimulated by TNF alpha and that this effect is inhibited by a TZD in a PPAR gamma-independent manner. TZD treatment of HUVEC also inhibited the stimulatory effects of TNF alpha on NUR77 promoter activity, again in a PPAR gamma-independent manner, confirming the transcriptional nature of this effect. TZD treatment also attenuated the binding of nuclear proteins to the nuclear factor kappa B (NF-kappa B)-binding site of the NUR77 promoter in HUVEC in a PPAR gamma-independent manner. In addition, TZD treatment also inhibited TNF alpha-mediated induction of NF-kappa B1 mRNA expression. Our results suggest a potential PPAR gamma-independent molecular mechanism for the anti-atherogenic effects of TZDs involving NF-kappa B-mediated transcriptional inhibition of cytokine-mediated induction of the orphan nuclear receptor NUR77 in HUVEC. Journal of Endocrinology (2011) 208, R1-R7