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pubmed:abstractText |
The peroxisome proliferator-activated receptor gamma (PPAR gamma) plays an important role in vascular regulation. However, the impact of oxidative stress on PPAR gamma expression and activity has not been clearly defined. Human umbilical vein endothelial cells (HUVECs) were exposed to graded concentrations of H(2)O(2) for 0.5-72h, or bovine aortic endothelial cells (BAECs) were exposed to alterations in extracellular thiol/disulfide redox potential (E(h)) of the cysteine/cystine couple. Within 2h, H(2)O(2) reduced HUVEC PPAR gamma mRNA and activity and reduced the expression of two PPAR gamma-regulated genes without altering PPAR gamma protein levels. After 4h H(2)O(2) exposure, mRNA levels remained reduced, whereas PPAR gamma activity returned to control levels. PPAR gamma mRNA levels remained depressed for up to 72 h after exposure to H(2)O(2), without any change in PPAR gamma activity. Catalase prevented H(2)O(2)-induced reductions in PPAR gamma mRNA and activity. H(2)O(2) (1) reduced luciferase expression in HUVECs transiently transfected with a human PPAR gamma promoter reporter, (2) failed to alter PPAR gamma mRNA half-life, and (3) transiently increased expression and activity of c-Fos and phospho-c-Jun. Treatment with the AP1 inhibitor curcumin prevented H(2)O(2)-mediated reductions in PPAR gamma expression. In addition, medium having an oxidized E(h) reduced BAEC PPAR gamma mRNA and activity. These findings demonstrate that oxidative stress, potentially through activation of inhibitory redox-regulated transcription factors, attenuates PPAR gamma expression and activity in vascular endothelial cells through suppression of PPAR gamma transcription.
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