Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway

Both nitric oxide (NO center dot) and peroxisome proliferator-activated receptors (PPARs) protect the endothelium and regulate its function. Here, we tested for crosstalk between these signaling pathways. Human umbilical vein and hybrid EA.hy926 endothelial cells were exposed to S-nitrosoglutathione (GSNO) or diethylenetriamine NONOate (DETA NONOate). Electrophoretic mobility shift assays using PPAR-response element (PPRE) probe showed that NO center dot caused a rapid dose-dependent increase in PPAR gamma binding, an effect that was confirmed in vivo by chromatin inummoprecipitation. Conversely, N-G-monomethyl-L-arginine, a NOS inhibitor, decreased PPAR gamma binding. NO center dot-mediated PPAR gamma binding and NO center dot induction of cyclooxygenase-2 (COX-2), diacylglycerol (DAG) kinase alpha (DGK alpha), and heme oxygenase-1 (HO-1), genes with well-characterized PPRE motifs, were cGMP independent. NO center dot dose dependently activated p38 MAPK, and p38 MAPK inhibition with SB202190 or knockdown with siRNA was shown to block NO center dot activation of PPAR gamma. Likewise, p38 MAPK and PPAR gamma inhibitors or knockdown of either transcript all significantly blocked NO center dot induction of PPRE-regulated genes. PPAR gamma activation by p38 MAPK may contribute to the anti-inflammatory and cytoprotective effects of NO center dot in the vasculature. This crosstalk mechanism suggests new strategies for preventing and treating vascular dysfunction.