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

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

¹Correspondence: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: rdanner{at}cc.nih.gov

Both nitric oxide (NO^•) 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^• caused a rapid dose-dependent increase in PPAR binding, an effect that was confirmed in vivo by chromatin immunoprecipitation. Conversely, N^G-monomethyl-L-arginine, a NOS inhibitor, decreased PPAR binding. NO^•-mediated PPAR binding and NO^• induction of cyclooxygenase-2 (COX-2), diacylglycerol (DAG) kinase alpha (DGK), and heme oxygenase-1 (HO-1), genes with well-characterized PPRE motifs, were cGMP independent. NO^• dose dependently activated p38 MAPK, and p38 MAPK inhibition with SB202190 or knockdown with siRNA was shown to block NO^• activation of PPAR. Likewise, p38 MAPK and PPAR inhibitors or knockdown of either transcript all significantly blocked NO^• induction of PPRE-regulated genes. PPAR activation by p38 MAPK may contribute to the anti-inflammatory and cytoprotective effects of NO^• in the vasculature. This crosstalk mechanism suggests new strategies for preventing and treating vascular dysfunction.—Ptasinska, A., Wang, S., Zhang, J., Wesley, R. A., Danner, R. L. Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway.

Key Words: endothelial cells • gene expression • inflammation • peroxisome proliferator response element • vascular homeostasis

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