Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway.
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 PPARgamma binding, an effect that was confirmed in vivo by chromatin immunoprecipitation. Conversely, N(G)-monomethyl-L-arginine, a NOS inhibitor, decreased PPARgamma binding. NO*-mediated PPARgamma binding and NO* induction of cyclooxygenase-2 (COX-2), diacylglycerol (DAG) kinase alpha (DGKalpha), 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 PPARgamma. Likewise, p38 MAPK and PPARgamma inhibitors or knockdown of either transcript all significantly blocked NO* induction of PPRE-regulated genes. PPARgamma 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
Anetta
A
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Wang
Shuibang
S
Zhang
Jianhua
J
Wesley
Robert A
RA
Danner
Robert L
RL
D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D019852:Diacylglycerol Kinase / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D009569:Nitric Oxide / Q000494:pharmacology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D008565:Membrane Proteins; D047495:PPAR gamma; D009569:Nitric Oxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019852:Diacylglycerol Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP