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Nitric oxide activation of peroxisome proliferator‐activated receptor gamma through a p38 MAPK signaling pathway
Author(s) -
Ptasinska Anetta,
Wang Shuibang,
Zhang Jianhua,
Wesley Robert A.,
Danner Robert L.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6822com
Subject(s) - microbiology and biotechnology , peroxisome proliferator activated receptor , mapk/erk pathway , p38 mitogen activated protein kinases , nitric oxide synthase , chemistry , nitric oxide , signal transduction , heme oxygenase , gene knockdown , receptor , biology , heme , biochemistry , endocrinology , apoptosis , enzyme
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 dieth‐ylenetriamine NONOate (DETA NONOate). Electro‐phoretic mobility shift assays using PPAR‐response element (PPRE) probe showed that NO · caused a rapid dose‐dependent increase in PPARγ binding, an effect that was confirmed in vivo by chromatin immunopre‐cipitation. Conversely, N G monomethyl‐L‐arginine, a NOS inhibitor, decreased PPARγ binding. NO · ‐medi‐ated PPARγ binding and NO · induction of cyclooxy‐genase‐2 (COX‐2), diacylglycerol (DAG) kinase alpha (DGKx), 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 PPARγ. Likewise, p38 MAPK and PPARγ inhibitors or knockdown of either transcript all significantly blocked NO · induction of PPRE‐regulated genes. PPARγ activation by p38 MAPK may contribute to the anti‐inflammatory and cytoprotective effects of NO · in the vascu‐lature. 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. FASEB J. 21, 950–961 (2007)