The antiinflammatory effect of laminar flow: the role of PPARgamma, epoxyeicosatrienoic acids, and soluble epoxide hydrolase.
نویسندگان
چکیده
We previously reported that laminar flow activates peroxisome proliferator-activated receptor gamma (PPARgamma) in vascular endothelial cells in a ligand-dependent manner that involves phospholipase A2 and cytochrome P450 epoxygenases. In this study, we investigated whether epoxyeicosatrienoic acids (EETs), the catalytic products of cytochrome P450 epoxygenases, are PPARgamma ligands. Competition and direct binding assays revealed that EETs bind to the ligand-binding domain of PPARgamma with K(d) in the microM range. In the presence of adamantyl-ureido-dodecanoic acid (AUDA), a soluble epoxide hydrolase (sEH)-specific inhibitor, EETs increased PPARgamma transcription activity in endothelial cells and 3T3-L1 preadipocytes. Inclusion of AUDA in the perfusing media enhanced, but overexpression of sEH reduced, the laminar flow-induced PPARgamma activity. Furthermore, laminar flow augmented cellular levels of EETs but decreased sEH at the levels of mRNA, protein, and activity. Blocking PPARgamma by GW9662 abolished the EET/AUDA-mediated antiinflammatory effect, which indicates that PPARgamma is an effector of EETs.
منابع مشابه
Design, Synthesis and Biological Activity of 4,6-disubstituted Pyridin-2(1H)-ones as Novel Inhibitors of Soluble Epoxide Hydrolase
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Soluble epoxide hydrolase enzyme is a promising therapeutic target for hypertension, vascular inflammation, pain and some other risk factors of cardiovascular diseases. The most potent sEH inhibitors reported in the literature are urea-based ones which often have poor bioavailability. In this study, in a quest for finding potent inhibitors of soluble epoxide hydrolase, some 4,6-disubstituted py...
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عنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 102 46 شماره
صفحات -
تاریخ انتشار 2005