Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Liu Y,Zhang Y,Schmelzer K,Lee TS,Fang X,Zhu Y,Spector AA,Gill S,Morisseau C,Hammock BD,Shyy JYdoi
10.1073/pnas.0508081102keywords:
subject
Has Abstractpub_date
2005-11-15 00:00:00pages
16747-52issue
46eissn
0027-8424issn
1091-6490pii
0508081102journal_volume
102pub_type
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