期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 46, 页码 16747-16752出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508081102
关键词
endothelial cells; shear stress
资金
- NHLBI NIH HHS [HL77448, HL72845, R01 HL077448, R01 HL072845] Funding Source: Medline
- NIEHS NIH HHS [ES05707, P42 ES004699, P30 ES005707, ES04699, R37 ES002710, R01 ES002710, F32 ES005707, ES02710] Funding Source: Medline
We previously reported that laminar flow activates peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma ligands. Competition and direct binding assays revealed that EETs bind to the ligand-binding domain of PPAR gamma with K-d in the mu M range. In the presence of adamantyl-ureido-dodecanoic acid (AUDA), a soluble epoxide hydrolase (sEH)-specific inhibitor, EETs increased PPAR gamma 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 PPAR gamma activity. Furthermore, laminar flow augmented cellular levels of EETs but decreased sEH at the levels of mRNA, protein, and activity. Blocking PPAR gamma by GW9662 abolished the EET/AUDA-mediated antiinflammatory effect, which indicates that PPAR gamma is an effector of EETs.
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