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PNAS 102 (46): 16747-16752

Copyright © 2005 by the National Academy of Sciences.

MEDICAL SCIENCES

The antiinflammatory effect of laminar flow: The role of PPAR{gamma}, epoxyeicosatrienoic acids, and soluble epoxide hydrolase

Yi Liu * {dagger}, Yingjia Zhang * {dagger}, Kara Schmelzer {ddagger}, Tzong-Shyuan Lee *, Xiang Fang §, Yi Zhu *, Arthur A. Spector §, Sarjeet Gill ¶, Christophe Morisseau {ddagger}, Bruce D. Hammock {ddagger}, ||, and John Y.-J. Shyy *, ||

*Division of Biomedical Sciences and Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521; {ddagger}Department of Entomology and Cancer Research Center, University of California, Davis, CA 95616; and §Department of Biochemistry, University of Iowa, Iowa City, IA 52242

Contributed by Bruce D. Hammock, September 16, 2005

Abstract: 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 Kd in the µM 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.

Key Words: endothelial cells • shear stress

Author contributions: Y.L., Y. Zhang, Y. Zhu, B.D.H., and J.Y.-J.S. designed research; Y.L., Y. Zhang, K.R.S., and T.-S.L. performed research; Y.L., Y. Zhang, K.R.S., X.F., A.A.S., S.G., C.M., and B.D.H. contributed new reagents/analytic tools; Y. Zhu, A.A.S., S.G., B.D.H., and J.Y.-J.S. analyzed data; and Y.L., Y. Zhang, and J.Y.-J.S. wrote the paper.

Conflict of interest statement: No conflicts declared.

Freely available online through the PNAS open access option.

Abbreviations: AUDA, adamantyl-ureido-dodecanoic acid; EC, endothelial cell; BAEC, bovine aortic EC; CYP, cytochrome P450 epoxygenase; DHET, dihydroxyeicosatrienoic acid; EET, epoxyeicosatrienoic acid; HUVEC, human umbilical vein EC; LBD, ligand-binding domain; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; sEH, soluble epoxide hydrolase.

{dagger} Y.L. and Y. Zhang contributed equally to this work.

|| To whom correspondence may be addressed. E-mail: john.shyy{at}ucr.edu or bdhammock{at}ucdavis.edu.

© 2005 by The National Academy of Sciences of the USA

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