The antiinflammatory effect of laminar flow: The role of PPARγ, epoxyeicosatrienoic acids, and soluble epoxide hydrolase

Yi Liu, Yingjia Zhang, Kara Schmelzer, Tzong Shyuan Lee, Xiang Fang, Yi Zhu, Arthur A. Spector, Sarjeet Gill, Christophe Morisseau, Bruce D. Hammock, John Y J Shyy

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204 Scopus citations

Abstract

We previously reported that laminar flow activates peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ ligands. Competition and direct binding assays revealed that EETs bind to the ligand-binding domain of PPARγ with Kd in the μM range. In the presence of adamantyl-ureido-dodecanoic acid (AUDA), a soluble epoxide hydrolase (sEH)-specific inhibitor, EETs increased PPARγ 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 PPARγ activity. Furthermore, laminar flow augmented cellular levels of EETs but decreased sEH at the levels of mRNA, protein, and activity. Blocking PPARγ by GW9662 abolished the EET/AUDA-mediated antiinflammatory effect, which indicates that PPARγ is an effector of EETs.

Original languageEnglish (US)
Pages (from-to)16747-16752
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number46
DOIs
StatePublished - Nov 15 2005

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Keywords

  • Endothelial cells
  • Shear stress

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Liu, Y., Zhang, Y., Schmelzer, K., Lee, T. S., Fang, X., Zhu, Y., Spector, A. A., Gill, S., Morisseau, C., Hammock, B. D., & Shyy, J. Y. J. (2005). The antiinflammatory effect of laminar flow: The role of PPARγ, epoxyeicosatrienoic acids, and soluble epoxide hydrolase. Proceedings of the National Academy of Sciences of the United States of America, 102(46), 16747-16752. https://doi.org/10.1073/pnas.0508081102