TY - JOUR
T1 - The antiinflammatory effect of laminar flow
T2 - The role of PPARγ, epoxyeicosatrienoic acids, and soluble epoxide hydrolase
AU - Liu, Yi
AU - Zhang, Yingjia
AU - Schmelzer, Kara
AU - Lee, Tzong Shyuan
AU - Fang, Xiang
AU - Zhu, Yi
AU - Spector, Arthur A.
AU - Gill, Sarjeet
AU - Morisseau, Christophe
AU - Hammock, Bruce D.
AU - Shyy, John Y.J.
PY - 2005/11/15
Y1 - 2005/11/15
N2 - 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.
AB - 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.
KW - Endothelial cells
KW - Shear stress
UR - http://www.scopus.com/inward/record.url?scp=28044434102&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28044434102&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508081102
DO - 10.1073/pnas.0508081102
M3 - Article
C2 - 16267130
AN - SCOPUS:28044434102
SN - 0027-8424
VL - 102
SP - 16747
EP - 16752
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -