Laminar flow activates peroxisome proliferator-activated receptor-gamma in vascular endothelial cells.
BACKGROUND
Steady laminar flow is atheroprotective, in part because of its antiinflammatory effects on vascular endothelial cells (ECs). We studied the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) in ECs in response to laminar flow and the associated antiinflammatory effect.


RESULTS
Using flow channel with cultured ECs, we found that laminar flow activated the PPARgamma-mediated PPAR-responsive element (PPRE) activity and increased the mRNA encoding CD36, a PPARgamma-targeted gene. Analysis of the CD36 promoter revealed that PPRE was required for flow activation. Laminar flow induced the GAL-PPARgamma-LBD fusion protein, which suggests that flow activation of PPARgamma was ligand dependent. The pharmaceutical inhibitors of phospholipase A2 (PLA2) and cytochrome P450 epoxygenases (CYP450s) were able to block the laminar flow-activated PPARgamma. We also showed that lipid extracts from flow media contained ligands for the activation of PPARgamma in other cell types. This paracrine activation exerted antiinflammatory effects in ECs and THP-1 cells, including the suppression of cytokine-induced nuclear factor-kappaB activation and expression of intercellular adhesion molecule-1.


CONCLUSIONS
Laminar flow activates endogenous PPARgamma in ECs, which is ligand dependent. The flow production of PPARgamma ligands is through the PLA2-CYP450 pathway, and the induced PPARgamma ligands exert antiinflammatory effects in several types of cells.
Liu
Yi
Y
Division of Biomedical Sciences, University of California at Riverside, Riverside, CA 92521-0121, USA.
Zhu
Yi
Y
Rannou
Francois
F
Lee
Tzong-Shyuan
TS
Formentin
Kitty
K
Zeng
Lingfang
L
Yuan
Xiaohui
X
Wang
Nanping
N
Chien
Shu
S
Forman
Barry M
BM
Shyy
John Y-J
JY
D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics; D002417:Cattle; D002478:Cells, Cultured / Q000166:cytology; D002522:Chlorocebus aethiops; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D016328:NF-kappa B / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology; D054467:Phospholipases A2; D011753:Pyrones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012212:Rheology; D000077154:Rosiglitazone; D013314:Stress, Mechanical; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection
D018955:CD36 Antigens; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009281:Naphthalenes; D047495:PPAR gamma; D011753:Pyrones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D003577:Cytochrome P-450 Enzyme System; D010741:Phospholipases A; D054467:Phospholipases A2