Published Online
on August 16, 2004

A more recent version of this article appeared on August 31, 2004

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Submitted on November 6, 2003
Revised on March 30, 2004
Accepted on April 9, 2004

Laminar Flow Activates Peroxisome Proliferator-Activated Receptor- in Vascular Endothelial Cells

Yi Liu PhD, Yi Zhu MD, Francois Rannou MD, PhD, Tzong-Shyuan Lee DVM, PhD, Kitty Formentin PhD, Lingfang Zeng PhD, Xiaohui Yuan PhD, Nanping Wang MD, Shu Chien MD, PhD, Barry M. Forman MD, PhD, and John Y.-J. Shyy PhD^*

From the Division of Biomedical Sciences, University of California at Riverside (Y.L., Y.Z., F.R., T.-S.L., K.F., L.Z., J.Y.-J.S.); Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California at San Diego, La Jolla (N.W., S.C.); and Division of Molecular Medicine, City of Hope National Medical Center, Duarte, Calif (X.Y., B.M.F.).

^* To whom correspondence should be addressed. E-mail: john.shyy{at}ucr.edu.

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- (PPAR) in ECs in response to laminar flow and the associated antiinflammatory effect.

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

Conclusions--Laminar flow activates endogenous PPAR in ECs, which is ligand dependent. The flow production of PPAR ligands is through the PLA2-CYP450 pathway, and the induced PPAR ligands exert antiinflammatory effects in several types of cells.

Key words: cells, endothelial • receptors, peroxisome proliferator-activated • inflammation

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