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. Key Words: cells, endothelial Ⅲ receptors, peroxisome proliferator-activated Ⅲ inflammation D epending on the geometry of the arterial tree, blood flow in the straight part of vessels is steady and laminar, whereas that in the bends and branches is disturbed. 1 The focal distribution of atherosclerotic lesions in the disturbed flow areas indicates the pivotal role of local flow in atherogenesis. 2 Because early atherosclerotic events involve the inflammatory responses of vascular endothelial cells (ECs), disturbed flow patterns with high shear stress gradients are considered to be proinflammatory, whereas steady laminar flow is antiinflammatory. 3,4 Using flow channel systems, we and others demonstrated that the application of flow to cultured ECs transiently induced genes encoding chemoattractants, adhesion molecules, and cytokines, which is due in part to the activation of nuclear factor-B (NF-B) and AP-1. 5,6 The induction of these genes has been suggested to be the endothelial response to the rapid change of shear stress (/t). 7 In agreement with this hypothesis, prolonged laminar flow suppresses the expression of proinflammatory molecules. 8 To date, the molecular basis underlying the antiinflammatory effect of laminar flow is still elusive.
Conclusions-LaminarPeroxisome proliferator-activated receptor (PPAR) -␣, -/␦, and -␥ constitute a subfamily of nuclear receptors. Among PPARs, PPAR␥ is largely expressed in monocytes/ macrophages, adipocytes, and intestinal cells in which PPAR␥ regulates genes involved in cell differentiation and lipid uptake and storage (eg, aP2, CD36). 9 The ligand-binding domain (LBD) of PPAR␥ can bind a wide range of ligands that have distinct structures, 10 including the natural ligand 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) and synthetic ligand thiozolidinediones (TZDs). PPAR␥ is also present in...