PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells

Background-Adhesion molecule expression on the endothelial cell (EC) surface is critical for leukocyte recruitment to atherosclerotic lesions. Better understanding of transcriptional regulation of adhesion molecules in ECs may provide important insight into plaque formation. Peroxisome proliferator-activated receptor-alpha (PPAR alpha), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives. The present study investigated PPAR alpha expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1). Methods and Results-Immunohistochemistry revealed that human carotid artery ECs express PPAR alpha. Pretreatment of cultured human ECs with the PPARa activators fenofibrate or WY14643 inhibited TNF-alpha-induced VCAM-1 in a time- and concentration-dependent manner, an effect not seen with PPAR gamma activators. Both PPAR alpha activators decreased cytokine-induced VCAM-1 mRNA expression without altering its mRNA half-life. Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays suggest that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-kappa B. Finally, PPAR alpha activators significantly reduced adhesion of U937 cells to cultured human ECs. Conclusions-Human ECs express PPAR alpha, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression. Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPAR alpha.