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

Background-Adhesion molecule expression on the endothelial cell (EC) surfac e is critical for leukocyte recruitment to atherosclerotic lesions. Better understanding of transcriptional regulation of adhesion molecules in ECs ma y provide important insight into plaque formation. Peroxisome proliferator- activated receptor-alpha (PPAR alpha), a member of the nuclear receptor fam ily, regulates gene expression in response to certain fatty acids and fibri c 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 t ime- and concentration-dependent manner, an effect not seen with PPAR gamma activators. Both PPAR alpha activators decreased cytokine-induced VCAM-1 m RNA 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 i nhibiting 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 expres sion. Such findings also have implications regarding the clinical use of li pid-lowering agents, like fibric acids, which can activate PPAR alpha.