PPARa Activators Inhibit Cytokine-Induced Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells
نویسندگان
چکیده
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-a (PPARa), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives. The present study investigated PPARa 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 PPARa. Pretreatment of cultured human ECs with the PPARa activators fenofibrate or WY14643 inhibited TNF-a–induced VCAM-1 in a timeand concentration-dependent manner, an effect not seen with PPARg activators. Both PPARa 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-kB. Finally, PPARa activators significantly reduced adhesion of U937 cells to cultured human ECs. Conclusions—Human ECs express PPARa, 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 PPARa. (Circulation. 1999;99:3125-3131.)
منابع مشابه
PPARα and GR Differentially Down-Regulate the Expression of Nuclear Factor-κB-Responsive Genes in Vascular Endothelial Cells.
The antiinflammatory action of glucocorticoids is mediated partly by the inhibition of the expression of several cytokines and adhesion molecules. Some activators for nuclear receptors other than the GR have also been shown to inhibit the expression of these inflammatory molecules, although their molecular mechanisms remain unidentified. We therefore examined the effects of the PPARa activator ...
متن کاملRadiation-induced expression of platelet endothelial cell adhesion molecule-1 in cerebral endothelial cells
Background: Radiation-induced molecular changes on the endothelial surface of brain arteriovenous malformations (AVM) may be used as markers for specific vascular targeting agents. In this study, we examined the level of expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) on brain endothelial cell surface after radiation treatment, with the aim of targeting the radiation-induc...
متن کاملPPARalpha 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 (PPARalpha), a member of the nuclear receptor family, regulates gene exp...
متن کاملEffect of Tribulus Terrestris L. on Expression of ICAM-1, VCAM-1, E-Selectin and Proteome Profile of Human Endothelial Cells In-Vitro
Background: Atherosclerosis is a chronic inflammation that interferes with blood arteries functions due to the accumulation of low density lipids and cholesterol. Objective: To investigate the effect of aqueous extract and saponin fraction of Tribulus terrestris L. (TT) on the proteome and expression of intracellular adhesion molecule-1 (ICAM-1), vascu...
متن کاملThe effect of microRNA-125 on the adhesion molecule expression of integrin beta2 and adhesive determination of endothelial cells isolated from human aorta to monocyte
Background: The immune-mediated responses in vascular cells may include the increased expression of endothelial adhesion molecules, leukocyte rolling and infiltration, cellular lipid dysregulation and vascular smooth muscle cells (VSMCs) differentiation. Investigating the cellular and molecular events involved in the rolling process is useful for treatment or prevention of the vessel stenosis es...
متن کامل