PPARalpha ligands reduce PCB-induced endothelial activation: possible interactions in inflammation and atherosclerosis.
Exposure to polychlorinated biphenyls (PCBs) can activate inflammatory responses in vascular endothelial cells. Activation of peroxisome proliferator-activated receptors (PPARs) by nutrients or synthetic agonists has been shown to block pro-inflammatory responses both in vitro and in vivo. Here we demonstrate that activation of PPARalpha by synthetic agonists can reduce 3,3'4,4'-tetrachlorobiphenyl (PCB77)-induced endothelial cell activation. Primary vascular endothelial cells were pretreated with the PPARalpha ligands fenofibrate or WY14643 followed by exposure to PCB77. PPARalpha activation protected endothelial cells against PCB77-induced expression of the pro-inflammatory proteins vascular cell adhesion molecule-1 (VCAM-1), cycloxygenase-2 (COX-2), and PCB77-induced expression and activity of the aryl hydrocarbon receptor (AHR) responsive cytochrome P450 1A1 (CYP1A1). Furthermore, basal AHR expression was downregulated by fenofibrate and WY14643. We also investigated the possible interactions between PCBs, and basal PPAR activity and protein expression. Treatment with PCB77 significantly reduced basal mRNA expression of PPARalpha and the PPAR responsive gene CYP4A1, as well as PPARalpha protein expression. Also, PCB77 exposure caused a significant decrease in basal PPAR-dependent reporter gene expression in MCF-7 cells. Overall, these findings suggest that PPARalpha agonists can reduce PCB77 induction of endothelial cell activation by inhibition of the AHR pathway, and that coplanar PCB induced pro-inflammatory effects could be mediated, in part, by inhibition of PPARalpha expression and function.
Arzuaga
Xabier
X
Molecular and Cell Nutrition Laboratory, College of Agriculture, University of Kentucky, Lexington, KY 40536-0200, USA.
Reiterer
Gudrun
G
Majkova
Zuzana
Z
Kilgore
Michael W
MW
Toborek
Michal
M
Hennig
Bernhard
B
D000818:Animals; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000139:chemically induced* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D004785:Environmental Pollutants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology*; D008024:Ligands; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D011078:Polychlorinated Biphenyls / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D004785:Environmental Pollutants; D008024:Ligands; D047493:PPAR alpha; D018336:Receptors, Aryl Hydrocarbon; D019010:Vascular Cell Adhesion Molecule-1; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D051546:Cyclooxygenase 2