PCB 126 toxicity is modulated by cross-talk between caveolae and Nrf2 signaling.
Environmental toxicants such as polychlorinated biphenyls (PCBs) have been implicated in the promotion of multiple inflammatory disorders including cardiovascular disease, but information regarding mechanisms of toxicity and cross-talk between relevant cell signaling pathways is lacking. To examine the hypothesis that cross-talk between membrane domains called caveolae and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways alters PCB-induced inflammation, caveolin-1 was silenced in vascular endothelial cells, resulting in a decreased PCB-induced inflammatory response. Cav-1 silencing (siRNA treatment) also increased levels of Nrf2-ARE transcriptional binding, resulting in higher mRNA levels of the antioxidant genes glutathione s-transferase and NADPH dehydrogenase quinone-1 in both vehicle and PCB-treated systems. Along with this upregulated antioxidant response, Cav-1 siRNA treated cells exhibited decreased mRNA levels of the Nrf2 inhibitory protein Keap1 in both vehicle and PCB-treated samples. Silencing Cav-1 also decreased protein levels of Nrf2 inhibitory proteins Keap1 and Fyn kinase, especially in PCB-treated cells. Further, endothelial cells from wildtype and Cav-1-/- mice were isolated and treated with PCB to better elucidate the role of functional caveolae in PCB-induced endothelial inflammation. Cav-1-/- endothelial cells were protected from PCB-induced cellular dysfunction as evidenced by decreased vascular cell adhesion molecule (VCAM-1) protein induction. Compared to wildtype cells, Cav-1-/- endothelial cells also allowed for a more effective antioxidant response, as observed by higher levels of the antioxidant genes. These data demonstrate novel cross-talk mechanisms between Cav-1 and Nrf2 and implicate the reduction of Cav-1 as a protective mechanism for PCB-induced cellular dysfunction and inflammation.
Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; University of Kentucky Superfund Research Center, Lexington, KY 40536, USA.
Michael C
MC
Petriello
University of Kentucky Superfund Research Center, Lexington, KY 40536, USA; Department of Food Science and Biotechnology of Animal Resources, College of Animal Bioscience and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
Sung Gu
SG
Han
University of Kentucky Superfund Research Center, Lexington, KY 40536, USA; Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY 40506, USA.
Bradley J
BJ
Newsome
Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; University of Kentucky Superfund Research Center, Lexington, KY 40536, USA; Department of Animal and Food Sciences, College of Agriculture, Food and Environment, University of Kentucky, KY 40506, USA.
Bernhard
B
Hennig
D000818:Animals; D021941:Caveolae / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004785:Environmental Pollutants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D004785:Environmental Pollutants; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D011078:Polychlorinated Biphenyls; D009245:NADH Dehydrogenase; D005982:Glutathione Transferase; D051057:Proto-Oncogene Proteins c-akt; C023035:3,4,5,3',4'-pentachlorobiphenyl
Antioxidant response; Caveolin-1; Endothelial cell dysfunction; Nrf2; Oxidative stress; Polychlorinated biphenyl