Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 192-199 |
| Number of pages | 8 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 277 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jun 1 2014 |
Bibliographical note
Funding Information:Funding: This work was supported by the National Institute of Environmental Health Sciences at the National Institutes of Health [ P42ES007380 ], the University of Kentucky Agricultural Experiment Station and the American Heart Association ( 13PRE15860000 ).
Funding Information:
This research was supported by grants from NIEHS/NIH (P42ES007380), the University of Kentucky Agricultural Experiment Station, and American Heart Association. The authors would also like to thank the laboratories of Drs. Susan Smyth and Andrew Morris of the University of Kentucky for their assistance with mouse endothelial cell isolations.
Keywords
- Antioxidant response
- Caveolin-1
- Endothelial cell dysfunction
- Nrf2
- Oxidative stress
- Polychlorinated biphenyl
ASJC Scopus subject areas
- Toxicology
- Pharmacology
