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Zearalenone-Induced Interaction between PXR and Sp1 Increases Binding of Sp1 to a Promoter Site of the eNOS, Decreasing Its Transcription and NO Production in BAECs

1
Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul 07804, Korea
2
Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-ro, Nam-gu, Daegu 42415, Korea
*
Author to whom correspondence should be addressed.
Toxins 2020, 12(6), 421; https://doi.org/10.3390/toxins12060421
Received: 29 May 2020 / Revised: 22 June 2020 / Accepted: 23 June 2020 / Published: 25 June 2020
(This article belongs to the Special Issue Effects of Feedborne Mycotoxins on Animal Health)
Zearalenone (ZEN) is a non-steroidal mycotoxin that has various toxicological impacts on mammalian health. Here, we found that ZEN significantly affected the production of nitric oxide (NO) and the expression of endothelial NO synthase (eNOS) of bovine aortic endothelial cells (BAECs). A promoter analysis using 5′-serially deleted human eNOS promoter revealed that the proximal region (−135 to +22) was responsible for ZEN-mediated reduction of the human eNOS promoter activity. This effect was reversed by mutation of two specificity protein 1 (Sp1) binding elements in the human eNOS promoter. A chromatin immunoprecipitation assay revealed that ZEN increased Sp1 binding to the bovine eNOS promoter region (−113 to −12), which is homologous to −135 to +22 of the human eNOS promoter region. We also found that ZEN promoted the binding of the pregnane X receptor (PXR) to Sp1 of the bovine eNOS, consequently decreasing eNOS expression. This reduction of eNOS could have contributed to the decreased acetylcholine-induced vessel relaxation upon ZEN treatment in our ex vivo study using mouse aortas. In conclusion, our data demonstrate that ZEN decreases eNOS expression by enhancing the binding of PXR-Sp1 to the eNOS promoter, thereby decreasing NO production and potentially causing vessel dysfunction. View Full-Text
Keywords: zearalenone; eNOS; PXR; Sp1; NO zearalenone; eNOS; PXR; Sp1; NO
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MDPI and ACS Style

Lee, H.-J.; Park, J.-H.; Oh, S.-Y.; Cho, D.-H.; Kim, S.; Jo, I. Zearalenone-Induced Interaction between PXR and Sp1 Increases Binding of Sp1 to a Promoter Site of the eNOS, Decreasing Its Transcription and NO Production in BAECs. Toxins 2020, 12, 421.

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