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57 NRF2 REGULATES HYPEROXIA-MEDIATED NOX4 EXPRESSION AND REACTIVE OXYGEN SPECIES PRODUCTION.
  1. S. Pendyala,
  2. I. A. Gorshkova,
  3. D. He,
  4. H. Cho,
  5. S. R. Kleeberger,
  6. V. Natarajan
  1. University of Chicago, Chicago, IL; Research Triangle Park, NC.

Abstract

Rationale We have demonstrated earlier that Nox4, a homologue of Nox2 (gp91phox), is highly expressed in human pulmonary artery endothelial cells (HPAECs) and involved in hyperoxia-induced reactive oxygen species (ROS) production and signal transduction. Nrf2 is a transcriptional factor that is activated in hyperoxia and is known to regulate a number of genes involved in antioxidant defense mechanisms in the lung. Here we have investigated the role of Nrf2 in regulating hyperoxia-induced Nox4 expression and ROS generation in HPAECs.

Methods/Results In HPAECs, mRNA expression of Nox4 is several-folds higher compared with Nox2 (gp91phox), and exposure of cells to hyperoxia (95% O2) resulted in up-regulation of expression of Nox4 and p22phox but not Nox1 or Nox3. Nrf2 is up-regulated in short-term (3 hours) hyperoxia as much as twofold. Down-regulation of Nrf2 mRNA with siRNA attenuated Nox4 expression in normoxic HPAECs; however, enhanced ROS generation under both normoxia and hyperoxia (3 hours). Exposure of Nrf2 wild-type mice to hyperoxia (100% O2) for 24 and 48 hours resulted in enhanced Nox4 expression in the lung compared with normoxia. Further, Nrf2−/− mice exposed to hyperoxia (24 and 48 hours) showed decreased Nox4 expression in the lung compared with normoxia. However, the expression of Nox2 was increased in Nrf2−/− mice exposed to hyperoxia.

Conclusion These results demonstrate that hyperoxia-induced Nox4 expression and ROS production is regulated by Nrf2 in lung endothelium.

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