Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells

Chung-Yu Hsieh, Huai-Yu Hsiao, Wan-Yi Wu, Ching-Ann Liu, Yu-Chih Tsai, Yuen-Jen Chao, Danny-Ling Wang, Hsyue-Jen Hsieh

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43 Citations (Scopus)

Abstract

Background. Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress. Results. Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1. Conclusion. Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.
Original languageEnglish
JournalJournal of Biomedical Science
Volume16
Issue number1
DOIs
Publication statusPublished - 2009
Externally publishedYes

Keywords

  • heme oxygenase 1
  • phosphatidylinositol 3 kinase
  • protein kinase C inhibitor
  • reactive oxygen metabolite
  • transcription factor Nrf2
  • enzyme inhibitor
  • hydrogen peroxide
  • nitric oxide synthase
  • oxidizing agent
  • article
  • controlled study
  • endothelium cell
  • gene control
  • genetic transcription
  • human
  • human cell
  • nucleotide sequence
  • priority journal
  • protein expression
  • active transport
  • cell culture
  • cell nucleus
  • cytology
  • drug antagonism
  • gene expression regulation
  • genetics
  • mechanical stress
  • metabolism
  • physiology
  • shear strength
  • 1-Phosphatidylinositol 3-Kinase
  • Active Transport, Cell Nucleus
  • Cell Nucleus
  • Cells, Cultured
  • Endothelial Cells
  • Enzyme Inhibitors
  • Gene Expression Regulation
  • Heme Oxygenase-1
  • Humans
  • Hydrogen Peroxide
  • NF-E2-Related Factor 2
  • Nitric Oxide Synthase
  • Oxidants
  • Reactive Oxygen Species
  • Shear Strength
  • Stress, Mechanical

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  • Cite this

    Hsieh, C-Y., Hsiao, H-Y., Wu, W-Y., Liu, C-A., Tsai, Y-C., Chao, Y-J., Wang, D-L., & Hsieh, H-J. (2009). Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells. Journal of Biomedical Science, 16(1). https://doi.org/10.1186/1423-0127-16-12