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Laminar Flow Induction of Antioxidant Response Element-mediated Genes in Endothelial Cells

Chen, Xi-Lin ; Varner, Signe E. ; Rao, Anjali S. ; Grey, Janice Y. ; Thomas, Suzanne ; Cook, Christopher K. ; Wasserman, Martin A. ; Medford, Russell M. ; Jaiswal, Anil K. ; Kunsch, Charles

The Journal of biological chemistry, 2003-01, Vol.278 (2), p.703-711 [Periódico revisado por pares]

Elsevier Inc

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  • Título:
    Laminar Flow Induction of Antioxidant Response Element-mediated Genes in Endothelial Cells
  • Autor: Chen, Xi-Lin ; Varner, Signe E. ; Rao, Anjali S. ; Grey, Janice Y. ; Thomas, Suzanne ; Cook, Christopher K. ; Wasserman, Martin A. ; Medford, Russell M. ; Jaiswal, Anil K. ; Kunsch, Charles
  • É parte de: The Journal of biological chemistry, 2003-01, Vol.278 (2), p.703-711
  • Descrição: Atherosclerotic lesions preferentially develop in areas of the vasculature exposed to nonlaminar blood flow and low fluid shear stress, whereas laminar flow and high fluid shear stress are athero-protective. We have identified a set of genes including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), ferritin (heavy and light chains), microsomal epoxide hydrolase, glutathione S-transferase, and γ-glutamylcysteine synthase, whose expression is induced by exposure to prolonged physiological levels of steady laminar flow (shear stress = 20 dyn/cm2) in endothelial cells (EC). These genes contain an antioxidant response element (ARE) or ARE-like transcriptional regulatory sequence in their promoters and generally function to protect cells against oxidant stress. We demonstrate that exposure of EC to laminar flow activates ARE-mediated transcriptional activity. Mutation of the ARE from either the NQO1 or HO-1 promoter abolished laminar flow-induced NQO1 and HO-1 transcriptional activation. Expression of antisense Nrf2 (a transcriptional factor for ARE), a dominant negative Nrf2, or the cytoplasmic inhibitor of Nrf2 (Keap1/INrf2) inhibited laminar flow-induced NQO1 promoter activation in EC. In addition, expression of NQO1 or Nrf2 inhibited tumor necrosis factor-α-induced activation of VCAM-1 (vascular cell adhesion molecule-1) gene expression in EC. These data define the ARE as a novel endothelial shear stress response element. Furthermore, laminar flow activation of antioxidant genes via an ARE-dependent transcriptional mechanism may represent a novel athero-protective and anti-inflammatory mechanism in the vasculature.
  • Editor: Elsevier Inc
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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