Abstract
Vascular endothelial cells stimulation is associated with the activation of different signalling pathways and transcription factors. Acute shear stress is known to induce different pro-inflammatory mediators such as IL-8. Nrf2 is activated by prolonged high shear stress promoting an antiinflammatory and athero-protective environment. However, little is known about the impact of acute shear stress on Nrf2 and Keap1 function and its role in IL-8 regulation. We aimed to examine Nrf2-Keap1 complex activation in-vitro and its role in regulating IL-8 transcripts under acute arterial shear stress (12dyn/cm2) in venous endothelial cells (ECs). We note that acute high shear stress caused a significant upregulation of Nrf2 target genes, HO-1 and GCLM and an increased IL-8 upregulation at 90 and 120 min.
Mechanistically, acute high shear did not affect Nrf2 nuclear translocation but resulted in reduced nuclear Keap1, suggesting that the reduction in nuclear Keap1 may result in increased free nuclear nrf2 to induce transcription. Consistently, the suppression of Keap1 using shRNA (shKeap1) resulted in significant upregulation of IL-8 transcripts in response to acute shear stress. Interestingly; the over expression of Nrf2 using Nrf2-Ad-WT or Sulforaphane was also associated with significant upregulation of IL-8 compared to controls. This study highlights the role of Keap1 in Nrf2 activation under shear stress and indicates that activation of Nrf2 may be deleterious in ECs in the context of acute haemodynamic injury.
Mechanistically, acute high shear did not affect Nrf2 nuclear translocation but resulted in reduced nuclear Keap1, suggesting that the reduction in nuclear Keap1 may result in increased free nuclear nrf2 to induce transcription. Consistently, the suppression of Keap1 using shRNA (shKeap1) resulted in significant upregulation of IL-8 transcripts in response to acute shear stress. Interestingly; the over expression of Nrf2 using Nrf2-Ad-WT or Sulforaphane was also associated with significant upregulation of IL-8 compared to controls. This study highlights the role of Keap1 in Nrf2 activation under shear stress and indicates that activation of Nrf2 may be deleterious in ECs in the context of acute haemodynamic injury.
Original language | English |
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Journal | Perfusion |
Early online date | 25 Apr 2021 |
DOIs | |
Publication status | E-pub ahead of print - 25 Apr 2021 |
Bibliographical note
Publisher Copyright:© The Author(s) 2021.
Keywords
- shear stress
- vein grafts
- endothelial inflammation
- NRF2-KEAP1
- intimal hyperplasia
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Dive into the research topics of 'Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells'. Together they form a unique fingerprint.Student Theses
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Investigating the NF-KappaB and Nrf2/Keap1 pathways in venous endothelial cells under acute shear stress: Implications for vein graft failure
Author: Ward, A., 25 Sep 2018Supervisor: George, S. (Supervisor) & Zakkar, M. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)
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