Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells

Abstract

Vascular endothelial cell 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 (12 dyn/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 minutes. 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.

miR-342-5p downstream to Notch enhances arterialization of endothelial cells in response to shear stress by repressing MYC

“…Among the limitations of this study, the shear stress level (15 dyn/cm 2 ) loaded artificially in this study has been demonstrated to be high for venous EC and fetal and adult arteries, 27 , 52 and may lead to altered cell viability and an increased expression of inflammatory factors. 53 , 54 Further investigation is needed to evaluate the response of miR-342 under more physiological shear stress levels in vivo . Moreover, the precise expression and function of miR-342 in different EC subtypes, especially arterial and venous ECs in different tissues and organs, requires further validation under different physiological conditions.…”

Proteomics-based evaluation of the mechanism underlying vascular injury via DNA interstrand crosslinks, glutathione perturbation, mitogen-activated protein kinase, and Wnt and ErbB signaling pathways induced by crotonaldehyde

“…Indicators related to arterial dysfunction were first identified by the downregulation (FC = 0.45) of protein kinase C (protein accession number B4DFV1), resulting in enhanced Ca 2+− sensing receptor-mediated relaxation of phenylephrine-contracted mesenteric arteries [ 37 ]. Further, acute high shear stress caused significant upregulation of Nrf2 target genes, heme oxygenase-1 (HO-1) and GCLM, and increased expression of the latter might be deleterious to vascular cells in the context of acute hemodynamic injury [ 38 ].…”

Large animal model of vein grafts intimal hyperplasia: A systematic review

“…1,2 However, there remain significant gaps in our understanding of the complex processes that take place when a vein is implanted into arterial circulation. While cellular models can be used and undoubtedly yield useful data, [105][106][107] the comparatively simplistic nature of these systems makes insights gained from such models limited when it comes to translation. Considering unfeasibility of studying vein grafts disease temporal progression and mechanisms in the human body directly, different small and large animal models were developed as a surrogate.…”