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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.

Supplemental material, sj-pdf-1-prf-10.1177_02676591211012571 for Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells by Alexander O Ward, Graciela B Sala-Newby, Shameem Ladak, Gianni D Angelini, Massimo Caputo, M.-Saadeh Suleiman, Paul C Evans, Sarah J George and Mustafa Zakkar in Perfusion

Supplemental material, sj-pdf-1-prf-10.1177_02676591211012571 for Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells by Alexander O Ward, Graciela B Sala-Newby, Shameem Ladak, Gianni D Angelini, Massimo Caputo, M.-Saadeh Suleiman, Paul C Evans, Sarah J George and Mustafa Zakkar in Perfusion

Coronary artery bypass grafting remains the treatment of choice for a large cohort of patients with significant coronary disease. Despite the increased use of arterial grafts, the long saphenous vein remains the most commonly used conduit. Long-term graft patency continues to be the Achilles heel of saphenous vein grafts. This is due to the development of intimal hyperplasia, a chronic inflammatory disease that results in the narrowing and occlusion of a significant number of vein grafts. Research models for intimal hyperplasia are essential for a better understanding of pathophysiological processes of this condition. Large animal models resemble human anatomical structures and have been used as a surrogate to study disease development and prevention over the years. In this paper, we systematically review all published studies that utilized large animal models of vein graft disease with a focus on the type of model and any therapeutic intervention, specifically the use of external stents/mesh.

Objective Gastroesophageal reflux is thought to be a risk factor for laryngotracheal stenosis. Bile acids are a component of gastric refluxate and have previously been implicated in the development of fibrosis in other airway subsites. There is clear evidence that bile acids reflux into the upper airway. We therefore investigated the potential role of bile acids in the pathophysiology of laryngotracheal fibrosis and stenosis, specifically investigating the highly conserved process of epithelial–mesenchymal transition (EMT). Study Design Translational research study. Methods Human primary tracheal epithelial cells (PTECs) were challenged with the four most common digestive bile acids (cholic, chenodeoxycholic, deoxycholic, and lithocholic). EMT markers transforming growth factor (TGF)‐β1, Matrix metalloproteinase (MMP)‐9, and procollagen proteins were measured in the supernatant at 48 hours via enzyme‐linked immunosorbent assay. Real‐time polymerase chain reaction was also used to measure E‐cadherin and fibronectin expression. Results Significantly greater concentrations of TGF‐β1 and MMP‐9 were measured in the culture supernatants of cells treated with each bile acid at 10 µmol/L. Lithocholic acid and deoxycholic acid induced significantly increased expression of procollagen protein. Upregulation of fibronectin and downregulation of E‐cadherin were observed with all bile acids, except for deoxycholic acid. Conclusion This is the first proof of principle demonstration that physiologically relevant bile acid challenge induces EMT mechanisms in PTECs. This implies a potential role for bile acids in laryngotracheal scarring and airway remodeling of potential translational significance in laryngotracheal stenosis. Level of Evidence NA. Laryngoscope, 128:2029–2033, 2018