NF-κB inhibition prevents acute shear stress-induced inflammation in the saphenous vein graft endothelium

Ward, Amanda J.; Angelini, Gianni; Caputo, Massimo; Evans, Paul C.; Johnson, Jason L.; Suleiman, M‐Saadeh; Tulloh, Robert; George, Sarah J.; Zakkar, Mustafa

doi:10.1038/s41598-020-71781-6

Cited by 28 publications

(29 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To confirm the above results, we transfected HUVECs with WT-Nrf2 1x10 7 pfu/mL which resulted in a significant increase in Nrf2 protein levels was associated with an increase in HO-1 transcripts at static and under acute shear stress compared to control (figure 3C). Again we noted a concomitant upregulation of IL-8 at static and under acute shear stress (figure 3D).…”

Section: -Hyperactivation Of Nrf2 and Acute Shear Stress Leads To Induction Of A Proinflammatory Gene Responsementioning

confidence: 65%

“…Inflammation and oxidative stress are inextricably linked to vascular injury associated with damage to the vascular wall or harmful haemodynamic stimulation (5,7,8). Such pathogenic shifts in the endothelium, from quiescence to dysfunction, results in a change in gene expression profiles from antiinflammatory and antioxidant, to proinflammatory and oxidative (7,8,(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…It is recognised that veins in the human body are exposed to low shear stress compared with arteries. The acute stimulation of venous ECs by sudden haemodynamic changes such as grafting of a long saphenous vein into the arterial circulation can be associated with the upregulation of different inflammatory mediators and signalling pathways such as MAPK and NF-kB (7,8). However, little is known about Nrf2-Keap1 responses to an acute onset of shear stress in these venous ECs.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: -Hyperactivation Of Nrf2 and Acute Shear Stress Leads To Induction Of A Proinflammatory Gene Responsementioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Internal transcription factors, like Kruppel-like factor 4 (KLF4) and KLF5, and signalling pathways, like p38 mitogen-activated protein kinase (or p38) and nuclear factor kappa-light-chain-enhancer of activated B cells (or NF-κB), within the VSMCs have been identified as responsible for the phenotypic switching of these VSMCs from their quiescent and contractile state to the active and proliferative one [ 4 , 10 , 36 - 41 ] . The up regulation of these transcription factors seems to be linked to reduced expression of VSMCs contractile proteins.…”

Section: Resultsmentioning

confidence: 99%

Pathophysiology and Mechanisms of Saphenous Vein Graft Failure

Guida¹,

Angelini²

2022

Braz J Cardiovasc Surg

Self Cite

View full text Add to dashboard Cite

Introduction Coronary artery bypass grafting remains one of the best therapies for advanced coronary artery disease. The most used conduit remains the great saphenous vein, which is susceptible to short-term and long-term failure, the result of acute thrombosis, intimal hyperplasia, and late superimposed atheroma. In this review, we present the current findings related to the pathophysiology of vein graft failure. Methods A search of three databases - MEDLINE®, Web of Science™, and Cochrane Library - was undertaken for the terms “pathophysiology”, “prevention”, and “treatment” plus the term “vein graft failure”. Results The pathophysiology of saphenous graft failure can be classified in three distinct phases - acute thrombosis, intimal hyperplasia, and accelerated atherosclerosis. All these processes start with an underlying histological predisposition of the vein and at the time of harvesting and preparation for grafting. These mechanisms are a result of localized inflammatory and prothrombotic cascades that obey different causes, but ultimately result in the stenosis or occlusion of the vein graft. Conclusion The interaction between the different parts of the pathophysiology of vein graft failure is extremely complex and variable. Recent improvements in surgical techniques and secondary pharmaceutical prevention like early aspirin administration and long-term statin treatment have significantly reduced early and late saphenous vein graft failure. However, this continues to be a fascinating area of research with the potential for further improvement for patients and health service provision.

show abstract

“…Interestingly, these are all behaviors associated with low or recirculating shear stress patterns and not with increased shear stress levels. Adult endothelial cells, however, are adapted to the flow to which they are exposed and become activated in response to altered flow ( Ward et al, 2020 ). Furthermore, though physiological shear stress reduces activation and proliferation, when shear levels are extremely elevated (above 30 dyn/cm 2 in humans), the response is outward remodeling ( Dolan et al, 2013 ).…”

Section: Differences Between Vessel Enlargement In the Adult And Embrmentioning

confidence: 99%

Vessel Enlargement in Development and Pathophysiology

Gifre-Renom

Jones

2021

Front. Physiol.

View full text Add to dashboard Cite

From developmental stages until adulthood, the circulatory system remodels in response to changes in blood flow in order to maintain vascular homeostasis. Remodeling processes can be driven by de novo formation of vessels or angiogenesis, and by the restructuration of already existing vessels, such as vessel enlargement and regression. Notably, vessel enlargement can occur as fast as in few hours in response to changes in flow and pressure. The high plasticity and responsiveness of blood vessels rely on endothelial cells. Changes within the bloodstream, such as increasing shear stress in a narrowing vessel or lowering blood flow in redundant vessels, are sensed by endothelial cells and activate downstream signaling cascades, promoting behavioral changes in the involved cells. This way, endothelial cells can reorganize themselves to restore normal circulation levels within the vessel. However, the dysregulation of such processes can entail severe pathological circumstances with disturbances affecting diverse organs, such as human hereditary telangiectasias. There are different pathways through which endothelial cells react to promote vessel enlargement and mechanisms may differ depending on whether remodeling occurs in the adult or in developmental models. Understanding the molecular mechanisms involved in the fast-adapting processes governing vessel enlargement can open the door to a new set of therapeutical approaches to be applied in occlusive vascular diseases. Therefore, we have outlined here the latest advances in the study of vessel enlargement in physiology and pathology, with a special insight in the pathways involved in its regulation.

show abstract

NF-κB inhibition prevents acute shear stress-induced inflammation in the saphenous vein graft endothelium

Cited by 28 publications

References 35 publications

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

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

Pathophysiology and Mechanisms of Saphenous Vein Graft Failure

Vessel Enlargement in Development and Pathophysiology

Contact Info

Product

Resources

About