Role of NF-κB and PI 3-kinase/Akt in TNF-α-induced cytotoxicity in microvascular endothelial cells

2008 ◽  
Vol 295 (4) ◽  
pp. F932-F941 ◽  
Author(s):  
Zhu Zhou ◽  
Patricia Gengaro ◽  
Wei Wang ◽  
Xue-qing Wang ◽  
Chunling Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
Microvascular Endothelial Cells ◽  
Pyrrolidine Dithiocarbamate ◽  
Apoptotic Pathway ◽  
Akt Activation ◽  
Tnf Α ◽  
Microvascular Endothelial

The interaction of tumor necrosis factor (TNF)-α with the endothelium is a pivotal factor during endotoxemia. Inflammatory conditions are characterized by the activation of the transcription factor NF-κB and the expression of inflammatory mediators. Previous reports indicate that inhibition of NF-κB activation during sepsis may be beneficial to the microvasculature. In addition, the phosphatidylinositol-3-kinase/Akt signaling pathway (PI3-kinase/Akt) has been shown to be cytoprotective. In this study, we examined the effect of inhibition of NF-κB and PI3-kinase/Akt on cell viability, cytokine production, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) generation by TNF-α-treated cultured microvascular endothelial cells. TNF-α induced significant cytotoxicity and was associated with increased inflammatory cytokines and NO and increased expression of iNOS. The NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented these increases and significantly attenuated the TNF-α-induced cytotoxicity. TNF-α also caused PI3-kinase/Akt activation, which was further increased by PDTC and prevented by the PI3-kinase inhibitor, LY294002. Inhibition of PI3-kinase/Akt also significantly potentiated TNF-α-mediated cytotoxicity. LY294002 treatment resulted in the appearance of increased apoptosis, compatible with the known anti-apoptotic properties of PI3-kinase/Akt. The present results therefore demonstrate a cytotoxic effect of TNF-α in microvascular endothelial cells which can be attenuated by NF-κB inhibition. In addition, PI3-kinase/Akt activation during TNF-α exposure may represent a compensatory anti-necrotic and anti-apoptotic pathway. The cytoprotective effects of NF-κB inhibition and PI3-kinase/Akt activation may have potential implications in the treatment of endotoxemia and septic shock.

scholarly journals Pentoxifylline attenuation of experimental hepatopulmonary syndrome

2007 ◽  
Vol 102 (3) ◽  
pp. 949-955 ◽  
Author(s):  
Junlan Zhang ◽  
Yiqun Ling ◽  
Liping Tang ◽  
Bao Luo ◽  
Balu K. Chacko ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Hepatopulmonary Syndrome ◽  
Microvascular Endothelial Cells ◽  
Enos Expression ◽  
Akt Activation ◽  
Pulmonary Microvascular Endothelial Cells ◽  
Tnf Α

Hepatopulmonary syndrome (HPS) following rat common bile duct ligation results from pulmonary molecular changes that may be influenced by circulating TNF-α and increased vascular shear stress, through activation of NF-κB or Akt. Increased pulmonary microvascular endothelin B (ETB) receptor and endothelial nitric oxide synthase (eNOS) levels contribute to nitric oxide production and the development of experimental HPS. Pentoxifylline (PTX), a phosphodiesterase and nonspecific TNF-α inhibitor, ameliorates experimental HPS when begun before hepatic injury. However, how PTX influences the molecular events associated with initiation of experimental HPS after liver injury is established is unknown. We assessed the effects of PTX on the molecular and physiological features of HPS in vivo and on shear stress or TNF-α-mediated events in rat pulmonary microvascular endothelial cells in vitro. PTX significantly improved HPS without altering portal or systemic hemodynamics and downregulated pulmonary ETB receptor levels and eNOS expression and activation. These changes were associated with a reduction in circulating TNF levels and NF-κB activation and complete inhibition of Akt activation. In rat pulmonary microvascular endothelial cells, PTX inhibited shear stress-induced ETB receptor and eNOS expression and eNOS activation. These effects were also associated with inhibition of Akt activation and were reproduced by wortmanin. In contrast, TNF-α had no effects on endothelial ETB and eNOS alterations in vitro. PTX has direct effects in the pulmonary microvasculature, likely mediated through Akt inhibition, that ameliorate experimental HPS.

Effects of Antioxidant and Nitric Oxide on Chemokine Production in TNF-α-stimulated Human Dermal Microvascular Endothelial Cells

2004 ◽  
Vol 38 (5) ◽  
pp. 473-480 ◽  
Author(s):  
Mi-Zu Jiang ◽  
Hirokazu Tsukahara ◽  
Yusei Ohshima ◽  
Shuko Sato ◽  
Yukiko Todoroki ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Microvascular Endothelial Cells ◽  
Chemokine Production ◽  
Tnf Α ◽  
Microvascular Endothelial

scholarly journals Anti-Inflammatory Effect and Cellular Uptake Mechanism of Carbon Nanodots in in Human Microvascular Endothelial Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1247
Author(s):  
Sarah Belperain ◽  
Zi Yae Kang ◽  
Andrew Dunphy ◽  
Brandon Priebe ◽  
Norman H. L. Chiu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Interleukin 1 ◽  
Antioxidant Properties ◽  
Synthesis Method ◽  
Microvascular Endothelial Cells ◽  
Carbon Nanodots ◽  
Uptake Mechanism ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Microvascular Endothelial

Cardiovascular disease (CVD) has become an increasingly important topic in the field of medical research due to the steadily increasing rates of mortality caused by this disease. With recent advancements in nanotechnology, a push for new, novel treatments for CVD utilizing these new materials has begun. Carbon Nanodots (CNDs), are a new form of nanoparticles that have been coveted due to the green synthesis method, biocompatibility, fluorescent capabilities and potential anti-antioxidant properties. With much research pouring into CNDs being used as bioimaging and drug delivery tools, few studies have been completed on their anti-inflammatory potential, especially in the cardiovascular system. CVD begins initially by endothelial cell inflammation. The cause of this inflammation can come from many sources; one being tumor necrosis factor (TNF-α), which can not only trigger inflammation but prolong its existence by causing a storm of pro-inflammatory cytokines. This study investigated the ability of CNDs to attenuate TNF-α induced inflammation in human microvascular endothelial cells (HMEC-1). Results show that CNDs at non-cytotoxic concentrations reduce the expression of pro-inflammatory genes, mainly Interleukin-8 (IL-8), and interleukin 1 beta (IL-1β). The uptake of CNDs by HMEC-1s was examined. Results from the studies involving channel blockers and endocytosis disruptors suggest that uptake takes place by endocytosis. These findings provide insights on the interaction CNDs and endothelial cells undergoing TNF-α induced cellular inflammation.

scholarly journals Characterization of Calcium Signals Provoked by Lysophosphatidylinositol in Human Microvascular Endothelial Cells

2016 ◽  
pp. 53-62 ◽  
Author(s):  
Y. M. AL SULEIMANI ◽  
C. R. HILEY
Keyword(s):  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Kinase Inhibitor ◽  
Microvascular Endothelial Cells ◽  
Ip3 Receptors ◽  
Rapid Phase ◽  
Lipid Molecule ◽  
Lipid Signalling ◽  
Rhoa Kinase ◽  
Microvascular Endothelial

The lipid molecule, lysophosphatidylinositol (LPI), is hypothesised to form part of a novel lipid signalling system that involves the G protein-coupled receptor GPR55 and distinct intracellular signalling cascades in endothelial cells. This work aimed to study the possible mechanisms involved in LPI-evoked cytosolic Ca2+ mobilization in human brain microvascular endothelial cells. Changes in intracellular Ca2+ concentrations were measured using cell population Ca2+ assay. LPI evoked biphasic elevation of intracellular calcium concentration, a rapid phase and a sustained phase. The rapid phase was attenuated by the inhibitor of PLC (U 73122), inhibitor of IP3 receptors, 2-APB and the depletor of endoplasmic reticulum Ca2+ store, thapsigargin. The sustained phase, on the other hand, was enhanced by U 73122 and abolished by the RhoA kinase inhibitor, Y-27632. In conclusion, the Ca2+ signal evoked by LPI is characterised by a rapid phase of Ca2+ release from the endoplasmic reticulum, and requires activation of the PLC-IP3 signalling pathway. The sustained phase mainly depends on RhoA kinase activation. LPI acts as novel lipid signalling molecule in endothelial cells, and elevation of cytosolic Ca2+ triggered by it may present an important intracellular message required in gene expression and controlling of vascular tone.

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