Abstract P175: Soluble Guanylate Cyclase Activator Attenuates Tumor Necrosis Factor- α Induced Production of Endothelin-1 from Human Glomerular Endothelial Cells

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Bhavisha Bakrania ◽  
Frank T Spradley ◽  
Simon Satchell ◽  
Joey P Granger
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Soluble Guanylate Cyclase ◽  
Tnf Α ◽  
Human Glomerular Endothelial Cells ◽  
Factor Α ◽  
Sgc Activators ◽  
Necrosis Factor

Preeclampsia (PE) is a disorder associated with maternal hypertension, endothelial dysfunction and reductions in renal hemodynamics. Placental ischemia leads to increases in circulating maternal anti-angiogenic and pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) that induce endothelin-1 (ET-1), a potent vasoconstrictor. PE is also associated with depletion of nitric oxide, a facilitator of vasodilation, which binds to soluble guanylate cyclase (sGC), and synthesizes cGMP. In addition to promoting vasodilation, sGC activators and stimulators inhibit smooth muscle proliferation, leukocyte recruitment and platelet aggregation and are therefore, currently in clinical trials for treating cardiopulmonary disease. Although it is known that activating the nitric oxide signalling pathway induces vasodilation, its ability to inhibit TNF-α induced renal glomerular endothelial ET-1 production is unknown. We tested the hypothesis that cinaciguat, a sGC activator, attenuates ET-1 production induced by TNF-α in conditionally immortalized human glomerular endothelial cells. Cells were cultured; starved for 48 h; and treated for 12 h resulting in the following 4 groups having N=6/group: 1) Untreated, 2) 10 ng TNF-α 3) 10 μM cinaciguat + 10 ng TNF-α, and 4) 20 μM cinaciguat + 10 ng TNF-α. TNF-α (10 ng, 67.25±3.2 pg/mL) significantly increased ET-1 production compared to the untreated group (43.6±4.3 pg/mL, P<0.01). Interestingly, both cinaciguat treatment groups attenuated TNF-α induced ET-1 production, with significant reductions at a higher dose (20 μM, 57.38±1.42 pg/mL, P=0.02; 10 μM, 58.6±2.32 pg/mL, P=0.07). The results of this study demonstrate that activating sGC can attenuate ET-1 production. In conclusion, these findings suggest there is a therapeutic potential for treating preeclampsia with sGC activators.

In VitroProtective Effects of Two Extracts from Bergamot Peels on Human Endothelial Cells Exposed to Tumor Necrosis Factor-α (TNF-α)

2010 ◽  
Vol 58 (14) ◽  
pp. 8430-8436 ◽  
Author(s):  
Domenico Trombetta ◽  
Francesco Cimino ◽  
Mariateresa Cristani ◽  
Giuseppina Mandalari ◽  
Antonella Saija ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Human Endothelial Cells ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Factors mediating the hemodynamic effects of tumor necrosis factor-α in portal hypertensive rats

1999 ◽  
Vol 276 (3) ◽  
pp. G687-G693 ◽  
Author(s):  
Javier Muñoz ◽  
Agustín Albillos ◽  
María Pérez-Páramo ◽  
Irma Rossi ◽  
Melchor Alvarez-Mon
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Portal Pressure ◽  
Systemic Resistance ◽  
Short Term ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Nitric oxide, prostacyclin, and glucagon have been implicated in promoting the hyperdynamic circulatory state of portal hypertension. Recent evidence also indicates that increased tumor necrosis factor-α (TNF-α) production is involved in the pathogenesis of this hemodynamic abnormality. This study was aimed at investigating in rats with portal vein stenosis (PVS) the effects on splanchnic hemodynamics of blocking circulating TNF-α and the factors mediating the vascular action of this cytokine in this setting. Anti-TNF-α polyclonal antibodies or placebo was injected into rats ( n = 96) before and 4 days after PVS (short-term inhibition) and at 24 h and 4, 7, 10 days after PVS (long-term inhibition). Short-term TNF-α inhibition reduced portal venous inflow and cardiac index and increased splanchnic and systemic resistance. Portal pressure was unchanged, but portal-systemic shunting was decreased. After long-term TNF-α inhibition, portal venous inflow and portal pressure were unchanged, but arterial pressure and systemic resistance rose significantly. Anti-TNF-α PVS rats exhibited lower increments of systemic resistance after N ω-nitro-l-arginine methyl ester and indomethacin administration and lower serum levels of TNF-α, nitrates-nitrites, and 6-keto-PGF1α, both over the short and the long term. Serum glucagon levels rose after long-term inhibition. In conclusion, the specific role played by TNF-α in the development of the hyperdynamic state of portal hypertension appears to be mainly mediated through an increased release of nitric oxide and prostacyclin. Maintenance of the splanchnic hyperemia after long-term TNF-α inhibition could be due to a compensatory release of glucagon.

Shiga Toxin Type 1 Activates Tumor Necrosis Factor-α Gene Transcription and Nuclear Translocation of the Transcriptional Activators Nuclear Factor-κB and Activator Protein-1

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 558-566 ◽  
Author(s):  
Ramesh Sakiri ◽  
Belakere Ramegowda ◽  
Vernon L. Tesh
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Translocation ◽  
Vascular Lesions ◽  
Transcriptional Activators ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Shiga toxins (Stxs) produced by Shigella dysenteriae 1 andEscherichia coli have been implicated in the pathogenesis of bloody diarrhea, acute renal failure, and neurologic abnormalities. The pathologic hallmark of Stx-mediated tissue damage is the development of vascular lesions in which endothelial cells are swollen and detached from underlying basement membranes. However, in vitro studies using human vascular endothelial cells demonstrated minimal Stx-induced cytopathic effects, unless the target cells were also incubated with the proinflammatory cytokines tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). These cytokines have been shown to upregulate the expression of the Stx-binding membrane glycolipid globotriaosylceramide (Gb3). We show here that purified Stx1 induces TNF secretion by a human monocytic cell line, THP-1, in a dose- and time-dependent manner. Treatment of cells with both lipopolysaccharides (LPS) and Stx1 results in augmented TNF production. Treatment with the nontoxic Gb3-binding subunit of Stx1 or with an anti-Gb3 monoclonal antibody did not trigger TNF production. Northern blot analyses show that Stx1 causes increased TNF-α production through transcriptional activation. Increased levels of TNF-α mRNA are preceded by the nuclear translocation of the transcriptional activators NF-κB and AP-1 and the loss of cytoplasmic IκB-α. These data are the first to show that, in addition to direct cytotoxicity, Stxs possess cellular signaling capabilities sufficient to induce the synthesis of cytokines that may be necessary for target cell sensitization and the development of vascular lesions.

Shiga Toxin Type 1 Activates Tumor Necrosis Factor-α Gene Transcription and Nuclear Translocation of the Transcriptional Activators Nuclear Factor-κB and Activator Protein-1

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 558-566 ◽  
Author(s):  
Ramesh Sakiri ◽  
Belakere Ramegowda ◽  
Vernon L. Tesh
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Translocation ◽  
Vascular Lesions ◽  
Transcriptional Activators ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract Shiga toxins (Stxs) produced by Shigella dysenteriae 1 andEscherichia coli have been implicated in the pathogenesis of bloody diarrhea, acute renal failure, and neurologic abnormalities. The pathologic hallmark of Stx-mediated tissue damage is the development of vascular lesions in which endothelial cells are swollen and detached from underlying basement membranes. However, in vitro studies using human vascular endothelial cells demonstrated minimal Stx-induced cytopathic effects, unless the target cells were also incubated with the proinflammatory cytokines tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). These cytokines have been shown to upregulate the expression of the Stx-binding membrane glycolipid globotriaosylceramide (Gb3). We show here that purified Stx1 induces TNF secretion by a human monocytic cell line, THP-1, in a dose- and time-dependent manner. Treatment of cells with both lipopolysaccharides (LPS) and Stx1 results in augmented TNF production. Treatment with the nontoxic Gb3-binding subunit of Stx1 or with an anti-Gb3 monoclonal antibody did not trigger TNF production. Northern blot analyses show that Stx1 causes increased TNF-α production through transcriptional activation. Increased levels of TNF-α mRNA are preceded by the nuclear translocation of the transcriptional activators NF-κB and AP-1 and the loss of cytoplasmic IκB-α. These data are the first to show that, in addition to direct cytotoxicity, Stxs possess cellular signaling capabilities sufficient to induce the synthesis of cytokines that may be necessary for target cell sensitization and the development of vascular lesions.

scholarly journals Tumor Necrosis Factor α Primes Cerebral Endothelial Cells for Erythropoietin-Induced Angiogenesis

2010 ◽  
Vol 31 (2) ◽  
pp. 640-647 ◽  
Author(s):  
Lei Wang ◽  
Michael Chopp ◽  
Hua Teng ◽  
Marianne Bolz ◽  
Moniche Ãlvarez Francisco ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Tube Formation ◽  
Cerebral Endothelial Cells ◽  
Tnf Α ◽  
Factor Α ◽  
Epor Expression ◽  
Necrosis Factor

Erythropoietin (EPO) enhances angiogenesis in the ischemic brain. Stroke induces secretion of tumor necrosis factor α (TNF-α). We investigated the effect of TNF-α on EPO-induced in vitro angiogenesis in cerebral endothelial cells. Using a capillary-like tubular formation assay, we found that transient incubation of primary rat cerebral microvascular endothelial cells (RECs) with TNF-α substantially upregulated EPO receptor (EPOR) expression and addition of EPO into TNF-α-treated RECs significantly augmented the capillary-like tube formation. Blockage of TNF receptor 1 (TNFR1) suppressed TNF-α-upregulated EPOR expression and abolished EPO-induced tube formation. Attenuation of endogenous EPOR with small interfering RNA (siRNA) also inhibited EPO-enhanced tube formation. Treatment of RECs with EPO activated nuclear factor-kappa B (NF-κB) and Akt. Incubation of the TNF-α-treated endothelial cells with EPO activated vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), angiopoietin 1 (Ang1), and Tie2. Blockage of VEGFR2 and Tie2 resulted in reduction of EPO-augmented tube formation. These data indicate that interaction of TNF-α with TNFR1 sensitizes cerebral endothelial cells for EPO-induced angiogenesis by upregulation of EPOR, which amplifies the effect of EPO on activation of the VEGF/VEGFR2 and Ang1/Tie2 pathways. Our results provide the evidence for crosslink between TNF and EPOR to coordinate the onset of angiogenesis in cerebral endothelial cells.

scholarly journals CytochromeP-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-α via MAPK and PI3K/Akt signaling pathways

2007 ◽  
Vol 293 (1) ◽  
pp. H142-H151 ◽  
Author(s):  
Shilin Yang ◽  
Li Lin ◽  
Ji-Xiong Chen ◽  
Craig R. Lee ◽  
John M. Seubert ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tumor Necrosis Factor ◽  
Signaling Pathways ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Akt Signaling ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Endothelial cells play a vital role in the maintenance of cardiovascular homeostasis. Epoxyeicosatrienoic acids (EETs), cytochrome P-450 (CYP) epoxygenase metabolites of arachidonic acid in endothelial cells, possess potent and diverse biological effects within the vasculature. We evaluated the effects of overexpression of CYP epoxygenases on tumor necrosis factor-α (TNF-α)-induced apoptosis in bovine aortic endothelial cells. CYP epoxygenase overexpression significantly increased endothelial cell viability and inhibited TNF-α induction of endothelial cell apoptosis as evaluated by morphological analysis of nuclear condensation, DNA laddering, and fluorescent-activated cell sorting (FACS) analysis. CYP epoxygenase overexpression also significantly inhibited caspase-3 activity and downregulation of Bcl-2 expression induced by TNF-α. The antiapoptotic effects of CYP epoxygenase overexpression were significantly attenuated by inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK signaling pathways; however, inhibition of endothelial nitric oxide synthase activity had no effect. Furthermore, CYP epoxygenase overexpression significantly attenuated the extent of TNF-α-induced ERK1/2 dephosphorylation in a time-dependent manner and significantly increased PI3K expression and Akt phosphorylation in both the presence and absence of TNF-α. Collectively, these results suggest that CYP epoxygenase overexpression, which is known to increase EET biosynthesis, significantly protects endothelial cells from apoptosis induced by TNF-α. This effect is mediated, at least in part, through inhibition of ERK dephosphorylation and activation of PI3K/Akt signaling.

scholarly journals Nuclear Factor (NF)-κB–regulated X-chromosome–linked iap Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor α–induced Apoptosis

1998 ◽  
Vol 188 (1) ◽  
pp. 211-216 ◽  
Author(s):  
Christian Stehlik ◽  
Rainer de Martin ◽  
Ichiro Kumabashiri ◽  
Johannes A. Schmid ◽  
Bernd R. Binder ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
X Chromosome ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Ectopic Expression ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

By differential screening of tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS)- activated endothelial cells (ECs), we have identified a cDNA clone that turned out to be a member of the inhibitor of apoptosis (iap) gene family. iap genes function to protect cells from undergoing apoptotic death in response to a variety of stimuli. These iap genes, hiap1, hiap2, and xiap were found to be strongly upregulated upon treatment of ECs with the inflammatory cytokines TNF-α, interleukin 1β, and LPS, reagents that lead to activation of the nuclear transcription factor κB (NF-κB). Indeed, overexpression of IκBα, an inhibitor of NF-κB, suppresses the induced expression of iap genes and sensitizes ECs to TNF-α–induced apoptosis. Ectopic expression of one member of the human iap genes, human X-chromosome–linked iap (xiap), using recombinant adenovirus overrules the IκBα effect and protects ECs from TNF-α– induced apoptosis. We conclude that xiap represents one of the NF-κB–regulated genes that counteracts the apoptotic signals caused by TNF-α and thereby prevents ECs from undergoing apoptosis during inflammation.

scholarly journals Human endothelial cells display a rapid and fluid flow dependent tensional stress increase in response to tumor necrosis factor-α

2022 ◽  
Author(s):  
Matthias Brandt ◽  
Volker Gerke ◽  
Timo Betz
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Cellular Response ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Umbilical Vein ◽  
Traction Forces ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

As endothelial cells form the inner layer of blood vessels they display the first barrier to interstitial tissues, which results in a crucial role for inflammation. On the global, systemic level an important element of the complex process controlling the inflammatory response is the release of the cytokine tumor necrosis factor-α (TNF-α). While other pro-inflammatory agents like thrombin or histamine are known to induce acute but transient changes in endothelial cells which have been well studied biologically as well as mechanically, TNF-α is primarily known for its sustained effects on permeability and leukocyte recruitment. These functions are associated with transcriptional changes that take place on the timescale of hours and days. Here we show that already 4 minutes after the addition of TNF-α onto monolayers of human umbilical vein endothelial cells, a striking rise in mechanical substrate traction force and internal monolayer tension can be recorded. As expected, the traction forces act primarily at the boundary of the monolayer. While the traction forces increase monotonically during the initial cellular response, we find that the internal monolayer tension displays a rapid peak that can be abolished when applying a shear flow to the cells. The increased internal monolayer tension may provide a mechanical signal for the cells to prepare for the recruitment of leukocytes, additionally to the well studied biochemical response.

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