Nitric oxide inhibits endothelin-1 production through the suppression of nuclear factor κB

2002 ◽  
Vol 103 (s2002) ◽  
pp. 68S-71S ◽  
Author(s):  
Mamoru OHKITA ◽  
Masanori TAKAOKA ◽  
Yasuko SHIOTA ◽  
Rumi NOJIRI ◽  
Yasuo MATSUMURA
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Vascular Endothelial Cells ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Nuclear Factor ◽  
Ischaemia Reperfusion Injury ◽  
No Donor ◽  
Endothelin 1 ◽  
Tnf Α

We have reported previously that the nitric oxide (NO) donor FK409 {(±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide} improved renal dysfunction as well as renal lesions in rats with ischaemia/reperfusion injury. We also found that FK409 substantially reduced endothelin-1 (ET-1) production in cultured vascular endothelial cells (ECs). Nuclear factor κB (NF-κB) is known to play a key role in the development of ischaemic disorders through regulation of the expression of a variety of genes. In the present study, we examined the effects of FK409 on ET-1 production in cultured pig aortic ECs, and the possible involvement of NF-κB in the inhibitory effect of NO on ET-1 production. FK409 significantly attenuated basal and tumour necrosis factor-α (TNF-α)-induced preproET-1 mRNA expression in ECs. In addition, FK409 diminished basal and TNF-α-stimulated NF-κB activation in ECs. Pretreatment with N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal or BAY 11-7082, both of which are suppressors of NF-κB activation, effectively attenuated basal and TNF-α-induced ET-1 mRNA expression. These findings suggest that the suppression of NF-κB activation is at least partly involved in the FK409-induced inhibition of ET-1 production in ECs. We propose that NF-κB activation plays an important role in ET-1 production.

Increased endothelin-1 and endothelin receptor expression in myocytes of ischemic and reperfused rat hearts and ventricular myocytes exposed to ischemic conditions and its inhibition by nitric oxide generation

2003 ◽  
Vol 81 (2) ◽  
pp. 105-113 ◽  
Author(s):  
Xiaohong Tracey Gan ◽  
Subrata Chakrabarti ◽  
Morris Karmazyn
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Ventricular Myocytes ◽  
Receptor Expression ◽  
Neonatal Rat ◽  
No Donor ◽  
Myocardial Ischemia And Reperfusion ◽  
Endothelin 1 ◽  
Hypoxic Conditions ◽  
Rat Hearts

Endothelin-1 (ET-1) and nitric oxide (NO) exert opposite effects in the cardiovascular system, and there is evidence that the NO counters the potential deleterious effects of ET-1. We investigated whether NO affects the increased mRNA expression of ET-1 and endothelin receptors induced by (i) 30 min of ischemia with or without 30 min reperfusion in myocytes from isolated rat hearts or (ii) ischemic conditions (acidosis or hypoxia) in cultured rat neonatal ventricular myocytes. Ischemia with or without reperfusion produced more than a twofold increase in mRNA expression of ET-1 as well as the ETAand ETBreceptor (P < 0.05), although these effects were completely blocked by the NO donor 3-morpholinosydnonimine (SIN-1; 1 μM). To assess the possible factors regulating ET expression, myocytes were exposed to acidosis (pH 6.8–6.2) or to hypoxic conditions in an anaerobic chamber for 24 h in the presence or absence of SIN-1. At all acidic pHs, ET-1 and ETAreceptor mRNA expression was significantly (P < 0.05) elevated approximately threefold, although the magnitude of elevation was independent of the degree of acidosis. These effects were completely prevented by SIN-1. ETBreceptor expression was unaffected by acidosis. Hypoxia increased ET-1 as well as ETAand ETBreceptor expression threefold (P < 0.05), although this was unaffected by SIN-1. Our results demonstrate that myocardial ischemia and reperfusion upregulate the ET system, which is inhibited by NO. Although increased expression of the ET system can be mimicked by both acidosis and hypoxia, only the effects of the former are NO sensitive. NO may serve an endogenous inhibitory factor which regulates the expression of the ET system under pathological conditions.Key words: ET-1, ET receptors, NO, neonatal rat ventricular myocytes, hypoxia, acidosis.

scholarly journals Thrombin inhibits nuclear factor κB and RhoA pathways in cytokine-stimulated vascular endothelial cells when EPCR is occupied by protein C

2009 ◽  
Vol 101 (03) ◽  
pp. 513-520 ◽  
Author(s):  
Jong-Sup Bae ◽  
Alireza R. Rezaie
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecules ◽  
Protein C ◽  
Vascular Endothelial Cells ◽  
Nuclear Factor Κb ◽  
Small Gtpases ◽  
Vascular Endothelial ◽  
Nuclear Factor ◽  
Endothelial Protein C Receptor ◽  
Tnf Α

SummaryThe occupancy of endothelial protein C receptor (EPCR) by protein C switches the protease activated receptor 1 (PAR-1)-dependent signalling specificity of thrombin from a permeability enhancing to a barrier protective response in vascular endothelial cells. In this study, the modulatory effects of thrombin and thrombin receptor agonist peptides (TRAP) on tumour necrosis factor (TNF)-α-stimulated HUVECs in the absence and presence of the catalytically inactive protein C-S195A were evaluated by monitoring the expression of cell surface adhesion molecules (VCAM-1, ICAM-1 and E-selectin), adhesion of freshly isolated neutrophils to cytokine-stimulated endothelial cells, regulation of the Rho family of small GTPases and the activation of nuclear factor-κB (NF-κB) pathway. The analysis of results indicate that both thrombin and TRAP initiate proinflammatory responses in endothelial cells, thus neither PAR-1 agonist in-fluenced the proinflammatory effects of TNF-α in the absence of the protein C mutant. Interestingly, however, the occupancy of EPCR by the protein C mutant switched the PAR-1-dependent signaling specificity of thrombin, thus leading to thrombin inhibition of the expression of all three adhesion molecules as well as the binding of neutrophils to TNF-α-activated endothelial cells. Furthermore, similar to activated protein C, both thrombin and TRAP activated Rac1 and inhibited the activation of RhoA and NF-κB pathways in response to TNF-α in cells pre-treated with protein C-S195A. Based on these results we conclude that when EPCR is ligated by protein C, the cleavage of PAR-1 by thrombin initiates antiinflammatory responses, thus leading to activation of Rac1 and inhibition of RhoA and NF-κB signalling cascades in vascular endothelial cells.

scholarly journals TNF-α Protects Human Primary Articular Chondrocytes from Nitric Oxide-Induced Apoptosis Via Nuclear Factor-κB

2002 ◽  
Vol 82 (12) ◽  
pp. 1661-1672 ◽  
Author(s):  
Biserka Relić ◽  
Mohamed Bentires-Alj ◽  
Clio Ribbens ◽  
Nathalie Franchimont ◽  
Pierre-André Guerne ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Articular Chondrocytes ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Human Primary Articular Chondrocytes

scholarly journals Electromagnetic Fields Inhibit Endothelin-1 Production Stimulated by Thrombin in Endothelial Cells

2005 ◽  
Vol 33 (5) ◽  
pp. 545-554 ◽  
Author(s):  
S Morimoto ◽  
T Takahashi ◽  
K Shimizu ◽  
T Kanda ◽  
K Okaishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Nitric Oxide Synthase Inhibitor ◽  
Endothelin 1 ◽  
Synthase Inhibitor

Electromagnetic field (EMF) radiation has been found to induce arteriolar dilatation, but the mechanism of action remains largely unknown. This study investigated the effect of EMF radiation on the production of endothelin-1 (ET-1), a potent vasoconstrictor, by cultured endothelial cells. EMF radiation reduced ET-1 basal levels in human umbilical vein and microvascular endothelial cells, but failed to reduce ET-1 basal levels in bovine and human aortic endothelial cells. EMF radiation significantly inhibited thrombin-stimulated ET-1 production in all four endothelial cell types in a dose-dependent manner. EMF radiation significantly inhibited thrombin-induced endothelin-1 mRNA expression in all four cell types. The inhibitory effect of EMF radiation on ET-1 production was abolished by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (10−3 mol/l). These results demonstrate that EMF radiation modulates ET-1 production in cultured vascular endothelial cells and the inhibitory effect of EMF radiation is, at least partly, mediated through a nitric oxide-related pathway.

scholarly journals AdipoRon Attenuates Inflammation and Impairment of Cardiac Function Associated With Cardiopulmonary Bypass–Induced Systemic Inflammatory Response Syndrome

2021 ◽  
Vol 10 (6) ◽  
Author(s):  
Alexander Jenke ◽  
Mariam Yazdanyar ◽  
Shunsuke Miyahara ◽  
Agunda Chekhoeva ◽  
Moritz Benjamin Immohr ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiopulmonary Bypass ◽  
Mean Arterial Pressure ◽  
Circulatory Arrest ◽  
Nuclear Factor Κb ◽  
Deep Hypothermic Circulatory Arrest ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background Cardiac surgery using cardiopulmonary bypass (CPB) frequently provokes a systemic inflammatory response syndrome, which is triggered by TLR4 (Toll‐like receptor 4) and TNF‐α (tumor necrosis factor α) signaling. Here, we investigated whether the adiponectin receptor 1 and 2 agonist AdipoRon modulates CPB‐induced inflammation and cardiac dysfunction. Methods and Results Rats underwent CPB with deep hypothermic circulatory arrest and were finally weaned from the heart‐lung machine. Compared with vehicle, AdipoRon application attenuated the CPB‐induced impairment of mean arterial pressure following deep hypothermic circulatory arrest. During the weaning and postweaning phases, heart rate and mean arterial pressure in all AdipoRon animals (7 of 7) remained stable, while cardiac rhythm was irretrievably lost in 2 of 7 of the vehicle‐treated animals. The AdipoRon‐mediated improvements of cardiocirculatory parameters were accompanied by increased plasma levels of IL (interleukin) 10 and diminished concentrations of lactate and K + . In myocardial tissue, AdipoRon activated AMP‐activated protein kinase (AMPK) while attenuating CPB‐induced degradation of nuclear factor κB inhibitor α (IκBα), upregulation of TNF‐α, IL‐1β, CCL2 (C‐C chemokine ligand 2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and inducible nitric oxide synthase. Correspondingly, in cultured cardiac myocytes, cardiac fibroblasts, and vascular endothelial cells, AdipoRon activated AMPK, upregulated IL‐10, and attenuated activation of nuclear factor κB, as well as upregulation of TNF‐α, IL‐1β, CCL2, NADPH oxidase, and inducible nitric oxide synthase induced by lipopolysaccharide or TNF‐α. In addition, the treatment of cardiac myocytes with the AMPK activator 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside resulted in a similar inhibition of lipopolysaccharide‐ and TNF‐α–induced inflammatory cell phenotypes as for AdipoRon. Conclusions Our observations indicate that AdipoRon attenuates CPB‐induced inflammation and impairment of cardiac function through AMPK‐mediated inhibition of proinflammatory TLR4 and TNF‐α signaling in cardiac cells and upregulation of immunosuppressive IL‐10.

scholarly journals Nitric Oxide Regulates Receptor Activator of Nuclear Factor-κB Ligand and Osteoprotegerin Expression in Bone Marrow Stromal Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 751-759 ◽  
Author(s):  
Xian Fan ◽  
Eileen Roy ◽  
Liping Zhu ◽  
Tamara C. Murphy ◽  
Cheryl Ackert-Bicknell ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Resorption ◽  
Sodium Nitroprusside ◽  
Bone Remodeling ◽  
Stromal Cells ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
No Donor ◽  
Positive Effects ◽  
Receptor Activator

Abstract Bone remodeling reflects an equilibrium between bone resorption and formation. The local expression of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) in bone determines the entry of monoblastic precursors into the osteoclast lineage and subsequent bone resorption. Nitric oxide (NO) inhibits osteoclastic bone resorption in vitro and regulates bone remodeling in vivo. An interaction of NO with RANKL and OPG has not been studied. Here, we show that treatment of ST-2 murine stromal cells with the NO donor sodium nitroprusside (100 μm) for 24 h inhibited 1,25 dihydroxyvitamin D3-induced RANKL mRNA to less than 33 ± 7% of control level, whereas OPG mRNA increased to 204 ± 19% of control. NOR-4 replicated these NO effects. The effects of NO were dose dependent and associated with changes in protein levels: RANKL protein decreased and OPG protein increased after treatment with NO. PTH-induced RANKL expression in primary stromal cells was inhibited by sodium nitroprusside, indicating that the NO effect did not require vitamin D. NO donor did not change the stability of RANKL or OPG mRNAs, suggesting that NO affected transcription. Finally, cGMP, which can function as a second messenger for NO, did not reproduce the NO effect, nor did inhibition of endogenous guanylate cyclase prevent the NO effect on these osteoactive genes. The effect of NO to decrease the RANKL/OPG equilibrium should lead to decreased recruitment of osteoclasts and positive bone formation. Thus, drugs and conditions that cause local increase in NO formation in bone may have positive effects on bone remodeling.

Molecular Mechanisms of Curcumin in Neuroinflammatory Disorders: A Mini Review of Current Evidences

2019 ◽  
Vol 19 (3) ◽  
pp. 247-258 ◽  
Author(s):  
Mahsa Hatami ◽  
Mina Abdolahi ◽  
Neda Soveyd ◽  
Mahmoud Djalali ◽  
Mansoureh Togha ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
English Language ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Mitochondrial Dynamics ◽  
Nuclear Factor Κb ◽  
General Term ◽  
Neuroinflammatory Disease ◽  
Tnf Α ◽  
Factor Α

Objective: Neuroinflammatory disease is a general term used to denote the progressive loss of neuronal function or structure. Many neuroinflammatory diseases, including Alzheimer’s, Parkinson’s, and multiple sclerosis (MS), occur due to neuroinflammation. Neuroinflammation increases nuclear factor-κB (NF-κB) levels, cyclooxygenase-2 enzymes and inducible nitric oxide synthase, resulting in the release of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). It could also lead to cellular deterioration and symptoms of neuroinflammatory diseases. Recent studies have suggested that curcumin (the active ingredient in turmeric) could alleviate the process of neuroinflammatory disease. Thus, the present mini-review was conducted to summarize studies regarding cellular and molecular targets of curcumin relevant to neuroinflammatory disorders. Methods: A literature search strategy was conducted for all English-language literature. Studies that assessed the various properties of curcuminoids in respect of neuroinflammatory disorders were included in this review. Results: The studies have suggested that curcuminoids have significant anti- neuroinflammatory, antioxidant and neuroprotective properties that could attenuate the development and symptom of neuroinflammatory disorders. Curcumin can alleviate neurodegeneration and neuroinflammation through multiple mechanisms, by reducing inflammatory mediators (such as TNF-α, IL-1β, nitric oxide and NF-κB gene expression), and affect mitochondrial dynamics and even epigenetic changes. Conclusion: It is a promising subject of study in the prevention and management of the neuroinflammatory disease. However, controlled, randomized clinical trials are needed to fully evaluate its clinical potential.

A direct requirement of nuclear factor-κB for suppression of apoptosis in ventricular myocytes

2000 ◽  
Vol 279 (3) ◽  
pp. H939-H945 ◽  
Author(s):  
Shareef Mustapha ◽  
Alla Kirshner ◽  
Danielle De Moissac ◽  
Lorrie A. Kirshenbaum
Keyword(s):  
Dna Binding ◽  
Gene Transcription ◽  
Ventricular Myocytes ◽  
Vital Staining ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Cytoplasmic Factor ◽  
Tnf Α ◽  
Factor Α

Nuclear factor-κB (NF-κB) is a ubiquitously expressed cellular factor regulated by the cytoplasmic factor inhibitor protein κBα (IκBα). Activation of NF-κB by cytokines, including tumor necrosis factor-α (TNF-α), requires the phosphorylation and degradation of IκBα. An anti-apoptotic role for NF-κB has recently been suggested. In the present study, we ascertained whether death-promoting signals and apoptosis mediated by TNF-α are suppressed by NF-κB in postnatal ventricular myocytes. Stimulation of myocytes with TNF-α resulted in a 12.1-fold increase ( P < 0.01) in NF-κB-dependent gene transcription and DNA binding compared with controls. This was accompanied by a corresponding increase in the NF-κB target protein A20 as determined by Western blot analysis. Vital staining revealed that TNF-α was not cytotoxic to myocytes and did not provoke apoptosis. Adenovirus-mediated delivery of a nonphosphorylatable form of IκBα to inactivate NF-κB prevented TNF-α-stimulated NF-κB-dependent gene transcription and nuclear NF-κB DNA binding. Importantly, myocytes stimulated with TNF-α and defective for NF-κB activation resulted in a 2.2-fold increase ( P < 0.001) in apoptosis. To our knowledge, the data provide the first indication that a functional NF-κB signaling pathway is crucial for suppressing death-promoting signals mediated by TNF-α in ventricular myocytes.

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