Abstract 11678: Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xinyuan Li ◽  
Pu Fang ◽  
Ya-Feng Li ◽  
Yin-Ming Kuo ◽  
Andrew J Andrews ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Fluorescence Probe ◽  
Vascular Inflammation ◽  
Intercellular Adhesion Molecule ◽  
Mitochondrial Calcium ◽  
Activator Protein 1 ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Cell Activation

Background: Lysophosphatidylcholines (LPCs) are a class of pro-inflammatory lipids that play important roles in atherogenesis. LPC activates endothelial cells (ECs) to upregulate adhesion molecules and chemokines, which is the initiation step of atherogenesis. However, the mechanisms underlying LPC-triggered EC activation are not fully understood. Previously considered as the toxic by-products of cellular metabolism, mitochondrial ROS (mtROS) are recently found to directly contribute to both the innate and adaptive immune responses. Here we tested a novel hypothesis that mtROS serve as signaling mediators for LPC-induced EC activation. Methods and Results: Using electron spin resonance and flow cytometry with fluorescence probe MitoSOX, we found that several LPC species including LPC 16:0, 18:0, and 18:1 induced mtROS in human primary aortic ECs (HAECs). Mechanistically, our analysis using mitochondrial calcium inhibitor and Seahorse XF96 mitochondrial function analyzer showed that LPC induced mtROS via increasing mitochondrial calcium entry which resulted in mitochondrial proton leakage. In addition, we found that mtROS scavenger MitoTEMPO abolished LPC-induced EC activation by downregulating Intercellular adhesion molecule 1 (ICAM-1) and Vascular cell adhesion protein 1 (VCAM-1) in HAECs. Moreover, our analysis with transcription factor profiling screening showed that MitoTEMPO acts by blocking LPC-induced nuclear translocation of pro-inflammatory transcription factor activator protein-1 (AP-1). Conclusions: Our results indicate that mtROS are responsible for LPC-induced EC activation and that mtROS may serve as a novel therapeutic target for vascular inflammation.

scholarly journals Synthetic Colloids Attenuate Leukocyte-Endothelial Interactions by Inhibition of Integrin Function

2005 ◽  
Vol 103 (4) ◽  
pp. 759-767 ◽  
Author(s):  
Boris Nohé ◽  
Tanja Johannes ◽  
Jörg Reutershan ◽  
Albert Rothmund ◽  
Helene A. Haeberle ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Tissue Injury ◽  
Severe Infection ◽  
Intercellular Adhesion Molecule ◽  
Neutrophil Adhesion ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Cell Activation

Background It has been suspected that synthetic colloids may interfere with leukocyte adhesion by down-regulation of endothelial cell adhesion molecules. Although inhibition of endothelial inflammation might reduce leukocyte-related tissue injury, the same mechanism may be detrimental for host defense during severe infection. Regarding the widespread use of colloids, the authors performed a laboratory investigation to determine the mechanisms by which synthetic colloids interfere with leukocyte-endothelial interactions. Methods Adhesion molecule expression on native and cytokine-activated endothelium from umbilical veins was measured after pretreatment with gelatin and various preparations of dextran or hydroxyethyl starch. Inhibition of neutrophil adhesion to activated endothelium was examined in a flow chamber by perfusion of untreated and colloid-treated neutrophils over colloid-pretreated endothelium at 2 dyn/cm. Comparisons were made between untreated controls, colloid-pretreated endothelium, and colloid-cotreated neutrophils. Results Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were not attenuated by any colloid. Accordingly, colloid pretreatment of endothelium alone did not reduce neutrophil adhesion. In contrast, when neutrophils were cotreated by addition of colloids to the perfusate immediately before perfusion, adhesion decreased by 31-51% (P < 0.05) regardless of the colloid type. As indicated by the twofold increased rolling fractions, this reduction was due to an inhibition of neutrophil integrins. Conclusions This study shows that synthetic colloids inhibit neutrophil adhesion by a neutrophil-dependent mechanism rather than interfering with endothelial cell activation. This suggests that inhibition of leukocyte sequestration by volume support is a common and transient phenomenon depending on the colloid concentration in plasma.

scholarly journals The Transcription Factor Erg Controls Endothelial Cell Quiescence by Repressing Activity of Nuclear Factor (NF)-κB p65

2012 ◽  
Vol 287 (15) ◽  
pp. 12331-12342 ◽  
Author(s):  
Nicola H. Dryden ◽  
Andrea Sperone ◽  
Silvia Martin-Almedina ◽  
Rebecca L. Hannah ◽  
Graeme M. Birdsey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Sequences ◽  
Vascular Inflammation ◽  
Enrichment Analysis ◽  
Endothelial Activation ◽  
Organ Damage ◽  
Gene Set Enrichment Analysis ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1

The interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the transcription factor NF-κB is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-κB in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS −118 and −181) within the ICAM-1 promoter required for Erg-mediated repression. We show that Erg binds to both EBS −118 and EBS −181, the latter located within the NF-κB binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NF-κB-dependent ICAM-1 expression, indicating that Erg represses basal NF-κB activity. Erg prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of Erg and NF-κB-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.

scholarly journals Predictive Value of High ICAM-1 Level for Poor Treatment Response to Low-Dose Decitabine in Adult Corticosteroid Resistant ITP Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Chaoyang Li ◽  
Lizhen Li ◽  
Meng Sun ◽  
Jianzhi Sun ◽  
Linlin Shao ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Predictive Value ◽  
Cell Activation ◽  
Low Dose ◽  
Complete Response ◽  
Intercellular Adhesion Molecule ◽  
Hemorrhagic Disease ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Cell Activation ◽  
Multivariable Logistic Regression Model

Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease. Endothelial cell activation/injury has been found in some autoimmune diseases including SLE, systemic sclerosis, and rheumatoid arthritis, but its role in ITP pathogenesis remains unclear. This study attempted to elucidate the correlation between endothelial dysfunction and disease severity of ITP and find related markers to predict response to low-dose decitabine treatment. Compared with healthy volunteers, higher plasma levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), and Angiopoietin-2 were found in adult corticosteroid resistant ITP patients. Notably, ICAM-1 levels were negatively correlated with the platelet count, and positively associated with the bleeding score. Recently, we have reported the efficacy and safety of low-dose decitabine in adult patients with ITP who failed for the first line therapies. Here, we evaluated the correlation of plasma ICAM-1 level with the efficacy of low-dose decitabine therapy for corticosteroid resistant ITP. A total of 29 adult corticosteroid resistant ITP patients who received consecutive treatments of low-dose decitabine were enrolled in this study. Fourteen patients showed response (nine showed complete response and five showed partial response). The levels of ICAM-1 before and after treatment were significantly higher in the non-responsive ITP patients than in the responsive patients. As shown in the multivariable logistic regression model, the odds of developing no-response to low-dose decitabine increased by 36.8% for per 5 ng/ml increase in plasma ICAM-1 level [odds ratio (OR) 1.368, 95% confidence interval (CI): 1.060 to 1.764]. In summary, this was the first study to elucidate the relationship between endothelial dysfunction and corticosteroid resistant ITP and identify the potential predictive value of ICAM-1 level for response to low-dose decitabine.

scholarly journals Silibinin Inhibits ICAM-1 Expression via Regulation of N-Linked and O-Linked Glycosylation in ARPE-19 Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13
Author(s):  
Yi-Hao Chen ◽  
Ching-Long Chen ◽  
Chang-Min Liang ◽  
Jy-Been Liang ◽  
Ming-Cheng Tai ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Transmembrane Protein ◽  
Reporter Gene Assay ◽  
Intercellular Adhesion Molecule ◽  
Inhibitory Effects ◽  
Intercellular Adhesion Molecule 1 ◽  
Reporter Activity ◽  
Gene Assay ◽  
Stat1 Signaling ◽  
Necrosis Factor

To evaluate the effects of silibinin on intercellular adhesion molecule-1 (ICAM-1) expression, we used ARPE-19 cells as a model in which tumor necrosis factor (TNF-α) and interferon (IFN-γ) enhanced ICAM-1 expression. This upregulation was inhibited by silibinin. In an adherence assay using ARPE-19 and THP-1 cells, silibinin inhibited the cell adhesion function of ICAM-1. The inhibitory effects of silibinin on ICAM-1 expression were mediated via the blockage of nuclear translocation of p65 proteins in TNF-αand phosphorylation of STAT1 in IFN-γ-stimulated cells. In addition, silibinin altered the degree of N-linked glycosylation posttranslationally in ARPE-19 cells by significantly enhancingMGAT3gene expression. Silibinin can increase the O-GlcNAc levels of glycoproteins in ARPE-19 cells. In a reporter gene assay, PUGNAc, which can also increase O-GlcNAc levels, inhibited NF-κB reporter activity in TNF-α-induced ARPE-19 cells and this process was augmented by silibinin treatment. Overexpression ofOGTgene was associated with reduced TNF-α-induced ICAM-1 levels, which is consistent with that induced by silibinin treatment. Taken together, silibinin inhibits ICAM-1 expression and its function through altered O-linked glycosylation in NF-κB and STAT1 signaling pathways and decreases the N-linked glycosylation of ICAM-1 transmembrane protein in proinflammatory cytokine-stimulated ARPE-19 cells.

scholarly journals Inhibition of PAR1 attenuates meningeal macrophage activation and vascular inflammation in a rat model of thrombin-induced hydrocephalus

2019 ◽  
Author(s):  
Xiaodi Hao ◽  
Xianghua Ye ◽  
Dan Shen ◽  
Chensheng Le ◽  
Lusha Tong ◽  
...  
Keyword(s):  
Subarachnoid Space ◽  
Vascular Inflammation ◽  
Intercellular Adhesion Molecule ◽  
Intraventricular Injection ◽  
Thrombin Injection ◽  
Intercellular Adhesion Molecule 1 ◽  
Neuron Loss ◽  
Meningeal Inflammation ◽  
M1 Polarization ◽  
Pro Inflammatory Cytokines

Abstract Background and Purpose— Our previous studies demonstrated that intraventricular injection of thrombin could induce hydrocephalus. The inflammation of subarachnoid space plays a key role in hydrocephalus. As thrombin, inducing coagulation, could contribute to inflammation, its effects on subarachnoid space have not been well studied. Macrophagic dysfunction may contribute to this course. However, the mechanisms that how thrombin affects macrophage in subarachnoid space have not been illustrated. Our aim was to explore the possible role that macrophage played in thrombin-induced meningeal inflammation, and to furtherly understand its contribution during thrombin-induced hydrocephalus. Methods— There were two parts in this study. Firstly, rats had an intraventricular injection of saline or thrombin. Secondly, rats received thrombin injection with vehicle or PAR1 antagonist treatment. Immunofluorescence staining was applied to observe the activation of meningeal macrophage and the expression of NeuN in the cortex. Meanwhile, the expression of intercellular adhesion molecule 1 (ICAM1) in meningeal vessels were tested to detect the vascular inflammation. Western blot was applied to measure the secretion of pro-inflammatory cytokines (IL-1β and IFNγ). Results— Our results demonstrated that intraventricular injection of thrombin caused significant activation of meningeal macrophages, vascular inflammation, and neuron loss. Inhibition of PAR1 pathway attenuated the M1 polarization of meningeal macrophage, reduced the inflammatory infiltrations and prevented the neuron loss, as well as hydrocephalus after thrombin injection. Conclusions— Clinically available PAR1 antagonists may offer a novel therapeutic approach candidate for the prevention or the management of inflammation in hemorrhage-induced hydrocephalus.

scholarly journals Elevated antiviral, myeloid and endothelial inflammatory markers in severe COVID-19

2020 ◽  
Author(s):  
Ryan S Thwaites ◽  
Ashley Sanchez Sevilla Uruchurtu ◽  
Matthew Siggins ◽  
Felicity Liew ◽  
Clark D Russell ◽  
...  
Keyword(s):  
Lung Injury ◽  
Cell Activation ◽  
Vascular Inflammation ◽  
Endothelial Cell Activation ◽  
Gm Csf ◽  
Cytokine Levels ◽  
Angiopoietin 2 ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Host Inflammatory Response

Introductory paragraphThe mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical ‘cytokine storms’. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.

Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs

1999 ◽  
Vol 277 (3) ◽  
pp. L596-L605 ◽  
Author(s):  
Clare E. Howlett ◽  
James S. Hutchison ◽  
John P. Veinot ◽  
Aaron Chiu ◽  
Pradeep Merchant ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nuclear Factor Κb ◽  
Inhaled Nitric Oxide ◽  
Intercellular Adhesion Molecule ◽  
Activator Protein 1 ◽  
Intercellular Adhesion Molecule 1 ◽  
Vascular Leak ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation ◽  
First Time

Inhaled nitric oxide (NO), frequently administered in combination with hyperoxic gas mixtures, was recently shown to protect against the injurious consequences of prolonged hyperoxia. We investigated the possibility that this protective effect is attributable to the ability of NO to block pulmonary apoptosis. We show that rats exposed to 100% O2for 60 h develop severe lung injury consisting of pronounced vascular leak and alveolar apoptosis as inferred from the presence of positive terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and DNA ladders in agarose gels and a decrease in constitutive procaspase-3 levels. However, the inclusion of NO (20 parts/million) in the hyperoxic gas mixture significantly attenuated both the vascular leak and apoptosis. NO reversed the hyperoxia-associated changes in the activity of the redox-sensitive transcription factors nuclear factor-κB, activator protein-1, and Sp1 after 24 h, lowered intercellular adhesion molecule-1 levels, and increased glutathione content. We therefore show, for the first time, that NO can protect against both hyperoxia-induced apoptosis and inflammation. The data suggest that this protection may occur at the transcriptional and caspase-activation levels.

scholarly journals Microarray Analysis of the Molecular Mechanism Involved in Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Cheng Tan ◽  
Xiaoyang Liu ◽  
Jiajun Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factor ◽  
Signaling Pathway ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Intercellular Adhesion Molecule ◽  
Rrna Processing ◽  
Ppi Network ◽  
Intercellular Adhesion Molecule 1

Purpose. This study aimed to investigate the underlying molecular mechanisms of Parkinson’s disease (PD) by bioinformatics.Methods. Using the microarray dataset GSE72267 from the Gene Expression Omnibus database, which included 40 blood samples from PD patients and 19 matched controls, differentially expressed genes (DEGs) were identified after data preprocessing, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein-protein interaction (PPI) network, microRNA- (miRNA-) target regulatory network, and transcription factor- (TF-) target regulatory networks were constructed.Results. Of 819 DEGs obtained, 359 were upregulated and 460 were downregulated. Two GO terms, “rRNA processing” and “cytoplasm,” and two KEGG pathways, “metabolic pathways” and “TNF signaling pathway,” played roles in PD development. Intercellular adhesion molecule 1 (ICAM1) was the hub node in the PPI network; hsa-miR-7-5p, hsa-miR-433-3p, and hsa-miR-133b participated in PD pathogenesis. Six TFs, including zinc finger and BTB domain-containing 7A, ovo-like transcriptional repressor 1, GATA-binding protein 3, transcription factor dp-1, SMAD family member 1, and quiescin sulfhydryl oxidase 1, were related to PD.Conclusions. “rRNA processing,” “cytoplasm,” “metabolic pathways,” and “TNF signaling pathway” were key pathways involved in PD.ICAM1, hsa-miR-7-5p, hsa-miR-433-3p, hsa-miR-133b, and the abovementioned six TFs might play important roles in PD development.

Continuous therapy with transdermal nitroglycerin does not affect biomarkers of vascular inflammation and injury in healthy volunteers

2009 ◽  
Vol 87 (6) ◽  
pp. 455-459 ◽  
Author(s):  
George R. Thomas ◽  
Jonathan M. DiFabio ◽  
Tommaso Gori ◽  
David J.A. Jenkins ◽  
John D. Parker
Keyword(s):  
Healthy Volunteers ◽  
Vascular Inflammation ◽  
Venous Blood ◽  
Intercellular Adhesion Molecule ◽  
Control Group ◽  
Continuous Exposure ◽  
Intercellular Adhesion Molecule 1 ◽  
Continuous Therapy ◽  
Factor Α ◽  
Dimethyl Arginine

Continuous exposure to nitroglycerin (GTN) results in development of tolerance and is associated with increased free radical production and abnormal endothelial function. Elevated plasma biomarkers of inflammation have been shown to be associated with endothelial dysfunction in most cardiovascular conditions. It remains unclear whether exposure to GTN is also associated with increased biomarkers of endothelial and vascular injury or vascular inflammation. In an investigator-blind study, a total of 28 healthy volunteers were randomized to continuous therapy with GTN (0.6 mg/h 24 h/day for 7 days) or no therapy. Venous blood was collected on day 0 and day 7. Plasma levels of markers such as asymmetric dimethyl-arginine (ADMA), human soluble P-selectin, interleukin-6, tumor necrosis factor-α, intercellular adhesion molecule-1, and oxidized low-density lipoproteins were measured. The levels of blood markers on day 0 were similar in the control and GTN-treated groups. After 7 days of GTN exposure, there were no significant changes in the different markers of vascular inflammation and injury either in the GTN or control group (all p > 0.5). The present study documents that prolonged continuous therapy with transdermal GTN therapy is not associated with changes in markers of vascular inflammation and injury.

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