scholarly journals Administration of SGLT2 inhibitor empagliflozin against TNF‐α induced endothelial dysfunction in human venous and arterial endothelial cells.

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Laween Uthman ◽  
Anna Homayr ◽  
Markus W. Hollmann ◽  
Coert J. Zuurbier ◽  
Nina C. Weber
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Sglt2 Inhibitor ◽  
Tnf Α ◽  
Arterial Endothelial Cells

scholarly journals The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice

2010 ◽  
Vol 299 (3) ◽  
pp. H605-H612 ◽  
Author(s):  
Xiuping Chen ◽  
Hanrui Zhang ◽  
Steve McAfee ◽  
Cuihua Zhang
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Sodium Nitroprusside ◽  
Oxidized Ldl ◽  
Reciprocal Relationship ◽  
Reciprocal Regulation ◽  
Tnf Α ◽  
Ldl Uptake ◽  
Apoe Ko Mice ◽  
Apoe Ko

We hypothesized that the reciprocal association between adiponectin and lectin-like oxidized LDL (ox-LDL) receptor (LOX)-1 contributes to the regulation of aortic endothelial dysfunction in atherosclerosis. To test this hypothesis, endothelium-dependent (ACh) and endothelium-independent (sodium nitroprusside) vasorelaxation of isolated aortic rings from control mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE KO mice treated with either adiponectin (15 μg·day−1·mouse−1 sc for 8 days) or neutralizing antibody to LOX-1 (anti-LOX-1, 16 μg/ml, 0.1 ml/mouse ip for 7 days) were examined. Although vasorelaxation to sodium nitroprusside was not different between control and ApoE KO mice, relaxation to ACh was impaired in ApoE KO mice. Adiponectin and anti-LOX-1 restored nitric oxide-mediated endothelium-dependent vasorelaxation in ApoE KO mice. Aortic ROS formation and ox-LDL uptake were increased in ApoE KO mice. Both adiponectin and anti-LOX-1 treatment reduced ROS production and aortic ox-LDL uptake. In mouse coronary artery endothelial cells, TNF-α incubation increased endothelial LOX-1 expression. Adiponectin reduced TNF-α-induced LOX-1 expression. Consistently, in ApoE KO mice, adiponectin treatment reversed elevated LOX-1 expression in aortas. Immunofluorescence staining showed that adiponectin was mainly colocalized with endothelial cells. Although adiponectin expression was lower in ApoE KO versus control mice, anti-LOX-1 increased aortic adiponectin expression, suggesting a reciprocal regulation between adiponectin and LOX-1. Moreover, both adiponectin and anti-LOX-1 reduced NF-κB expression in ApoE KO mice. Thus, adiponectin and LOX-1 may converge on NF-κB signaling to regulate their function. In conclusion, our results indicate that the reciprocal regulation between adiponectin and LOX-1 amplifies oxidative stress and ox-LDL uptake, leading to endothelial dysfunction in atherosclerosis.

Resveratrol attenuates TNF-α-induced activation of coronary arterial endothelial cells: role of NF-κB inhibition

2006 ◽  
Vol 291 (4) ◽  
pp. H1694-H1699 ◽  
Author(s):  
Anna Csiszar ◽  
Kira Smith ◽  
Nazar Labinskyy ◽  
Zsuzsanna Orosz ◽  
Aracelie Rivera ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Reporter Gene ◽  
Endothelial Activation ◽  
Bone Morphogenetic Protein 2 ◽  
Luciferase Expression ◽  
Pyrrolidine Dithiocarbamate ◽  
Tnf Α ◽  
Gene Assay ◽  
Cardioprotective Effects ◽  
Arterial Endothelial Cells

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its cardioprotective effects are not completely understood. Because TNF-α-induced endothelial activation and vascular inflammation play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits TNF-α-induced signal transduction in human coronary arterial endothelial cells (HCAECs). We found that TNF-α significantly increased adhesiveness of the monocytic THP-1 cells to HCAECs, an effect that could be inhibited by pretreatment with resveratrol and the NF-κB inhibitor pyrrolidine dithiocarbamate. Previously, we found that TNF-α activates NAD(P)H oxidases, and our recent data showed that TNF-α-induced endothelial activation was prevented by the NAD(P)H oxidase inhibitor apocynin or catalase plus SOD. Resveratrol also inhibited H2O2-induced monocyte adhesiveness. Using a reporter gene assay, we found that, in HCAECs, TNF-α significantly increased NF-κB activity, which could be inhibited by resveratrol (>50% inhibition at 10−6 mol/l) and pyrrolidine dithiocarbamate. Resveratrol also inhibited TNF-α-induced, NF-κB-driven luciferase expression in rat aortas electroporated with the reporter gene construct. In TNF-α-treated HCAECs, resveratrol (in the submicromolar range) significantly attenuated expression of NF-κB-dependent inflammatory markers inducible nitric oxide synthase, IL-6, bone morphogenetic protein-2, ICAM-1, and VCAM. Thus resveratrol at nutritionally relevant concentrations inhibits TNF-α-induced NF-κB activation and inflammatory gene expression and attenuates monocyte adhesiveness to HCAECs. We propose that these anti-inflammatory actions of resveratrol are responsible, at least in part, for its cardioprotective effects.

Challenge with LPS or TNF-α Demonstrates Unique Differences in Primary Arterial Endothelial Cells Pretreated with Recombinant Human Activated Protein C.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1935-1935
Author(s):  
James A. Martin ◽  
David E. Joyce ◽  
Rashna Balsara ◽  
Victoria A. Ploplis ◽  
Francis J. Castellino
Keyword(s):  
Endothelial Cells ◽  
Protein C ◽  
Inflammatory Responses ◽  
Transcript Levels ◽  
Total Rna ◽  
Inflammatory Agent ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Arterial Endothelial Cells ◽  
Rna Transcript

Abstract A human recombinant form of the endogenous anticoagulant APC (rhAPC) has been approved for treatment of severe sepsis, a condition with 30-50% mortality and affecting 750,000 US patients per year. Clinical and in vitro studies show that rhAPC has pro-fibrinolytic, anti-inflammatory, and anti-apoptotic properties. In order to better understand the anti-inflammatory mechanism of rhAPC and its receptor EPCR on primary murine aortic endothelial cells (EC), responses were compared between wild type (WT) and low-expressing endothelial protein C receptor (EPCRδ/δ) EC by total RNA for specified endothelial inflammatory markers. The purpose was to determine the effect of rhAPC and low expression of EPCR on murine arterial EC responses to tumor necrosis factor alpha (TNF-α) or endotoxin (LPS). EC from C57BL/6 mice aorta, WT or EPCRδ/δ, were isolated, cultured, and positively selected for EC markers (CD105, CD106). EC in serum free media were pretreated with 5ug/mL rhAPC (Eli Lilly) for 16 hours followed by challenge with 100ng/mL TNF-α or 10ug/mL LPS for 8 hours. Total RNA was analyzed by Quantitative Real-time PCR (QRT-PCR) for CXC chemokines MIP-2 and KC, adhesion markers E-Selectin or ICAM-1, cytokines MCP-1 and IL-6, and NFκB-1. Mean +/− standard error of the mean for the time points (T0, 0.5hr, 1hr, 2hr, 4hr, and 8hr) after TNF-α or LPS were compared between treatment groups. Both TNF-α and LPS produced expected characteristic fold changes of RNA expression over the eight hour time period in the murine EC. Without rhAPC EPCRδ/δ EC showed a similar response compared to WT EC. When pretreated with rhAPC for 16 hours followed by LPS challenge, EC RNA transcript levels for CXC chemokines and adhesion markers were suppressed more in EPCRδ/δ compared to WT EC. When pretreated with rhAPC for 16 hours followed by TNF-α challenge, RNA transcript levels for CXC chemokines and adhesion markers were elevated or showed little change in WT EC and EPCRδ/δ EC compared to EC not given rhAPC. Nuclear factor NFκB-1 RNA was suppressed in both WT EC and EPCRδ/δ EC with rhAPC pretreatment and subsequent inflammatory agent (LPS or TNF-α). Most striking was the unexpected suppressed response of rhAPC pretreated EPCRδ/δ EC compared to WT EC after addition of either inflammatory agent. Further studies suggested that surface EPCR protein did not appear to be enhanced with any treatment combination, or with rhAPC alone. These results are consistent with previously reported endothelial cell specific rhAPC response of CXC chemokines and the ability of rhAPC to suppress other TNF-α mediated inflammatory responses (eg. MCP-1 and NFkB-1). In addition, rhAPC pretreatment appeared to suppress LPS mediated inflammatory responses, including CXC chemokines. The enhanced suppression of inflammatory responses seen in arterial EPCRδ/δ EC compared to WT EC remains unexplained. Results from this study also indicate primary murine arterial endothelial cells treated with rhAPC respond differently to challenge with TNF-α versus LPS.

scholarly journals KLF2 is a therapeutic target for COVID-19 induced endothelial dysfunction

2021 ◽  
Author(s):  
Suowen Xu ◽  
Sihui Luo ◽  
Xueying Zheng ◽  
Jianping Weng
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
Cardiovascular Complications ◽  
Monocyte Adhesion ◽  
Sequencing Data ◽  
Atorvastatin Treatment ◽  
Tnf Α ◽  
Adhesive Molecules ◽  
Umbilical Vein Endothelial Cells

AbstractCoronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its mechanism being incompletely understood. Emerging evidence has demonstrated that the endothelium represents the Achilles' heel in COVID-19 patients and that endothelial dysfunction precipitates COVID-19 and accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. Primary human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) were treated with serum from control subjects or COVID-19 patients. Downstream monocyte adhesion and associated gene/protein expression was evaluated in endothelial cells exposed to COVID-19 patient serum in the presence of KLF2 activator (Atorvastatin) or KLF2 overexpression by an adenoviral vector. Here, we demonstrate that the expression of KLF2 was significantly reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1β and TNF-α, two cytokines observed in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis and reduced angiogenesis). Treatment of HPMECs with atorvastatin or KLF2 adenovirus ameliorate COVID-19 serum-induced increase in endothelial inflammation and monocyte adhesion by increasing KLF2 expression. Altogether, the present study demonstrates that genetic and pharmacological activation of KLF2 represses COVID-19 associated endothelial dysfunction, heralding a potentially new direction to treat endothelialitis accompanying COVID-19.

Tumour necrosis factor-α gene expression and production in human umbilical arterial endothelial cells

2000 ◽  
Vol 98 (4) ◽  
pp. 461-470 ◽  
Author(s):  
Thomas NEUHAUS ◽  
Gudrun TOTZKE ◽  
Elisabeth GRUENEWALD ◽  
Hans-Peter JUESTEN ◽  
Agapios SACHINIDIS ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Dependent Manner ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
Factor Α ◽  
Arterial Endothelial Cells ◽  
Necrosis Factor

Endothelial cells act as an interface between the blood and tissues, and are known to be involved in inflammatory processes. These cells are responsive to and produce different cytokines. Tumour necrosis factor-α (TNF-α) not only is one of the most important inflammatory peptides, but also can be induced by lipopolysaccharide (LPS). The focus of the present study was on TNF-α gene expression and production in human umbilical arterial endothelial cells (HUAEC), including the kinetics of this process. Interleukin-1α (IL-1α), LPS and TNF-α, which are all known to be elevated in septic shock, were used as stimulators at concentrations commonly found in patients with sepsis. Through the use of reverse transcriptase/PCR, immunohistochemical reactions and ELISA techniques, we showed that, in HUAEC, all three stimuli were able to induce gene expression and production of TNF-α. Furthermore, this induction by IL-1α, LPS and TNF-α occurred in a time- and concentration-dependent manner in these cells. TNF-α expression and production was induced by all three agents at concentrations commonly found in patients with sepsis. TNF-α mRNA was observed within 30 min regardless of the stimulus used, but the levels peaked at different times. Since it is well established that TNF-α is able to induce the synthesis of IL-1α in endothelial cells and, as shown in the present study, TNF-α and IL-1α are themselves able to induce the synthesis of TNF-α in endothelial cells, an autocrine potentiation of cytokine release in sepsis can be proposed. This situation could lead to a locally acting ‘vicious cycle’ which, when considered in addition to the known ability of TNF-α to induce apoptosis, could mean that various organs will be damaged, a condition associated with sepsis. Thus these results provide further evidence for the important role played by the endothelium in inflammation.

Epigallocatechin gallate preserves endothelial function by reducing the endogenous nitric oxide synthase inhibitor level

2006 ◽  
Vol 84 (2) ◽  
pp. 163-171 ◽  
Author(s):  
Wei-Jun Tang ◽  
Chang-Ping Hu ◽  
Mei-Fang Chen ◽  
Pan-Yue Deng ◽  
Yuan-Jian Li
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Epigallocatechin Gallate ◽  
Adma Level ◽  
Nitric Oxide Synthase Inhibitor ◽  
Tnf Α ◽  
Endogenous Nitric Oxide ◽  
Nitrite Nitrate ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Asymmetric dimethylarginine (ADMA), the endogenous nitric oxide synthase inhibitor, is thought to be a key factor contributing to endothelial dysfunction. Tea catechins can cause an endothelium-dependent vasorelaxation. The present study examined the effect of epigallocatechin gallate (EGCG), the major component of tea catechins, on endothelial dysfunction induced by native low density lipoprotein (LDL) in rats and oxidized LDL (ox-LDL) in cultured endothelial cells, and whether the protective effect of EGCG is related to reduction of ADMA level. A single injection of LDL (4 mg·kg–1, i.v.) markedly reduced endothelium-dependent relaxation and the serum nitrite/nitrate (NO) level, and increased serum concentrations of ADMA, malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α). EGCG (10 or 50 mg·kg–1, i.p.) significantly attenuated the inhibition of vasodilator response to acetylcholine and the decreased serum nitrite/nitrate level, and reduced the elevated levels of ADMA, MDA, and TNF-α. Exposure of endothelial cells to ox-LDL (100 μg·mL–1) for 24 h markedly increased the medium levels of lactate dehydrogenase (LDH), ADMA, TNF-α, and MDA, and decreased the level of nitrite/nitrate in the medium and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in the endothelial cells. EGCG (10 and 100 μg·mL–1) significantly decreased the levels of LDH, ADMA, TNF-α, and MDA, and increased the level of nitrite/nitrate and the activity of DDAH. These results suggest that EGCG protects endothelial dysfunction induced by native LDL in vivo or by ox-LDL in endothelial cells, and the protective effect of EGCG on the endothelium is related to decrease in ADMA level via increasing of DDAH activity.

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