scholarly journals Flavanone metabolites decrease monocyte adhesion to TNF-α-activated endothelial cells by modulating expression of atherosclerosis-related genes

2013 ◽  
Vol 110 (4) ◽  
pp. 587-598 ◽  
Author(s):  
Audrey Chanet ◽  
Dragan Milenkovic ◽  
Sylvain Claude ◽  
Jeanette A. M. Maier ◽  
Muhammad Kamran Khan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Vascular Function ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Inhibitory Effect ◽  
Mechanisms Of Action ◽  
Monocyte Adhesion ◽  
Tnf Α ◽  
The Impact

Flavanones are found specifically and abundantly in citrus fruits. Their beneficial effect on vascular function is well documented. However, little is known about their cellular and molecular mechanisms of action in vascular cells. The goal of the present study was to identify the impact of flavanone metabolites on endothelial cells and decipher the underlying molecular mechanisms of action. We investigated the impact of naringenin and hesperetin metabolites at 0·5, 2 and 10 μm on monocyte adhesion to TNF-α-activated human umbilical vein endothelial cells (HUVEC) and on gene expression. Except hesperetin-7-glucuronide and naringenin-7-glucuronide (N7G), when present at 2 μm, flavanone metabolites (hesperetin-3′-sulphate, hesperetin-3′-glucuronide and naringenin-4′-glucuronide (N4′G)) significantly attenuated monocyte adhesion to TNF-α-activated HUVEC. Exposure of both monocytes and HUVEC to N4′G and N7G at 2 μm resulted in a higher inhibitory effect on monocyte adhesion. Gene expression analysis, using TaqMan Low-Density Array, revealed that flavanone metabolites modulated the expression of genes involved in atherogenesis, such as those involved in inflammation, cell adhesion and cytoskeletal organisation. In conclusion, physiologically relevant concentrations of flavanone metabolites reduce monocyte adhesion to TNF-α-stimulated endothelial cells by affecting the expression of related genes. This provides a potential explanation for the vasculoprotective effects of flavanones.

Mechanisms of MAdCAM-1 gene expression in human intestinal microvascular endothelial cells

2005 ◽  
Vol 288 (2) ◽  
pp. C272-C281 ◽  
Author(s):  
Hitoshi Ogawa ◽  
David G. Binion ◽  
Jan Heidemann ◽  
Monica Theriot ◽  
Pamela J. Fisher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Primary Cultures ◽  
Microvascular Endothelial Cells ◽  
Cellular Density ◽  
Tnf Α ◽  
Gene And Protein Expression ◽  
Microvascular Endothelial

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a homing receptor preferentially expressed on gut-associated endothelial cells that plays a central role in leukocyte traffic into the mucosal immune compartment. Although the molecular mechanisms underlying endothelial ICAM-1 or E-selectin expression have been intensively investigated, the mechanisms that regulate human MAdCAM-1 expression have not been defined. We report MAdCAM-1 gene and protein expression in primary cultures of human intestinal microvascular endothelial cells (HIMEC) that was not demonstrated in human umbilical vein endothelial cells. Similar to ICAM-1 and E-selectin expression, MAdCAM-1 gene expression in HIMEC was inducible with TNF-α, IL-1β, or LPS activation. However, in striking contrast to ICAM-1 and E-selectin expression, MAdCAM-1 mRNA and protein expression in HIMEC was heavily dependent on culture duration and/or cellular density, suggesting a prominent role for cell-cell interaction among these endothelial cells in the expression of the mucosal addressin. MAdCAM-1 expression was inhibited by both SN-50 (NF-κB inhibitor) and LY-294002 [phosphatidylinositol 3-kinase (PI3-K) inhibitor], whereas ICAM-1 and E-selectin expression was inhibited by SN-50 but not by LY-294002. The Akt phosphorylation by TNF-α or LPS was greater at higher cell density, demonstrating a pattern similar to that of MAdCAM-1 expression. NF-κB activation was not affected by cellular density in HIMEC. MAdCAM-1 expression in human gut endothelial cells is regulated by distinct signaling mechanisms involving both NF-κB and PI3-K/Akt. These data also suggest that PI3-K/Akt is involved in the gut-specific differentiation of HIMEC, which results in expression of the mucosal addressin MAdCAM-1.

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.

scholarly journals Different RNA splicing mechanisms contribute to diverse infective outcome of classical swine fever viruses of differing virulence: insights from the deep sequencing data in swine umbilical vein endothelial cells

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2113 ◽  
Author(s):  
Pengbo Ning ◽  
Yulu Zhou ◽  
Wulong Liang ◽  
Yanming Zhang
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Rna Splicing ◽  
Molecular Mechanisms ◽  
Computational Study ◽  
Umbilical Vein ◽  
Classical Swine Fever ◽  
Pathway Enrichment Analysis ◽  
Splicing Regulation ◽  
Umbilical Vein Endothelial Cells

Molecular mechanisms underlying RNA splicing regulation in response to viral infection are poorly understood. Classical swine fever (CSF), one of the most economically important and highly contagious swine diseases worldwide, is caused by classical swine fever virus (CSFV). Here, we used high-throughput sequencing to obtain the digital gene expression (DGE) profile in swine umbilical vein endothelial cells (SUVEC) to identify different response genes for CSFV by using both Shimen and C strains. The numbers of clean tags obtained from the libraries of the control and both CSFV-infected libraries were 3,473,370, 3,498,355, and 3,327,493 respectively. In the comparison among the control, CSFV-C, and CSFV-Shimen groups, 644, 158, and 677 differentially expressed genes (DEGs) were confirmed in the three groups. Pathway enrichment analysis showed that many of these DEGs were enriched in spliceosome, ribosome, proteasome, ubiquitin-mediated proteolysis, cell cycle, focal adhesion, Wnt signalling pathway, etc., where the processes differ between CSFV strains of differing virulence. To further elucidate important mechanisms related to the differential infection by the CSFV Shimen and C strains, we identified four possible profiles to assess the significantly expressed genes only by CSFV Shimen or CSFV C strain. GO analysis showed that infection with CSFV Shimen and C strains disturbed ‘RNA splicing’ of SUVEC, resulting in differential ‘gene expression’ in SUVEC. Mammalian target of rapamycin (mTOR) was identified as a significant response regulator contributed to impact on SUVEC function for CSFV Shimen. This computational study suggests that CSFV of differing virulence could induce alterations in RNA splicing regulation in the host cell to change cell metabolism, resulting in acute haemorrhage and pathological damage or infectious tolerance.

scholarly journals Stromal vascular fraction promotes migration of fibroblasts and angiogenesis through regulation of extracellular matrix in the skin wound healing process

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Hongsen Bi ◽  
Hui Li ◽  
Chen Zhang ◽  
Yiqing Mao ◽  
Fangfei Nie ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Healing Process ◽  
Stromal Vascular Fraction ◽  
Wound Healing Process ◽  
Matrix Remodeling ◽  
Skin Defect ◽  
The Impact

Abstract Background A refractory wound is a typical complication of diabetes and is a common outcome after surgery. Current approaches have difficulty in improving wound healing. Recently, non-expanded stromal vascular fraction (SVF), which is derived from mature fat, has opened up new directions for the treatment of refractory wound healing. The aim of the current study is to systematically investigate the impact of SVF on wound healing, including the rate and characteristics of wound healing, ability of fibroblasts to migrate, and blood transport reconstruction, with a special emphasis on their precise molecular mechanisms. Methods SVF was isolated by digestion, followed by filtration and centrifugation, and then validated by immunocytochemistry, a MTS proliferation assay and multilineage potential analysis. A wound model was generated by creating 6-mm-diameter wounds, which include a full skin defect, on the backs of streptozocin-induced hyperglycemic mice. SVF or human adipose-derived stem cell (hADSC) suspensions were subcutaneously injected, and the wounds were characterized over a 9-day period by photography and measurements. A scratch test was used to determine whether changes in the migratory ability of fibroblasts occurred after co-culture with hADSCs. Angiogenesis was observed with human umbilical vein endothelial cells. mRNA from fibroblasts, endotheliocyte, and skin tissue were sequenced by high-throughput RNAseq, and differentially expressed genes, and pathways, potentially regulated by SVF or hADSCs were bioinformatically analyzed. Results Our data show that hADSCs have multiple characteristics of MSC. SVF and hADSCs significantly improved wound healing in hyperglycemic mice. hADSCs improve the migratory ability of fibroblasts and capillary structure formation in HUVECs. SVF promotes wound healing by focusing on angiogenesis and matrix remodeling. Conclusions Both SVF and hADSCs improve the function of fibroblast and endothelial cells, regulate gene expression, and promote skin healing. Various mechanisms likely are involved, including migration of fibroblasts, tubulogenesis of endothelial cells through regulation of cell adhesion, and cytokine pathways.

Abstract 713: S 18886 Inhibits Thromboxane A 2 Receptor-dependent Tissue Factor Expression, Procoagulant Activity And NADP(H) Oxidase Activation In Stimulated Endothelial Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Serena Del Turco ◽  
Giuseppina Basta ◽  
Guido Lazzerini ◽  
Laurent Chancharme ◽  
Laurence Lerond ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Receptor Antagonist ◽  
Tissue Factor ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Factor Xa ◽  
Cell Types ◽  
Procoagulant Activity ◽  
Tp Receptor ◽  
Tnf Α

Background Tissue factor (TF) expression and surface exposure are key events in thrombosis, likely contributing to clinical events in vascular disease. Thromboxane (TX)A 2 , an unstable metabolite of arachidonic acid released from vaious cell types, is known for its pro-aggregating and vasoconstrictor properties. Cellular effects of TXA 2 are effected through the TP (TX-prostaglandin endoperoxide) receptor, also expressed in endothelial cells (EC). The TP receptor antagonist S 18886 (Terutroban) demonstrated antithrombotic and antiatherogenic effects in activated EC. As the underlying molecular mechanisms are largely unexplored, we studied the effects of TP agonism and of antagonism on TF expression and procoagulant activity in human umbilical vein endothelial cells (HUVEC), and signal transduction pathways involved. Methods and Results HUVEC ± 30 min pretreatment with the TP antagonist S 18886 were stimulated with the TP receptor agonist U 46619 or TNF-α for 6 hours. TF total expression and surface exposure were assessed by enzyme immunoassays, and TF-dependent procoagulant activity by the generation of Factor Xa. HUVEC exposed to U 46619 featured a concentration-dependent increase in TF total expression and surface exposure. These were associated with enhanced procoagulant activity. S 18886 (1 μmol/L) significantly reduced U 46619 (1 μM)-induced TF expression (−20% ± 7%, P<0.05) and procoagulant activity (−32% ± 11%, P<0.05). Interestingly, S 18886 (1 μmol/L) prevented the increase of TF expression after TNF-α (20 ng/mL) stimulation (−25% ± 9%, P<0.05). Both U 46619- and TNF-α-induced TF expression were mediated by the increase of intracellular reactive oxygen species (ROS), and this was inhibited by S 18886 (−44% ± 6% and −24% ± 5% P<0.05, respectively). S 18886 decreased the membrane association of p47-phox component of NADP(H) oxidase, accounting for the reduced production of ROS. Conclusions Our results show that endothelial TP receptor mediates TF expression, surface exposure and activity stimulated both by TP agonists and by TNF-α. This occurs through NADP(H) oxidase activation and the consequent generation of ROS. These procoagulant and oxidant pathways are inhibited by the TP receptor antagonist S 18886.

Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4249-4257 ◽  
Author(s):  
Joost O. Fledderus ◽  
Johannes V. van Thienen ◽  
Reinier A. Boon ◽  
Rob J. Dekker ◽  
Jakub Rohlena ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Umbilical Vein ◽  
Expression Profiles ◽  
Binding Activity ◽  
Tnf Α ◽  
Proinflammatory Gene ◽  
Umbilical Vein Endothelial Cells ◽  
Proinflammatory Gene Expression

Abstract Absence of shear stress due to disturbed blood flow at arterial bifurcations and curvatures leads to endothelial dysfunction and proinflammatory gene expression, ultimately resulting in atherogenesis. KLF2 has recently been implicated as a transcription factor involved in mediating the anti-inflammatory effects of flow. We investigated the effect of shear on basal and TNF-α–induced genomewide expression profiles of human umbilical vein endothelial cells (HUVECs). Cluster analysis confirmed that shear stress induces expression of protective genes including KLF2, eNOS, and thrombomodulin, whereas basal expression of TNF-α–responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF-α–induced gene expression was mostly NF-κB dependent. Furthermore, human endothelial cells overlying atherosclerotic plaques had increased amounts of phosphorylated nuclear ATF2 compared with endothelium at unaffected sites. In HUVECs, a dramatic reduction of nuclear binding activity of ATF2 was observed under shear and appeared to be KLF2 dependent. Reduction of ATF2 with siRNA potently suppressed basal proinflammatory gene expression under no-flow conditions. In conclusion, we demonstrate that shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expression.

Fish oil fatty acids improve postprandial vascular reactivity in healthy men

2008 ◽  
Vol 114 (11) ◽  
pp. 679-686 ◽  
Author(s):  
Christopher K. Armah ◽  
Kim G. Jackson ◽  
Izzy Doman ◽  
Lewis James ◽  
Farah Cheghani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Fish Oil ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Positive Impact ◽  
Oxidase Gene ◽  
The Impact

Chronic fish oil intervention had been shown to have a positive impact on endothelial function. Although high-fat meals have often been associated with a loss of postprandial vascular reactivity, studies examining the effects of fish oil fatty acids on vascular function in the postprandial phase are limited. The aim of the present study was to examine the impact of the addition of fish oil fatty acids to a standard test meal on postprandial vascular reactivity. A total of 25 men received in a random order either a placebo oil meal (40 g of mixed fat; fatty acid profile representative of the U.K. diet) or a fish oil meal (31 g of mixed fat and 9 g of fish oil) on two occasions. Vascular reactivity was measured at baseline (0 h) and 4 h after the meal by laser Doppler iontophoresis, and blood samples were taken for the measurement of plasma lipids, total nitrite, glucose and insulin. eNOS (endothelial NO synthase) and NADPH oxidase gene expression were determined in endothelial cells after incubation with TRLs (triacylglycerol-rich lipoproteins) isolated from the plasma samples taken at 4 h. Compared with baseline, sodium nitroprusside (an endothelium-independent vasodilator)-induced reactivity (P=0.024) and plasma nitrite levels (P=0.001) were increased after the fish oil meal. In endothelial cells, postprandial TRLs isolated after the fish oil meal increased eNOS and decreased NADPH oxidase gene expression compared with TRLs isolated following the placebo oil meal (P≤0.03). In conclusion, meal fatty acids appear to be an important determinant of vascular reactivity, with fish oils significantly improving postprandial endothelium-independent vasodilation.

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