scholarly journals Oxidized LDL Suppresses NF-κB and Overcomes Protection from Apoptosis in Activated Endothelial Cells

2001 ◽  
Vol 12 (3) ◽  
pp. 456-463
Author(s):  
KATHRIN HEERMEIER ◽  
WOLFGANG LEICHT ◽  
ALOIS PALMETSHOFER ◽  
MARKUS ULLRICH ◽  
CHRISTOPH WANNER ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Cell Survival ◽  
Apoptotic Cell ◽  
Oxidized Ldl ◽  
Density Lipoprotein ◽  
Nuclear Factor Κb ◽  
Chronic Inflammatory Disease ◽  
Tnf Α ◽  
Induced Apoptosis

Abstract. Atherosclerosis is a chronic inflammatory disease associated with enhanced apoptotic cell death in vascular cells, partly induced by oxidized low-density lipoprotein (OxLDL). However, proinflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α) activate endothelial cells (EC) and inhibit apoptosis through induction of nuclear factor κB (NF-κB)-dependent genes. This study therefore investigated whether OxLDL or its component, lysophosphatidylcholine (LPC), interacts with the effect of LPS or TNF-α on cell survival. Human EC were incubated with LPS, TNF-α, OxLDL, or LPC alone or in combinations. OxLDL (100 to 200 μg/ml) and LPC (100 to 300 μM) induced apoptosis dose-dependently. LPS and TNF-α had no effect on cell survival in the presence or absence of OxLDL or LPC. LPS and TNF-α both induced the antiapoptotic gene A20, whereas OxLDL and LPC suppressed its induction. Expression of A20 is regulated by NF-κB. OxLDL and LPC dose-dependently suppressed NF-κB activity. For functional analysis, bovine EC were transfected with A20 encoding expression constructs in sense and antisense orientation. Bovine EC that overexpressed A20 were protected against OxLDL-induced apoptosis, whereas expression of antisense A20 rendered cells more sensitive to OxLDL. These results suggest that OxLDL not only induces cell death, as has been shown before, but also compromises antiapoptotic protection of activated EC. OxLDL sensitizes EC to apoptotic triggers by interfering with the induction of A20 during the inflammatory response seen in atherosclerotic lesions. This inhibition is based on repression of NF-κB activation. The effect may be caused by the OxLDL component LPC.

H2 inhibits TNF-α-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor κB activation in endothelial cells

2011 ◽  
Vol 33 (9) ◽  
pp. 1715-1722 ◽  
Author(s):  
Guohua Song ◽  
Hua Tian ◽  
Jia Liu ◽  
Hongle Zhang ◽  
Xuejun Sun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Tnf Α

scholarly journals Dihydrotestosterone Inhibits Lectin-Like Oxidized-LDL Receptor-1 Expression in Aortic Endothelial Cells via a NF-κB/AP-1-Mediated Mechanism

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3405-3415 ◽  
Author(s):  
Yang Qiu ◽  
Tomoko Tanaka ◽  
Hajime Nawata ◽  
Toshihiko Yanase
Keyword(s):  
Endothelial Cells ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Nuclear Factor Κb ◽  
High Cholesterol Diet ◽  
Sham Operation ◽  
Aortic Endothelial Cells ◽  
Aortic Endothelial

The mechanisms involved in the antiatherosclerotic effects of androgens are unclear. Although lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells plays critical roles in atherosclerosis, the effects of androgens on endothelial LOX-1 expression has not been examined. Therefore, to investigate the effects of dihydrotestosterone (DHT) on LOX-1 expression in rabbit aortic endothelial cells and cultured human aortic endothelial cells (HAEC), pellets containing DHT or placebo were sc implanted into 26 male New Zealand white rabbits at the time of castration or sham operation. The rabbits were then fed a high-cholesterol diet (HCD) for 2 wk. Microscopic examination of the aortic arch revealed that DHT significantly reduced HCD-induced LOX-1 expression in endothelial cells compared with placebo. In cultured HAEC, DHT at concentrations above 10−9 to 10−7 mol/liter inhibited TNFα-induced LOX-1 mRNA and protein expression. Deletion and mutation analysis of human LOX-1 promoter-luciferase constructs transfected into HAEC with an androgen receptor (AR) expression plasmid revealed that the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE; nucleotides −60/−53) contributed to the inhibitory effects of DHT on TNFα-induced LOX-1 expression. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that TNFα- and TPA-dependent enrichment of p65 and phosphorylated c-Jun in the TRE chromatin region was inhibited by DHT-AR. Consistent with these results, DHT also suppressed TPA-induced expression of LOX-1. In conclusion, DHT exerts antiatherosclerotic effects by suppressing endothelial LOX-1 expression. This effect is partly mediated by the suppression of nuclear factor-κB- and activator protein 1-dependent activation of the LOX-1 promoter.

scholarly journals Verocytotoxin-Induced Apoptosis of Human Microvascular Endothelial Cells

2001 ◽  
Vol 12 (4) ◽  
pp. 767-778
Author(s):  
ANTONETTA H. J. M. PIJPERS ◽  
PETRA A. VAN SETTEN ◽  
LAMBERTUS P. W. J. VAN DEN HEUVEL ◽  
KAREL J. M. ASSMANN ◽  
HENDRIKUS B. P. M. DIJKMAN ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Protein Synthesis ◽  
Endothelial Cell ◽  
Umbilical Vein ◽  
Microvascular Endothelial Cells ◽  
Tnf Α ◽  
Microvascular Endothelial ◽  
Induced Apoptosis ◽  
Umbilical Vein Endothelial Cells

Abstract. The pathogenesis of the epidemic form of hemolytic uremic syndrome is characterized by endothelial cell damage. In this study, the role of apoptosis in verocytotoxin (VT)-mediated endothelial cell death in human glomerular microvascular endothelial cells (GMVEC), human umbilical vein endothelial cells, and foreskin microvascular endothelial cells (FMVEC) was investigated. VT induced apoptosis in GMVEC and human umbilical vein endothelial cells when the cells were prestimulated with the inflammatory mediator tumor necrosis factor-α (TNF-α). FMVEC displayed strong binding of VT and high susceptibility to VT under basal conditions, which made them suitable for the study of VT-induced apoptosis without TNF-α interference. On the basis of functional (flow cytometry and immunofluorescence microscopy using FITC-conjugated annexin V and propidium iodide), morphologic (transmission electron microscopy), and molecular (agarose gel electrophoresis of cellular DNA fragments) criteria, it was documented that VT induced programmed cell death in microvascular endothelial cells in a dose- and time-dependent manner. Furthermore, whereas partial inhibition of protein synthesis by VT was associated with a considerable number of apoptotic cells, comparable inhibition of protein synthesis by cycloheximide was not. This suggests that additional pathways, independent of protein synthesis inhibition, may be involved in VT-mediated apoptosis in microvascular endothelial cells. Specific inhibition of caspases by Ac-Asp-Glu-Val-Asp-CHO, but not by Ac-Tyr-Val-Ala-Asp-CHO, was accompanied by inhibition of VT-induced apoptosis in FMVEC and TNF-α-treated GMVEC. These data indicate that VT can induce apoptosis in human microvascular endothelial cells.

scholarly journals Differential inhibition of oxidized LDL-induced apoptosis in human endothelial cells treated with different flavonoids

2005 ◽  
Vol 93 (5) ◽  
pp. 581-591 ◽  
Author(s):  
Yu-Jin Jeong ◽  
Yean-Jung Choi ◽  
Hyang-Mi Kwon ◽  
Sang-Wook Kang ◽  
Hyoung-Sook Park ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Umbilical Vein ◽  
Oxidized Ldl ◽  
Epigallocatechin Gallate ◽  
Ldl Oxidation ◽  
Toxic Dose ◽  
Induced Apoptosis

High plasma level of cholesterol is a well-known risk factor for atherosclerotic diseases. Oxidized LDL induces cellular and nuclear damage that leads to apoptotic cell death. We tested the hypothesis that flavonoids may function as antioxidants with regard to LDL incubated with 5 μm-Cu2+ alone or in combination with human umbilical vein endothelial cells (HUVEC). Cytotoxicity and formation of thiobarbituric acid-reactive substances induced by Cu2+-oxidized LDL were examined in the presence of various subtypes of flavonoid. Flavanols, flavonols and flavanones at a non-toxic dose of 50 μm markedly inhibited LDL oxidation by inhibiting the formation of peroxidative products. In contrast, the flavones luteolin and apigenin had no such effect, with >30 % of cells killed after exposure to 0.1 mg LDL/ml. Protective flavonoids, especially (−)-epigallocatechin gallate, quercetin, rutin and hesperetin, inhibited HUVEC nuclear condensation and fragmentation induced by Cu2+-oxidized LDL. In addition, immunochemical staining and Western blot analysis revealed that anti-apoptotic Bcl-2 expression was enhanced following treatment with these protective flavonoids. However, Bax expression and caspase-3 cleavage stimulated by 18 h incubation with oxidized LDL were reduced following treatment with these protective flavonoids. The down-regulation of Bcl-2 and up-regulation of caspase-3 activation were reversed by the cytoprotective flavonoids, (−)-epigallocatechin gallate, quercetin and hesperetin, at ≥10 μm. These results suggest that flavonoids may differentially prevent Cu2+-oxidized LDL-induced apoptosis and promote cell survival as potent antioxidants. Survival potentials of certain flavonoids against cytotoxic oxidized LDL appeared to stem from their disparate chemical structure. Furthermore, dietary flavonoids may have therapeutic potential for protecting the endothelium from oxidative stress and oxidized LDL-triggered atherogenesis.

scholarly journals Basic Fibroblast Growth Factor Selectively Enhances TNF-α—Induced Apoptotic Cell Death in Glomerular Endothelial Cells: Effects on Apoptotic Signaling Pathways

2000 ◽  
Vol 11 (12) ◽  
pp. 2199-2211
Author(s):  
UDO K. MESSMER ◽  
VERENA A. BRINER ◽  
JOSEF PFEILSCHIFTER
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Fibroblast Growth ◽  
Glomerular Endothelial Cells ◽  
Tnf Α

Abstract. Endothelial cell damage of glomeruli and kidney arterioles seems to play a pivotal role in several pathologic situations, such as Gram-negative sepsis, glomerulonephritis, and acute renal failure. Bacterial lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) have been identified as potent inducers of apoptotic cell death in bovine glomerular endothelial cells. Both agents elicited apoptotic DNA laddering within 12 to 24 h. Basic fibroblast growth factor (bFGF) was generally described as a protective factor for endothelial cells against radiation-, TNF-α—, and UV-light—induced programmed cell death. Therefore, whether bFGF also affects apoptosis of microvascular endothelial cells was questioned. Surprising was that simultaneous treatment of glomerular endothelial cells with bFGF and either LPS or TNF-α left LPS-induced death unaffected, whereas TNF-α—induced death induction was potentiated, amounting to 48.9 ± 6.3% versus 22.4 ± 4.3% DNA degradation with TNF-α alone. Comparably, acidic FGF also selectively potentiated TNF-α—induced apoptosis. In mechanistic terms, bFGF synergistically increased TNF-α—induced mitochondrial permeability transition, the release of cytochrome c from mitochondria to the cytosol, and upregulation of the proapoptotic protein Bak and significantly enhanced activation of caspase-8 protease activity. In contrast, stress-activated protein kinase and nuclear factor κB activation, which represent primary signals of TNF/TNF receptor interaction, downregulation of the antiapoptotic protein Bcl-xL, and caspase-3—like protease activation, were unaffected. As bFGF did not affect LPS-induced apoptotic cell death, bFGF also left LPS-induced Bak upregulation and Bcl-xL downregulation unaffected. The results point to a selective bFGF-mediated enhancement of distinct proapoptotic pathways induced by TNF-α in glomerular endothelial cells.

NF-κB activation and susceptibility to apoptosis after polyamine depletion in intestinal epithelial cells

2001 ◽  
Vol 280 (5) ◽  
pp. G992-G1004 ◽  
Author(s):  
Li Li ◽  
Jaladanki N. Rao ◽  
Barbara L. Bass ◽  
Jian-Ying Wang
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Nuclear Translocation ◽  
Intestinal Epithelial Cells ◽  
Apoptotic Cell ◽  
Binding Activity ◽  
Cell Renewal ◽  
Intestinal Epithelial ◽  
Tnf Α ◽  
Induced Apoptosis

The maintenance of intestinal mucosal integrity depends on a balance between cell renewal and cell death, including apoptosis. The natural polyamines, putrescine, spermidine, and spermine, are essential for mucosal growth, and decreasing polyamine levels cause G1 phase growth arrest in intestinal epithelial (IEC-6) cells. The present study was done to determine changes in susceptibility of IEC-6 cells to apoptosis after depletion of cellular polyamines and to further elucidate the role of nuclear factor-κB (NF-κB) in this process. Although depletion of polyamines by α-difluoromethylornithine (DFMO) did not directly induce apoptosis, the susceptibility of polyamine-deficient cells to staurosporine (STS)-induced apoptosis increased significantly as measured by changes in morphological features and internucleosomal DNA fragmentation. In contrast, polyamine depletion by DFMO promoted resistance to apoptotic cell death induced by the combination of tumor necrosis factor-α (TNF-α) and cycloheximide. Depletion of cellular polyamines also increased the basal level of NF-κB proteins, induced NF-κB nuclear translocation, and activated the sequence-specific DNA binding activity. Inhibition of NF-κB binding activity by sulfasalazine or MG-132 not only prevented the increased susceptibility to STS-induced apoptosis but also blocked the resistance to cell death induced by TNF-α in combination with cycloheximide in polyamine-deficient cells. These results indicate that 1) polyamine depletion sensitizes intestinal epithelial cells to STS-induced apoptosis but promotes the resistance to TNF-α-induced cell death, 2) polyamine depletion induces NF-κB activation, and 3) disruption of NF-κB function is associated with altered susceptibility to apoptosis induced by STS or TNF-α. These findings suggest that increased NF-κB activity after polyamine depletion has a proapoptotic or antiapoptotic effect on intestinal epithelial cells determined by the nature of the death stimulus.

Dual functional roles of Tie-2/angiopoietin in TNF-α-mediated angiogenesis

2004 ◽  
Vol 287 (1) ◽  
pp. H187-H195 ◽  
Author(s):  
Jian-Xiong Chen ◽  
Ying Chen ◽  
Laura DeBusk ◽  
Wenyu Lin ◽  
Pengnain Charles Lin
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Low Doses ◽  
Functional Roles ◽  
Akt Phosphorylation ◽  
Dual Functional ◽  
Tnf Α ◽  
Corneal Angiogenesis ◽  
High Doses ◽  
Induced Apoptosis

Inflammation and angiogenesis are associated with pathological disorders. TNF-α is a major inflammatory cytokine that also regulates angiogenesis. TNF-α has been shown to regulate Tie-2 and angiopoietin (Ang) expression, but the functional significance is less clear. In this study, we showed that TNF-α induced a weak angiogenic response in a mouse cornea assay. Systemic overexpression of Ang-1 or Ang-2 dramatically increased corneal angiogenesis induced by TNF-α. In the absence of TNF-α, neither Ang-1 nor Ang-2 promoted corneal angiogenesis. Low doses (0–25 ng/ml) of TNF-α increased vascular branch formation of cultured endothelial cells. Overexpression of Ang-1 or Ang-2 enhanced the effects of TNF-α. These data suggest that Tie-2 signaling synergistically amplifies and participates in TNF-α-mediated angiogenesis. In addition, high doses (≥50 ng/ml) of TNF-α induced apoptosis in endothelial cells, but addition of Ang-1 or Ang-2 significantly reduced cell death. Enhanced endothelial cell survival was correlated with Akt phosphorylation. Collectively, our data reveal dual functional roles of Tie-2: low doses enhance TNF-α-induced angiogenesis, and high doses attenuate TNF-α-induced cell death. The study provides evidence supporting a role for Tie-2 in inflammatory angiogenesis.

scholarly journals Bcl-3 Expression Promotes Cell Survival following Interleukin-4 Deprivation and Is Controlled by AP1 and AP1-Like Transcription Factors

2000 ◽  
Vol 20 (10) ◽  
pp. 3407-3416 ◽  
Author(s):  
Angelita Rebollo ◽  
Laure Dumoutier ◽  
Jean-Christophe Renauld ◽  
Angel Zaballos ◽  
Verónica Ayllón ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factors ◽  
Cell Survival ◽  
Binding Sites ◽  
Apoptotic Cell ◽  
Binding Activity ◽  
Interleukin 4 ◽  
Survival Factor ◽  
Induced Apoptosis

ABSTRACT We have analyzed the interleukin-4 (IL-4)-triggered mechanisms implicated in cell survival and show here that IL-4 deprivation induces apoptotic cell death but does not modulate Bcl-2 or Bcl-x expression. Since Bcl-x expression is insufficient to ensure cell survival in the absence of IL-4, we speculate that additional molecules replace the antiapoptotic role of Bcl-2 and Bcl-x in an alternative IL-4-triggered pathway. Cell death is associated with Bcl-3 downregulation and Bcl-3 expression blocks IL-4 deprivation-induced apoptosis, suggesting that Bcl-3 acts as a survival factor in the absence of growth factor. To characterize the IL-4-induced regulation of murine Bcl-3 expression, we cloned the promoter of this gene. Sequencing of the promoter showed no TATA box element but did reveal binding sites for AP1, AP1-like, and SP1 transcription factors. Retardation gels showed that IL-4 specifically induces AP1 and AP1-like binding activity and that mutation of these binding sites abolishes the IL-4-induced Bcl-3 promoter activity, suggesting that these transcription factors are important in Bcl-3 promoter transactivation. IL-4 deprivation induces downregulation of Jun expression and upregulation of Fos expression, both of which are proteins involved in the formation of AP1 and AP1-like transcription factors. Overexpression of Jun family proteins transactivates the promoter and restores Bcl-3 expression in the absence of IL-4 stimulation. Taken together, these data describe a new biological role for Bcl-3 and define the regulatory pathway implicated in Bcl-3 expression.

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