scholarly journals Apolipoprotein(a) stimulates nuclear translocation of β-catenin: a novel pathogenic mechanism for lipoprotein(a)

2013 ◽  
Vol 24 (3) ◽  
pp. 210-221 ◽  
Author(s):  
Taewoo Cho ◽  
Rocco Romagnuolo ◽  
Corey Scipione ◽  
Michael B. Boffa ◽  
Marlys L. Koschinsky
Keyword(s):  
Endothelial Cells ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Vascular Endothelial Cell ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Endothelial Cell Function ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Cox 2

Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease risk. This may be attributable to the ability of Lp(a) to elicit endothelial dysfunction. We previously reported that apolipoprotein(a) (apo(a); the distinguishing kringle-containing component of Lp(a)) elicits cytoskeletal rearrangements in vascular endothelial cells, resulting in increased cellular permeability. These effects require a strong lysine-binding site (LBS) in apo(a). We now report that apo(a) induces both nuclear β-catenin–mediated cyclooxygenase-2 (COX-2) expression and prostaglandin E2 secretion, indicating a proinflammatory role for Lp(a). Apo(a) caused the disruption of VE-cadherin/β-catenin complexes in a Src-dependent manner, decreased β-catenin phosphorylation, and increased phosphorylation of Akt and glycogen synthase kinase-3β, ultimately resulting in increased nuclear translocation of β-catenin; all of these effects are downstream of apo(a) attenuation of phosphatase and tensin homologue deleted on chromosome 10 activity. The β-catenin–mediated effects of apo(a) on COX-2 expression were absent using a mutant apo(a) lacking the strong LBS. Of interest, the normal and LBS mutant forms of apo(a) bound to human umbilical vein endothelial cells in a similar manner, and the binding of neither was affected by lysine analogues. Taken together, our findings suggest a novel mechanism by which apo(a) can induce proinflammatory and proatherosclerotic effects through modulation of vascular endothelial cell function.

Peroxynitrite increases iNOS through NF-κB and decreases prostacyclin synthase in endothelial cells

2002 ◽  
Vol 282 (2) ◽  
pp. C395-C402 ◽  
Author(s):  
Christy-Lynn M. Cooke ◽  
Sandra T. Davidge
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Reactivity ◽  
Cell Function ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Cell Nuclei ◽  
Endothelial Cell Function ◽  
Protein Mass ◽  
Prostacyclin Synthase

Peroxynitrite, a marker of oxidative stress, is elevated in conditions associated with vascular endothelial cell dysfunction, such as atherosclerosis, preeclampsia, and diabetes. However, the effects of peroxynitrite on endothelial cell function are not clear. The endothelium-derived enzymes nitric oxide synthase (NOS) and prostaglandin H synthase (PGHS) mediate vascular reactivity and contain oxidant-sensitive isoforms (iNOS and PGHS-2) that can be induced by nuclear factor (NF)-κB activation. We investigated the effect(s) of peroxynitrite on NOS and PGHS pathways in endothelial cells. We hypothesized that peroxynitrite will increase levels of iNOS and PGHS-2 through activation of NF-κB. Western immunoblots of endothelial cells show that 3-morpholinosydnonimine (SIN-1; 0.5 mM), a peroxynitrite donor, increased iNOS protein mass, which can be inhibited by pyrroline dithiocarbamate (an NF-κB inhibitor) (167 ± 24.2 vs. 78 ± 19%, P < 0.05, n = 6). SIN-1 treatment also significantly increased NF-κB translocation into endothelial cell nuclei (135 ± 10%, P < 0.05). Endothelial NOS, PGHS-1, and PGHS-2 protein levels were not altered by SIN-1. However, prostacyclin synthase protein mass, but not mRNA, was significantly reduced in SIN-1-treated endothelial cells (78 ± 8.9%, P < 0.05). Our results illustrate novel mechanisms through which peroxynitrite may modulate vascular endothelial function.

scholarly journals Vialinin A, an Edible Mushroom-Derived p-Terphenyl Antioxidant, Prevents VEGF-Induced Neovascularization In Vitro and In Vivo

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Himangshu Sonowal ◽  
Kirtikar Shukla ◽  
Sumedha Kota ◽  
Ashish Saxena ◽  
Kota V. Ramana
Keyword(s):  
Nuclear Translocation ◽  
Vascular Endothelial Cell ◽  
Natural Antioxidants ◽  
Edible Mushroom ◽  
Tube Formation ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
In Vivo Models

Increased side toxicities and development of drug resistance are the major concern for the cancer chemotherapy using synthetic drugs. Therefore, identification of novel natural antioxidants with potential therapeutic efficacies is important. In the present study, we have examined how the antioxidant and anti-inflammatory activities of vialinin A, a p-terphenyl compound derived from Chinese edible mushroomT. terrestrisandT. vialis, prevents human umbilical vascular endothelial cell (HUVEC) neovascularization in vitro and in vivo models. Pretreatment of HUVECs with vialinin A prevents vascular endothelial growth factor- (VEGF) induced HUVEC cell growth in a dose-dependent manner. Further, vialinin A also inhibits VEGF-induced migration as well as tube formation of HUVECs. Treatment of HUVECs prevents VEGF-induced generation of reactive oxygen species (ROS) and malondialdehyde (MDA) and also inhibits VEGF-induced NF-κB nuclear translocation as well as DNA-binding activity. The VEGF-induced release of various angiogenic cytokines and chemokines in HUVECs was also significantly blunted by vialinin A. Most importantly, in a mouse model of Matrigel plug assay, vialinin A prevents the formation of new blood vessels and the expression of CD31 and vWF. Thus, our results indicate a novel role of vialinin A in the prevention of neovascularization and suggest that anticancer effects of vialinin A could be mediated through its potent antioxidant and antiangiogenic properties.

Human apolipoprotein A-I induces cyclooxygenase-2 expression and prostaglandin I-2 release in endothelial cells through ATP-binding cassette transporter A1

2011 ◽  
Vol 301 (3) ◽  
pp. C739-C748 ◽  
Author(s):  
Donghui Liu ◽  
Liang Ji ◽  
Xunliang Tong ◽  
Bing Pan ◽  
Jing-Yan Han ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Cyclooxygenase 2 ◽  
Mitogen Activated Protein Kinase ◽  
Atp Binding ◽  
Dependent Manner ◽  
Atp Binding Cassette Transporter ◽  
Apolipoprotein A ◽  
Cox 2 ◽  
Atp Binding Cassette

High-density lipoprotein (HDL) can induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells to exert multiple antiatherogenic functions. This effect has been attributed mainly to the role of sphingosine-1-phosphate (S1P) integrated in HDL. However, whether apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, could induce COX-2 expression and PGI-2 release still remains unclear. In the present study, we selectively delipidated HDL and confirmed that apoA-I could facilitate COX-2 expression and PGI-2 production in human umbilical vein endothelial cells (HUVECs). ApoA-I, but not trypsinized apoA-I, induced COX-2 expression in a time- and dose-dependent manner consistent with a key role for apoA-I in this process. Additionally, cotreatment of apoA-I with S1P further enhanced COX-2 expression and PGI-2 production in HUVECs. These effects triggered by apoA-I were not inhibited by pertussis toxin, consistent with SIP receptor independent pathway for apoA-I effect. Moreover, we demonstrated that the activation of p38 mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK) 1/2, and JAK2 pathways by apoA-I was involved in the expression of COX-2 and the release of PGI-2 in HUVECs, and these effects were inhibited by their specific inhibitors, respectively. Small interfering RNA experiments showed that ATP binding-cassette transporter A1 (ABCA1) was required for COX-2 expression and PGI-2 release induced by apoA-I. Thus our results indicate that apoA-I induces COX-2 expression and PGI-2 release through ABCA1 and the activation of intracellular p38 MAPK, ERK1/2, as well as JAK2 pathways, and apoA-I can reinforce these effects with S1P in HUVECs. These novel effects of apoA-I could in part mediate antiatherogenic effects of HDL.

scholarly journals Low Concentration of S100A8/9 Promotes Angiogenesis-Related Activity of Vascular Endothelial Cells: Bridges among Inflammation, Angiogenesis, and Tumorigenesis?

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Changyou Li ◽  
Siyuan Li ◽  
Changkai Jia ◽  
Lingling Yang ◽  
Zicheng Song ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial Cell ◽  
Tumor Development ◽  
Inflammatory Cells ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Low Concentration ◽  
Huvec Cells

Previous studies showed that several members of the S100A family are involved in neovascularization and tumor development. This study checked whether low concentrations of S100A8 or S100A9 has any effect on the behaviour of vascular endothelial cells. A human umbilical vascular endothelial cell (HUVEC) line was used to measure vascular endothelial cell bioactivity related to angiogenesis, such as cell proliferation, migration, and vessel formation. In the low concentration range up to 10 μg/mL, either each alone or in combination, S100A8 and S100A9 proteins promoted proliferation of HUVEC cells in a dose-dependent manner. The presence of both proteins in culture showed additive effects over each single protein. Both proteins enhanced HUVEC cells to migrate across the transwell membrane and to form tube-like structures on the Matrigel surface. When mixed in Matrigel and injected subcutaneously in Balb/c mice, both proteins increased vessel development in the gel plugs. Microarray assay of HUVEC cells treated with 10 μg/mL S100A8 revealed that ribosome pathway, pathogenicEscherichia coliinfection pathway, apoptosis, and stress response genes were modulated by S100A8 treatment. We propose that S100A8 and S100A9 proteins from either infiltrating inflammatory cells or tumor cells play an important role in the interplay among inflammation, angiogenesis, and tumorigenesis.

scholarly journals Dehydroepiandrosterone Stimulates Endothelial Proliferation and Angiogenesis through Extracellular Signal-Regulated Kinase 1/2-Mediated Mechanisms

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 889-898 ◽  
Author(s):  
Dongmin Liu ◽  
Mary Iruthayanathan ◽  
Laurie L. Homan ◽  
Yiqiang Wang ◽  
Lingling Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Vascular Function ◽  
Nuclear Translocation ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Vascular Effect ◽  
Endothelial Proliferation ◽  
Ribosomal S6 Kinase

Dehydroepiandrosterone (DHEA) activates a plasma membrane receptor on vascular endothelial cells and phosphorylates ERK 1/2. We hypothesize that ERK1/2-dependent vascular endothelial proliferation underlies part of the beneficial vascular effect of DHEA. DHEA (0.1–10 nm) activated ERK1/2 in bovine aortic endothelial cells (BAECs) by 15 min, causing nuclear translocation of phosphorylated ERK1/2 and phosphorylation of nuclear p90 ribosomal S6 kinase. ERK1/2 phosphorylation was dependent on plasma membrane-initiated activation of Gi/o proteins and the upstream MAPK kinase because the effect was seen with albumin-conjugated DHEA and was blocked by pertussis toxin or PD098059. A 15-min incubation of BAECs with 1 nm DHEA (or albumin-conjugated DHEA) increased endothelial proliferation by 30% at 24 h. This effect was not altered by inhibition of estrogen or androgen receptors or nitric oxide production. There was a similar effect of DHEA to increase endothelial migration. DHEA also increased the formation of primitive capillary tubes of BAECs in vitro in solubilized basement membrane. These rapid DHEA-induced effects were reversed by the inhibition of either Gi/o-proteins or ERK1/2. Additionally, DHEA enhanced angiogenesis in vivo in a chick embryo chorioallantoic membrane assay. These findings indicate that exposure to DHEA, at concentrations found in human blood, causes vascular endothelial proliferation by a plasma membrane-initiated activity that is Gi/o and ERK1/2 dependent. These data, along with previous findings, define an important vascular endothelial cell signaling pathway that is activated by DHEA and suggest that this steroid may play a role in vascular function.

Surface-retained tPA is essential for effective fibrinolysis on vascular endothelial cells

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3182-3185 ◽  
Author(s):  
Yuko Suzuki ◽  
Hideki Yasui ◽  
Tomasz Brzoska ◽  
Hideo Mogami ◽  
Tetsumei Urano
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Enzymatic Activity ◽  
De Novo ◽  
Vascular Endothelial Cells ◽  
Secretory Granules ◽  
Vascular Endothelial Cell ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Vascular Endothelial

Abstract In a previous study, we demonstrated unique secretory dynamics of tissue plasminogen activator (tPA) in which tPA was retained on the cell surface in a heavy chain–dependent manner after exocytosis from secretory granules in vascular endothelial cells. Here, we examined how retained tPA expresses its enzymatic activity. Retained tPA effectively increased the lysine binding site–dependent binding of plasminogen on the cell surface and pericellular area; this was abolished by inhibition of enzymatic activity of either tPA or plasmin, which suggests that de novo generation of carboxyl-terminal lysine as a consequence of degradation of surface/pericellular proteins by plasmin is essential. Retained tPA initiated zonal clot lysis of a fibrin network that had been formed on vascular endothelial cells, which was preceded by the binding of plasminogen to the lysis front. Our results provide evidence that secreted and retained tPA is essential for maintaining both high fibrinolytic activity and effective clot lysis on the vascular endothelial cell surface.

Bradykinin activates the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway in vascular endothelial cells: localization of JAK/STAT signalling proteins in plasmalemmal caveolae

2000 ◽  
Vol 351 (1) ◽  
pp. 257-264 ◽  
Author(s):  
Hong JU ◽  
Virginia J. VENEMA ◽  
Haiying LIANG ◽  
M. Brennan HARRIS ◽  
Rong ZOU ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Serine Phosphorylation ◽  
Dependent Manner ◽  
Endothelial Cell Function ◽  
Signal Transducers ◽  
Stat Pathway ◽  
Signal Transducers And Activators

Bradykinin (BK) is an important physiological regulator of endothelial cell function. In the present study, we have examined the role of the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in endothelial signal transduction through the BK B2 receptor (B2R). In cultured bovine aortic endothelial cells (BAECs), BK activates Tyk2 of the JAK family of tyrosine kinases. Activation results in the tyrosine phosphorylation and subsequent nuclear translocation of STAT3. BK also activates the mitogen-activated p44 and p42 protein kinases, resulting in STAT3 serine phosphorylation. Furthermore, Tyk2 and STAT3 form a complex with the B2R in response to BK stimulation. Under basal conditions, Tyk2, STAT3 and the B2R are localized either partially or entirely in endothelial plasmalemmal caveolae. Following BK stimulation of BAECs, however, the B2R and STAT3 are translocated out of caveolae. Taken together, these data suggest that BK activates the JAK/STAT pathway in endothelial cells and that JAK/STAT signalling proteins are localized in endothelial caveolae. Moreover, caveolar localization of the B2R and STAT3 appears to be regulated in an agonist-dependent manner.

scholarly journals Combined Treatment of Hydroxytyrosol with Carbon Monoxide-Releasing Molecule-2 Prevents TNFα-Induced Vascular Endothelial Cell Dysfunction through NO Production with Subsequent NFκB Inactivation

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Houda Zrelli ◽  
Che Wei Wu ◽  
Nahla Zghonda ◽  
Hidehisa Shimizu ◽  
Hitoshi Miyazaki
Keyword(s):  
Carbon Monoxide ◽  
Nuclear Translocation ◽  
Vascular Endothelial Cells ◽  
Combined Treatment ◽  
Vascular Endothelial Cell ◽  
Therapeutic Benefit ◽  
Cellular Damage ◽  
No Production ◽  
Dependent Manner ◽  
Vascular Endothelial

This study investigated the atheroprotective properties of olive oil polyphenol, hydroxytyrosol (HT), in combination with carbon monoxide-releasing molecule-2 (CORM-2) that acts as a carbon monoxide donor using vascular endothelial cells (VECs). Our results showed that CORM-2 could strengthen the cytoprotective and anti-apoptotic effects of HT against TNFα-induced cellular damage by enhancing cell survival and the suppression of caspase-3 activation. While HT alone attenuated NFκBp65 phosphorylation and IκBαdegradation triggered by TNFαin a dose-dependent manner, combined treatment of HT with CORM-2 but not iCORM-2 nearly completely blocked these TNFαeffects. Furthermore, combined action of both compounds results in the inhibition of NFκB nuclear translocation. Results also indicate that both compounds time-dependently increased eNOS phosphorylation levels and the combination of HT with CORM-2 was more effective in enhancing eNOS activation and NO production in VECs. The NOS inhibitor, L-NMMA, significantly suppressed the combined effects of HT and CORM-2 on TNFα-triggered NFκBp65 and IκBαphosphorylation as well as decreased cell viability. Together, these data suggest that carbon monoxide-dependent regulation of NO production by the combination of HT with CORM-2 may provide a therapeutic benefit in the treatment of endothelial dysfunction and atherosclerosis.

ALTERATIONS IN VASCULAR ENDOTHELIAL CELL FUNCTION BY OXYGEN-FREE RADICALS

1987 ◽  
Author(s):  
M Shatos ◽  
J Doherty ◽  
D Allen ◽  
J Hoak
Keyword(s):  
Endothelial Cells ◽  
Free Radicals ◽  
Endothelial Cell ◽  
Xanthine Oxidase ◽  
Cell Function ◽  
Oxygen Free Radicals ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Endothelial Cell Function ◽  
Platelet Adherence

The vascular endothelium is a target for oxidant-induced damage in many disease states including hyperoxia, inflammation, ischemia and reperfusion injury. However, little is known concerning oxidant injury to endothelial cells and its relationship to hemostasis. Our studies have focused on the ability of oxygen free radicals to injure and/or alter selected vascular endothelial cell functions pertinent to the regulation of hemostasis. Xanthine and xanthine oxidase, a well-characterized generating system for the production of the superoxide anion radical (O− 2) was used to sublethally injure human umbilical vein endothelial cells (HUVE) in vitro. We examined the effects of a 15 min exposure of HUVE cells to xanthine (50μM), and xanthine oxidase (2.5-100mU) (previously determined to be non-toxic using trypan blue dye exclusion) on platelet adherence, and prostacyclin release using established assays. The antioxidant enzymes superoxide dismutase (SOD) 200μg/ml and catalase 50μg/ml were added to endothelium incubation systems to evaluate any protective effects upon O− 2-induced alterations. All experiments were conducted in a serum-free HEPES-Tyrode's buffer, pH 7.4 incubation system. Our results show that exposure of HUVE cells to sublethal concentrations of oxygen free radical generating systems causes significant enhancement of platelet adherence (65%) to injured endothelium. A 12-fold increase in prostacyclin release resulted after a 15 min treatment with xanthine and xanthine oxidase. The addition of exogenous PGI2 (150nM) to platelet-endothelial systems did not completely prevent the enhanced platelet adherence suggesting that lack of prostacyclin was not completely responsible for the adherence of platelets to O− 2 injured cells. When SOD and catalase, scavengers of O− 2 and H2O− 2, were added to treated cells, platelet adherence decreased by 42-77% and prostacyclin release approached that of control cultures. These data implicate an active participation of activated metabolites of molecular oxygen in the alteration of vascular endothelial cell function.

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