scholarly journals Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy

2021 ◽  
Vol 22 (4) ◽  
pp. 1828
Author(s):  
Seo Young Kwak ◽  
Sunhoo Park ◽  
Hyewon Kim ◽  
Sun-Joo Lee ◽  
Won-Suk Jang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Endothelial Damage ◽  
Plasminogen Activator Inhibitor 1 ◽  
Monocyte Migration ◽  
Radiation Induced ◽  
Umbilical Vein Endothelial Cells ◽  
Pai 1

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.

scholarly journals Endothelial METTL3 (Methyltransferase-Like 3) Inhibits Fibrinolysis by Promoting PAI-1 (Plasminogen Activator Inhibitor-1) Expression Through Enhancing Jun Proto-Oncogene N6-Methyladenosine Modification

2021 ◽  
Author(s):  
Qin Bai ◽  
Yao Lu ◽  
Yanhua Chen ◽  
Han Zhang ◽  
Weiwei Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Real Time ◽  
Plasminogen Activator ◽  
Crucial Role ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Umbilical Vein Endothelial Cells ◽  
Activator Inhibitor ◽  
Pai 1

Objective: METTL3 (methyltransferase-like protein 3)-mediated N 6 -methyladenosine modification is the most abundant RNA modification on eukaryote mRNAs and plays a crucial role in diverse physiological and pathological processes. However, whether N 6 -methyladenosine modification has function in thrombosis is unknown. This study aims to determine the role of METTL3 in the endothelial cells-mediated thrombosis. Approach and Results: RNA-sequencing and real-time quantitative PCR revealed that the expression of PAI-1 (plasminogen activator inhibitor-1) was downregulated in METTL3 knockdown human umbilical vein endothelial cells. In vitro experiments showed that METTL3 suppressed fibrinolysis. Mechanically, RNA methylation sequencing and meRIP-quantitative real-time PCR showed that METTL3 catalyzed N 6 -methyladenosine modification on 3′ UTR of JUN mRNA. Western blotting analysis showed that METTL3 promoted JUN protein expression. Chromatin immunoprecipitation analysis demonstrated that JUN bound to the PAI-1 promoter in human umbilical vein endothelial cells. Furthermore, mice challenged with lipopolysaccharide resulted in higher METTL3 expression in vessels. Endothelial-specific knockdown of Mettl3 decreased expression of active PAI-1 in plasma and attenuated fibrin deposition in livers and lungs during endotoxemia. Conclusions: Our study reveals that METTL3-mediated N 6 -methyladenosine modification plays a crucial role in fibrinolysis and is an underlying target for the therapy of thrombotic disorders.

Characterization of Epitheloid Cells from Human Omentum: Comparison with Endothelial Cells from Umbilical Veins

1991 ◽  
Vol 66 (03) ◽  
pp. 361-367 ◽  
Author(s):  
Y Latron ◽  
M C Alessi ◽  
F George ◽  
F Anfosso ◽  
P Poncelet ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Hormonal Regulation ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Cell Types ◽  
Mesothelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Umbilical Vein Endothelial Cells ◽  
Pai 1

SummaryCapillary cells represent 95% of the vascular bed, and cells from large and micro-vessels do not express identical functions. In order to study the hormonal regulation of plasminogen activator inhibitor 1 (PAI-1) secretion by human capillary cells we used epithelial cells from omental tissue (HOTMEC). As their endothelial origin is subject to controversy, we attempted to determine their characteristics by comparing them to human umbilical vein endothelial cells (HUVEC). Morphological and biological criteria were studied. By phase contrast microscopy HOTMEC elicited a cobblestone pattern similar to HUVEC. Weibel-Palade bodies were not found in the cytoplasm with electron microscopy. Fluorescence microscopy studies indicated that HOTMEC took up acetylated-LDL more intensely than HUVEC, and showed no staining for von Willebrand factor. The phenotype of HOTMEC was studied by flow cytometry using monoclonal antibodies (mo Ab) directed against epitopes either specific for endothelial cells or for mesothelial cells. We showed that in our preparations only 10% of cells reacted with mo Ab specific for endothelial cells. About 60% of the HOTMEC were labelled with an antibody directed against mesothelial cells. HOTMEC expressed fibrinolytic factors. Tissue plasminogen activator (t-PA) levels in HOTMEC conditioned medium were 50 fold higher than those of HUVEC, and the PAI-1 secretions were identical in both cell types. Insulin which is known to increase PAI-1 synthesis by hepatocytes did not enhance the PAI-1 level either in HOTMEC or in HUVEC conditioned media. Our results suggested that morphological and functional methods did not allow discrimination between the cell types present in the omentum tissue. They also showed that the population obtained from the omental tissue by collagenase digestion is heterogeneous, with few cells expressing endothelial markers.

The Effect of Interleukin-4 on Tumour Necrosis Factor-Alpha Induced Expression of Tissue Factor and Plasminogen Activator Inhibitor-1 in Human Umbilical Vein Endothelial Cells

1993 ◽  
Vol 70 (06) ◽  
pp. 1037-1042 ◽  
Author(s):  
N B Martin ◽  
A Jamieson ◽  
D P Tuffin
Keyword(s):  
Tumour Necrosis ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Interleukin 4 ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Umbilical Vein Endothelial Cells ◽  
Activator Inhibitor ◽  
Necrosis Factor ◽  
Pai 1

SummaryThe pro-inflammatory cytokine tumour necrosis factor-a (TNF-α) is able to alter the haemostatic balance of human umbilical vein endothelial cells (HUVECs) towards that of a procoagulant and anti-fibrinolytic state. Treatment of HUVECs in culture with human recombinant TNF-α (0.5-50 U/ml; 6 h) significantly increased total cell expression of tissue factor (TF) 10-fold from 40 mU/well to 400-500 mU/well. Levels of plasminogen activator inhibitor-1 (PAI-1) antigen secreted from HUVECs also increased up to 2-fold in concentration-dependent fashion following addition of TNF-α (10-100 U/ml; 24 h). TNF-α induced total and cell surface expression of TF on HUVECs was significantly inhibited when the cells were pre-incubated with interleukin-4 (IL-4; p <0.001). This effect was time and concentration dependent. Pretreatment of HUVECs with IL-4 for 4 h had no significant effect, but increasing inhibition of total TF expression occurred after 8 and 16 h pre-incubations. Treatment with IL-4 at 20 and 200 U/ml significantly inhibited cell surface TF responses induced by TNF-α, whereas a low concentration (0.2 U/ml) was without effect. In contrast, the production of PAI-1 from HUVECs stimulated by TNF-α (50 U/ml) was unaffected by the presence and/or prior incubation with 200 U/ml IL-4. Thus, IL-4 may regulate the pro-coagulant but not the antifibrinolytic effects of TNF-α at sites of vascular inflammation.

scholarly journals Positions of Hydroxyl Groups in Chrysin are Critical for Inhibiting Plasminogen Activator Inhibitor-1 Release from Human Umbilical Vein Endothelial Cells

2017 ◽  
Vol 12 (4) ◽  
pp. 1934578X1701200
Author(s):  
Naoki Ohkura ◽  
Kumiko Ando ◽  
Yuko Takata ◽  
Shiho Kanai ◽  
Kenichi Ishibashi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Hydroxyl Groups ◽  
Plasminogen Activator Inhibitor 1 ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells ◽  
Activator Inhibitor ◽  
Pai 1

Chrysin suppresses the TNFa-induced increase in the secretion of plasma plasminogen activator inhibitor 1 (PAI-1), a risk factor for thrombotic diseases, from human umbilical vein endothelial cells (HUVECs). The present study aimed to determine the association between the location of the hydroxyl groups in chrysin to levels of PAI-1 in the medium of HUVEC stimulated with TNFα, We cultured HUVEC for 3 h in medium containing chrysin or various flavonoids and then stimulated them with TNFα (10 ng/mL) for 12 h. Levels of PAI-1 antigen measured using ELISA showed that chrysin significantly inhibited the PAI-1 increase with an IC50 of 15.6 μM. The flavones, galangin, baicalein, 5-hydroxyflavone, 6-hydroxyflavone, 7-hydroxyflavone and quercetin did not significantly inhibit the PAI-1 increase. Apigenin and luteolin were cytotoxic and thus their ability to inhibit PAI-1 production could not be evaluated. Chrysin also inhibited PAI-1 mRNA expression whereas the other compounds did not. Hydroxyl groups located in the A-5 and A-7 positions were essential for the inhibitory activity, which along with cytotoxicity, was significantly influenced by adding a third hydroxyl group.

Fluvastatin Inhibits Basal and Stimulated Plasminogen Activator Inhibitor 1, but Induces Tissue Type Plasminogen Activator in Cultured Human Endothelial Cells

2000 ◽  
Vol 84 (07) ◽  
pp. 59-64 ◽  
Author(s):  
Luciana Mussoni ◽  
Cristina Banfi ◽  
Luigi Sironi ◽  
Magda Arpaia ◽  
Elena Tremoli
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
De Novo ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Mrna Levels ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe effects of fluvastatin, a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) inhibitor, on the biosynthesis of tissue plasminogen activator (t-PA) and of its major physiological inhibitor (plasminogen activator inhibitor type 1, PAI-1) were investigated in cultured human umbilical vein endothelial cells (HUVEC). Fluvastatin (0.1 to 2.5 µM), concentration-dependently reduced the release of PAI-1 antigen by unstimulated HUVEC, subsequent to a reduction in PAI-1 steady-state mRNA levels and de novo protein synthesis. In contrast, it increased t-PA secretion.The drug also reduced PAI-1 antigen secreted in response to 10 µg/ml bacterial lipopolysaccharide (LPS), 100 U/ml tumour necrosis factor α (TNFα) or 0.1 µM phorbol myristate acetate (PMA).Mevalonate (100 µM), a precursor of isoprenoids, added to cells simultaneously with fluvastatin, suppressed the effect of the drug on PAI-1 both in unstimulated and stimulated cells as well as on t-PA antigen. Among intermediates of the isoprenoid pathway, all-trans-geranylgeraniol (5 µM) but not farnesol (10 µM) prevented the effect of 2.5 µM fluvastatin on PAI-1 antigen, which suggests that the former intermediate of the isoprenoid synthesis is responsible for the observed effects.

scholarly journals Regulation by Nitric Oxide of Endotoxin-Induced Tissue Factor and Plasminogen Activator Inhibitor-1 in Endothelial Cells

2002 ◽  
Vol 88 (12) ◽  
pp. 1060-1065 ◽  
Author(s):  
Ana Pérez-Ruiz ◽  
Ramón Montes ◽  
Francisco Velasco ◽  
Chary López-Pedrera ◽  
José Páramo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Tissue Factor ◽  
Plasminogen Activator ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
No Production ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe increase in nitric oxide (NO) production in lipopolysaccharide (LPS)-induced sepsis is thought to contribute to the development of shock. However, NO could also play an antithrombotic role. Little is known about the modulating effect of NO on the endothelial overexpression and production of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) occurring in endotoxemia. We analyzed the effect of N(G)-nitro-L-arginine-methyl-ester (L-NAME), an inhibitor of NO synthases, and S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a NO donor, on the expression and synthesis of TF and PAI-1 by LPS-challenged human umbilical vein endothelial cells (HUVEC): L-NAME enhanced the increase in TF mRNA and antigen levels (P <0.05) observed in LPS-treated HUVEC; SNAP down-regulated the LPSinduced TF increment (p <0.05). However, no effects of NO on regulation of the LPS-dependent increase in PAI-1 could be seen. Thus, NO could play an antithrombotic role in sepsis by down-regulating the endothelial overexpression and production of TF.

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