scholarly journals Fibrin D-dimer impairs the accumulation and anticoagulant properties of heparan sulphate and stimulates secretion of plasminogen activator inhibitor-1 by rabbit coronary endothelial cells.

2003 ◽  
Vol 50 (1) ◽  
pp. 279-289 ◽  
Author(s):  
Natalia Yu Yevdokimova ◽  
Larisa D Veselovska ◽  
Genrietta K Gogolinska ◽  
Olexandra M Buchanevich ◽  
Galina V Kosyakova ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Heparan Sulphate ◽  
Plasminogen Activator Inhibitor ◽  
No Production ◽  
Plasminogen Activator Inhibitor 1 ◽  
Coronary Endothelial Cells ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
D Dimer

Fibrin split product D-dimer (DD) is most probably involved in the development of vascular disorders. At 1.5 microM concentration DD inhibited the incorporation of D-[1-(3)H]glucosamine hydrochloride and [2-(14)C]acetate x Na into pericellular heparan sulphate (HS) of rabbit coronary endothelial cells without affecting other groups of glycosaminoglycans (GAGs). At the same time, DD reduced HS ability to bind antithrombin (AT) and suppressed NO production. The effect of DD on pericellular GAGs was similar to that of N(omega)-methyl-L-arginine, the competitive inhibitor of endothelial NO synthase (eNOS). L-Ascorbic acid, eNOS activator, increased the level of endogenous NO in the DD-treated cells, and restored HS accumulation and antithrombin binding. It is suggested that DD influence on endothelial HS may be mediated by NO production. Another effect of DD, namely, stimulation of plasminogen activator inhibitor-1 (PAI-1) secretion did not depend on the NO level. The decreased HS content, reduced anticoagulant properties of HS, and increased PAI-1 secretion disorganized the endothelial matrix, and promoted fibrin formation and vascular damage. This points to DD as an important factor in the development of vascular disorders.

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.

Abstract T P75: Temporal Profiles of Plasminogen Activator Inhibitor-1 Concentration and Activity Changes in Circulation after Focal Stroke and Tissue Type Plasminogen Activator Administration in Rats

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Qi Liu ◽  
Xiang Fan ◽  
Helen Brogren ◽  
Ming-Ming Ning ◽  
Eng H Lo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Temporal Profiles ◽  
Activator Inhibitor ◽  
Pai 1

Aims: Plasminogen activator inhibitor-1 (PAI-1) is the main and potent endogenous tissue-type plasminogen activator (tPA) inhibitor, but an important question on whether PAI-1 in blood stream responds and interferes with the exogenously administered tPA remains unexplored. We for the first time investigated temporal profiles of PAI-1 concentration and activity in circulation after stroke and tPA administration in rats. Methods: Permanent MCAO focal stroke of rats were treated with saline or 10mg/kg tPA at 3 hours after stroke (n=10 per group). Plasma (platelet free) PAI-1 antigen and activity levels were measured by ELISA at before stroke, 3, 4.5 (1.5 hours after saline or tPA treatments) and 24 hours after stroke. Since vascular endothelial cells and platelets are two major cellular sources for PAI-1 in circulation, we measured releases of PAI-1 from cultured endothelial cells and isolated platelets after direct tPA (4 μg/ml) exposures for 60 min in vitro by ELISA (n=4 per group). Results: At 3 hours after stroke, both plasma PAI-1 antigen and activity were significantly increased (3.09±0.67, and 3.42±0.57 fold of before stroke baseline, respectively, all data are expressed as mean±SE). At 4.5 hours after stroke, intravenous tPA administration significantly further elevated PAI-1 antigen levels (5.26±1.24), while as expected that tPA neutralized most elevated PAI-1 activity (0.33±0.05). At 24 hours after stroke, PAI-1 antigen levels returned to the before baseline level, however, there was a significantly higher PAI-1 activity (2.51±0.53) in tPA treated rats. In vitro tPA exposures significantly increased PAI-1 releases into culture medium in cultured endothelial cells (1.65±0.08) and platelets (2.02±0.17). Conclution: Our experimental results suggest that tPA administration may further elevate stroke-increased blood PAI-1 concentration, but also increase PAI-1 activity at late 24 hours after stroke. The increased PAI-1 releases after tPA exposures in vitro suggest tPA may directly stimulate PAI-1 secretions from vascular walls and circulation platelets, which partially contributes to the PAI-1 elevation observed in focal stroke rats. The underlying regulation mechanisms and pathological consequence need further investigation.

scholarly journals THE FIBRINOLYTIC ALTERATION ASSOCIATED WITH DAILY ADMINISTRATION OF SILDENAFIL

2018 ◽  
Vol 11 (8) ◽  
pp. 107
Author(s):  
Fathelrahman M Hassan
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Daily Administration ◽  
Control Group ◽  
Average Weight ◽  
Plasminogen Activator Inhibitor 1 ◽  
Control Groups ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
D Dimer

Objective: The objective of this study was to determine the fibrinolytic alteration associated with daily administration of sildenafil.Methods: A total of 12 adult male rabbits without mortality rate had been fed standard and subdivided into four groups; their average weight was 1.5, 2.5, 1.9, and 2 kg randomly selected during the period of March 2012–July 2013. Depending on weight, the control groups (2.25 mg/1.5 kg day) and sildenafil groups (3 mg/2 kg/day, 2.85 mg/1.9 kg/day, and 1.7 mg/2.5 kg/day) were injected by normal saline and sildenafil concentration, respectively to create four groups, every group was composed of three rabbits; saline rabbit (control group, n=3) and sildenafil rabbits (sildenafil group, n=9). All rabbit’s plasma samples have been investigated for prothrombin time, activated partial thromboplastin time, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), prothrombin fragment 1+2, tissues plasminogen activator (tPA), plasmin antiplasmin (PAP), plasminogen, and D-dimer after 24 h of administration.Results: The PAP level was significantly (p<0.05) decreased following sildenafil injection. Sildenafil-injected (3 mg/ml) rabbits had decreased the means of PAI-1 and mean tPA, as early as 1-day post-injection, with a considerable lower PAP first determined 3 days after injection that continued into each rabbit 2 and 3.Conclusion: Better strategies are to initiate and manipulate this drug ought to reduce the chance of each thrombosis and hemorrhage, at the same time as minimizing the need for laboratory monitoring with the aid of the use of PAI-1, tPA, and PAP checks.

scholarly journals Plasminogen activator inhibitor-1 secretion of endothelial cells increases fibrinolytic resistance of an in vitro fibrin clot: evidence for a key role of endothelial cells in thrombolytic resistance

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4204-4213 ◽  
Author(s):  
S Handt ◽  
WG Jerome ◽  
L Tietze ◽  
RR Hantgan
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Time Dependent ◽  
Plasminogen Activator Inhibitor 1 ◽  
Necrosis Factor Alpha ◽  
Activator Inhibitor ◽  
Pai 1

Time-dependent thrombolytic resistance is a critical problem in thrombolytic therapy for acute myocardial infarction. Platelets have been regarded as the main source of plasminogen activator inhibitor-1 (PAI-1) found in occlusive platelet-rich clots. However, endothelial cells are also known to influence the fibrinolytic capacity of blood vessels, but their ability to actively mediate time-dependent thrombolytic resistance has not been fully established. We will show that, in vitro, tumor necrosis factor-alpha-stimulated endothelial cells secrete large amounts of PAI-1 over a period of hours, which then binds to fibrin and protects the clot from tissue plasminogen activator- induced fibrinolysis. In vivo, endothelial cells covering atherosclerotic plaques are influenced by cytokines synthesized by plaque cells. Therefore, we propose that continuous activation of endothelial cells in atherosclerotic blood vessels, followed by elevated PAI-1 secretion and storage of active PAI-1 in the fibrin matrix, leads to clot stabilization. This scenario makes endothelial cells a major factor in time-dependent thrombolytic resistance.

Thymosin β4 induces the synthesis of plasminogen activator inhibitor 1 in cultured endothelial cells and increases its extracellular expression

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1319-1324 ◽  
Author(s):  
Khalid N. I. Al-Nedawi ◽  
Malgorzata Czyz ◽  
Radoslaw Bednarek ◽  
Janusz Szemraj ◽  
Maria Swiatkowska ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Human Fibroblasts ◽  
Plasminogen Activator Inhibitor ◽  
Binding Activity ◽  
Mitogen Activated Protein Kinase ◽  
Thymosin Β4 ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Thymosin β4(Tβ4), a 4.9-kDa polypeptide primarily known as a main G-actin–sequestering peptide, is present in high concentrations in various cells and in the circulation. We have found that Tβ4 upregulates the expression of plasminogen activator inhibitor 1 (PAI-1) in endothelial cells measured both at the level of mRNA and protein synthesis. This effect seems to be cell specific and was not observed when other cells such as human fibroblasts, PC3, and U937 were tested. Tβ4 significantly activated the PAI-1 promoter in EA.hy 926 cells transiently transfected either with plasmid p800LUC containing PAI-1 promoter fragment (–800 to +71) or the PAI-1 promoter linked with green fluorescent protein. Tβ4 mediated up-regulation of PAI-1 involved activation of the mitogen-activated protein kinase cascade. Furthermore, Tβ4 enhanced c-Fos/c-Jun DNA-binding activity to the activator protein 1 (AP-1)–like element (–59 to –52). The specificity of this binding activity was demonstrated by competition electrophoretic mobility shift assay and after transfection of EA.hy 926 cells with the mutated PAI-1 promoter. Taken together, these data indicate that, in response to Tβ4 stimulation, AP-1 activity increases to enhance PAI-1 transcription through its unique AP-1–like element at –59 to –52 in the PAI-1 promoter.

scholarly journals Porphyromonas gingivalis Gingipains-Mediated Degradation of Plasminogen Activator Inhibitor-1 Leads to Delayed Wound Healing Responses in Human Endothelial Cells

2021 ◽  
pp. 1-14
Author(s):  
Li-Ting Song ◽  
Hiroyuki Tada ◽  
Takashi Nishioka ◽  
Eiji Nemoto ◽  
Takahisa Imamura ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Porphyromonas Gingivalis ◽  
Plasminogen Activator Inhibitor ◽  
Human Endothelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Delayed Wound Healing ◽  
Activator Inhibitor ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is constitutively produced by endothelial cells and plays a vital role in maintaining vascular homeostasis. Chronic periodontitis is an inflammatory disease characterized by bleeding of periodontal tissues that support the tooth. In this study, we aimed to determine the role of PAI-1 produced by endothelial cells in response to infections caused by the primary periodontal pathogen Porphyromonas gingivalis. We demonstrated that P. gingivalis infection resulted in significantly reduced PAI-1 levels in human endothelial cells. This reduction in PAI-1 levels could be attributed to the proteolysis of PAI-1 by P. gingivalis proteinases, especially lysine-specific gingipain-K (Kgp). We demonstrated the roles of these degradative enzymes in the endothelial cells using a Kgp-specific inhibitor and P. gingivalis gingipain-null mutants, in which the lack of the proteinases resulted in the absence of PAI-1 degradation. The degradation of PAI-1 by P. gingivalis induced a delayed wound healing response in endothelial cell layers via the low-density lipoprotein receptor-related protein. Our results collectively suggested that the proteolysis of PAI-1 in endothelial cells by gingipains of P. gingivalis might lead to the deregulation of endothelial homeostasis, thereby contributing to the permeabilization and dysfunction of the vascular endothelial barrier.

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.

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