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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular endothelium plays a pivotal role in regulating the hemostatic system. Various cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are known to perturb endothelial cells to reduce antithrombogenicity. On the other hand, blood flow has been shown to affect the endothelium to maintain its antithrombogenicity under some levels of shear stress in the laminar flow system. We examined the role of hemodynamic forces on the vascular system under cytokine stimulation using a cone-plate type viscometer. Treatment of endothelial cells with either IL-1 beta or TNF-alpha under static conditions increased PAI-1, vWF and prostacyclin release, while t-PA secretion was unchanged. When cells were exposed to steady shear stress of 0, 6, 12, 18 and 24 dyne/cm2, the release of t-PA, t-PA-PAI complex and prostacyclin elevated with the increase of shear stress intensity, while a gradual decrease of total PAI-1 secretion was observed and vWF secretion was unchanged. On the contrary, active PAI-1 secretion was significantly decreased under the shear stress of over 18 dyne/cm2. Interestingly, cytokines, which did not affect t-PA secretion of resting cells, increased the t-PA secretion and had an additive effect on prostacyclin secretion with shear stress under the shear stress of over 18 dyne/cm2. PAI-1 elevation induced by cytokines was markedly abolished under the same shear forces. No additive effect was observed in the secretion of vWF. Thus, shear stress attenuates the alteration of the balance in the fibrinolytic and coagulation system induced by cytokines. These findings clearly indicate that hemodynamic forces play a crucial role in regulating the hemostatic activity in vivo.
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PMID:[Effect of shear stress on hemostatic regulation in endothelium]. 784 84

The acute release of tissue-type plasminogen activator t-PA from the vascular endothelium is of decisive importance for the prevention of intravascular fibrin deposits. A dose-dependent t-PA release from the isolated perfused vascular preparations may be induced by mediators (platelet-activating factor, bradykinin, histamine) adrenergic and cholinergic transmitters (isoprenaline, acetylcholine), thrombin, heparin and analogues, and 1-desamino-8-D-arginine-vasopression (DDAVP). Most of the compounds were shown to enhance the t-PA activity also in animal experiments (rats, rabbits, mini pigs). The pharmacologic stimulation of the t-PA release may be convenient for short-term thrombosis, prophylaxis and partial thrombolysis. Presently, this could only be achieved by unfractionated and low molecular weight heparins which have been shown to release t-PA.
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PMID:Pharmacological stimulation of t-PA release. 791 Sep 71

The acute release of tissue-type plasminogen activator (t-PA) activity and of von Willebrand Factor (vWF) antigen from vascular endothelium was studied ex vivo using the rat hindquarter isolated perfusion model. The release of these proteins has been reported to occur simultaneously in response to a variety of endothelial cell agonists including bradykinin, thrombin and platelet activating factor. It has therefore been suggested that similar endothelial cell pathways and mechanisms are involved in the release of t-PA and vWF in vivo. This paper shows that the releases of t-PA and of vWF are not always closely linked and may depend on the agonist utilized to effect release. In our hands, the bradykinin-induced release of these proteins appears to be essentially identical, but this is not true for adenosine diphosphate (ADP). Rather, ADP is capable of causing the acute release of t-PA without the simultaneous release of vWF in the ex vivo rat hindquarter model. This indicates that the bradykinin- and ADP-induced pathways for t-PA release are probably distinct and that the releases of t-PA and vWF are not as closely linked as previously believed.
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PMID:Adenosine diphosphate stimulates the endothelial release of tissue-type plasminogen activator but not von Willebrand factor from isolated-perfused rat hind limbs. 816 98

Since basic fibroblast growth factor (bFGF) modulates the functions of vascular endothelial cells, we hypothesized that this factor may be involved in the regulation of the blood coagulation-fibrinolytic system mediated by the cells. Confluent cultures of vascular endothelial cells from human umbilical vein were treated with recombinant human bFGF (bFGF) in a serum-free medium and the content of tissue plasminogen activator antigen (t-PA:Ag) in the medium was determined by EIA. Treatment with bFGF resulted in a significant decrease in the release of t-PA:Ag from the cells accompanied with a less t-PA activity in the medium. In contrast, the t-PA:Ag release from human aortic endothelial cells was significantly increased by bFGF. The bFGF-induced decrease in the t-PA:Ag release from the venous endothelial cells was completely blocked by anti-bFGF antibody. The incorporation of [3H]leucine into the acid-insoluble fraction of the cells was significantly increased by bFGF; however, the activity of lactate dehydrogenase leaked into the medium was significantly decreased, suggesting that the suppression of the t-PA:Ag release caused by bFGF in the venous endothelial cells was not due to either a nonspecific inhibition of protein synthesis or a nonspecific cell damage. Since bFGF is postulated to be released from damaged endothelial cells, the present data suggest the regulation by bFGF of hemostasis mediated by endothelial cells when the vascular endothelium was damaged.
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PMID:Basic fibroblast growth factor suppresses tissue plasminogen activator release from cultured human umbilical vein endothelial cells but enhances that from cultured human aortic endothelial cells. 819 18

The plasminogen activator systems in the blood, the coagulation system, and the complement pathways are reviewed. The review describes the role of the vascular intima in activation of coagulation and fibrinolysis and the interrelations between the complement system and haemostatic mechanisms. Physiological activation of fibrinolysis may be triggered by and limited to fibrin because of a special affinity of plasminogen and plasminogen activators. The binding of plasminogen to fibrin is regulated by histidine-rich glycoprotein, and the primary physiological inhibitor of generated plasmin is alpha 2-antiplasmin and especially the plasminogen-binding form of this immediate plasmin inhibitor. Plasminogen activator inhibitors in the blood, that is, notably plasminogen activator inhibitor type 1 (PAI-1), bind circulating tissue-type plasminogen activator (t-PA). However, local fibrinolysis in vivo mediated by t-PA may be independent of complex formation between plasminogen activator inhibitors and t-PA in the fluid phase. Circulating plasminogen activator inhibitors might regulate fibrinolysis by increasing the clearance of t-PA from the blood. The urokinase-type and factor XII-dependent fibrinolytic proactivator system can be activated following t-PA-mediated generation of plasmin, and could thus serve as an amplification system of t-PA-induced fibrinolysis. It is claimed that the as yet uncharacterized proactivator is essential for optimal generation of plasminogen activator activity by the factor XII-dependent fibrinolytic system. The normal antithrombotic condition of the vascular intima probably results from lack of tissue factor activity and the presence of significant antithrombotic components comprising, among others, antithrombin III and the protein C-protein S system. A number of pathophysiologic stimuli, notably mediators of the acute phase response such as the cytokines interleukin-1 and tumour necrosis factor-alpha (cachectin), have the potential to induce the vascular endothelium to express procoagulant activity. Vascular endothelium promoting coagulant activity releases increased amounts of t-PA antigen and PAI-1 antigen into the circulation, and elevated levels in the blood of both may be regarded as a marker of a generalized procoagulant condition involving the vascular endothelium. In a prospective study in patients with unstable angina pectoris, patients in whom disease progresses and acute myocardial infarction develops, have increased amounts of t-PA antigen and PAI-1 antigen in the blood. This suggests that the procoagulant potential and atherosclerotic process of the vascular intima is more pronounced in the risk group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibrinolysis in patients with acute ischaemic heart disease. With particular reference to systemic effects of tissue-type plasminogen activator treatment on fibrinolysis, coagulation and complement pathways. 822 63

Oversulfated fucoidan fragments (20-40 and 40-60 kDa) were prepared, and their fibrinolytic and anticoagulant activities were compared with those of oversulfated fucoidan (100-130 kDa) reported previously [Soeda et al., Biochem. Pharmacol. 43, 1853-1858, 1992]. The results of these experiments indicated that the in vitro abilities of oversulfated fucoidan to stimulate tissue plasminogen activator (t-PA)-catalyzed plasminogen activation and to potentiate thrombin inhibition by antithrombin III or heparin cofactor II decreased with a decrease in its molecular size. However, the preventive effects of both fucoidan fragments on endotoxin-induced hepatic vein thrombosis in hyperlipemic rats were almost the same as that of oversulfated fucoidan (100-130 kDa). We also found that, unlike heparin treatment, the concentrations of serum and vascular endothelium t-PA in rats treated with oversulfated fucoidan or its fragments (1 mg each/kg/week) were maintained at normal levels. The 20-40 and 40-60 kDa fragments had an ability to decrease the elevated levels of serum cholesterol in hyperlipemic rats, whereas the 100-130 kDa fucoidan derivative did not. These results suggest that oversulfated fucoidan and its fragments have another function(s), besides the regulation of blood coagulation and fibrinolysis, and are of therapeutic benefit for the prevention of thrombus formation in hyperlipemia.
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PMID:Preparation of oversulfated fucoidan fragments and evaluation of their antithrombotic activities. 830 63

Glucocorticoids reduce prostaglandin synthesis in cultured vascular endothelium, but their effects on other haemostatic functions are unclear. We examined the effects of dexamethasone and cyclosporin A (CSA) on cultured human umbilical vein endothelial cells (HUVEC). One, 10 and 50 micrograms/ml CSA and 1 microgram/ml dexamethasone (Dx) were added to the culture medium for 3 h, 3 days and 6 days and compared with HUVEC cultured in medium and serum alone. After assay of accumulated release of tissue type plasminogen activator (t-PA) and endothelin 1 (ET), cells were stimulated with 1 U/ml of human thrombin for 1 h and medium collected for RIA of 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), thrombospondin (TSP), von Willebrand factor (vWf) and ELISA of plasminogen activator inhibitor 1 (PAI-1). CSA at 1 microgram/ml modestly reduced release of prostacyclin (PGI2) but had no reproducible effects on other metabolites. CSA at 10 and 50 micrograms/ml inhibited cell growth and thrombin stimulated release of PGI2 in a time- and dose-dependent manner. Inhibition of other endothelial metabolites was also observed at CSA 10 > micrograms/ml. Dexamethasone 1 microgram/ml reduced both cell number and PGI2 release and increased thrombin stimulated release of vWf, TSP and PAI-1 with increases in t-PA and endothelin 1 in the medium. CSA 1 microgram/ml and dexamethasone 1 microgram/ml together were additive in reducing PGI2 release and increasing PAI-1 secretion. These observations suggest a role for endothelial dysfunction in the hypertensive and thrombotic complications observed in steroid treated patients with CSA potentially contributing to such complications.
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PMID:Effects of cyclosporin A and dexamethasone on haemostatic and vasoactive functions of vascular endothelial cells. 858 11

Experimental and clinical observation suggest that patients with primary biliary cirrhosis (PBC) have endothelial dysfunction. Postischemic digital blood flow, nailfold capillaroscopy, von Willebrand factor (vWf) and tissue-type plasminogen activator (t-PA) plasma levels were examined in 59 PBC patients. Forty-six subjects (15 with liver diseases other than PBC, 11 hypercholesterolemics, 20 healthy subjects) served as controls. PBC versus healthy controls (209.8 +/- 1.4% and 16.54 +/- 1.44 ng/ml vs. 120.2 +/- 1.4% and 9.91 +/- 1.49 ng/ml; p<0.001) and related to bilirubin (r = 0.38, p<0.02; r = 0.47, p<0.0005, respectively). vWf was also increased in other liver diseases (249.9 +/- 1.7%; p<0.001) and related to bilirubin (r = 0.59, p<0.05). Postischemic finger blood flow negatively correlated with vWf(p<0.05 or less). Our data indicate that PBC patients have microvascular disease. Whether vessels other than those of the fingers were involved remained unclear. vWf and t-PA might reflect a dysfunction of teh hepatic vascular endothelium.
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PMID:Vascular impairment in patients with primary biliary cirrhosis. 865 55

Markers of endothelial cell activation were measured in 28 patients presenting with various forms of limited or focal type cutaneous vasculitis. Plasma levels of tissue plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor type 1 antigen (PAI-1:Ag) and PAI-1 activity, fibrin plate, von Willebrand factor antigen (vWF:Ag), tissue factor (TF) and soluble thrombomodulin (sTM) were measured. In comparison with the control group (n = 20) there was a significant increase in t-PA:Ag, vWF:Ag and TF (P < 0.05, Mann-Whitney U-test) in the cutaneous vasculitis group. This study confirms that measurable degrees of endothelial activation occur in cutaneous vasculitis. Cutaneous vasculitis includes a diverse group of clinical conditions, which are associated with inflammatory changes in cutaneous blood vessels with local fibrin deposition. The aetiology and pathogenesis of the majority of these entities remain unknown. Causative mediators are thought to include immune complexes, anti-endothelial cell antibodies, cytotoxic lymphocytes and viruses. Histologically, immune complexes and complement are frequently detected on the vessel wall, and serologically anti-endothelial antibodies are often detected in patients with vasculitis and in systemic lupus erythematosus (SLE) which correlate with the severity of cutaneous vasculitis, arthritis and nephritis. Lymphocyte-mediated toxicity to endothelial cells has been reported in a small number of patients with giant cell arteritis and Takayasu's arteritis. The vascular endothelium plays a central part in the control of haemostasis. Under physiological conditions endothelial cells present an anticoagulant surface to blood constituents, partially due to surface expression of heparan sulphate and thrombomodulin (TM). Heparan sulphate binds antithrombin III (ATIII), thereby accelerating inactivation of intrinsic coagulation enzymes. Thrombomodulin is an endothelial cell surface glycoprotein which promotes anticoagulation by forming a complex with thrombin which then activates protein C. Activated protein C together with a cofactor, protein S, inactivates FVa and FVIIIa. von Willebrand factor (vWF) is synthesized by endothelial cells, stored in Weibel-Palade bodies and released into the circulation upon endothelial stimulation. vWF mediates the binding of platelets to the subendothelium and is the carrier molecule for FVIIIC. The endothelium controls fibrinolysis by producing t-PA and its inhibitor PAI-1. Inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF) activate endothelial cells, causing a shift from an antithrombotic to prothrombotic state, including expression of tissue factor, increased synthesis of PAI-1 and decreased expression of TM. Fibrin deposition and intravascular thrombosis are seen in cutaneous vasculitis syndromes, suggesting local endothelial cell activation. The aim of this pilot study was to assess whether perturbation of the endothelium in cutaneous vasculitis could be detected in the patients' plasma samples. If so, further studies to assess any correlation in levels of these markers with disease activity might prove useful in the future.
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PMID:Endothelial cell activation in cutaneous vasculitis. 868 65

In experimental models, plasminogen activator-mediated degradation of the extracellular matrix is inhibited by type-1 plasminogen activator inhibitor (PAI-1). PAI-1 has also been shown to protect tumour stromal tissue from autoproteolytic activities and may thus substantially promote tumour growth and metastasis formation. Human renal cell carcinoma (RCC) cells express significant amounts of plasminogen activator activity. In the present study, the expression of its specific inhibitor PAI-1 has been investigated in 32 cases of RCC and compared with adjacent non-tumour renal tissues. RCC tissue exhibited higher levels of PAI-1, determined at both the antigen and the mRNA level by ELISA and Northern blot analysis respectively. Immunohistochemical analysis showed that PAI-1 antigen was primarily confined to tumour cells and vascular endothelium, a distribution similar to that previously reported for plasminogen activator activity in RCC. The close co-localization with endogenous plasminogen activator activity may be important in the regulation of RCC-associated proteolysis. The increased expression of PAI-1 and its predominant localization within the tumour may help to conserve tumour tissue integrity and may thus promote RCC progression and metastasis formation.
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PMID:Type-1 plasminogen activator inhibitor in human renal cell carcinoma. 869 52


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