Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to investigate the significance of high circulating levels of von Willebrand factor (vWF), recently observed in patients with vascular diseases, we compared the plasma levels of vWF with those of tissue-type plasminogen activator (t-PA) and the platelet content of serotonin (5-HT) in 40 patients with Raynaud's phenomenon (RP), primary or associated to systemic sclerosis (SSc), and in 14 patients with chronic peripheral obstructive disease due to arteriosclerosis (PAOD). VWF and t-PA plasma levels were significantly increased (p < 0.001) in SSc (vWF: 158.2, range 116.3-305.0%; t-PA: 10.2, range 6.4-17.8 ng/ml). By contrast, normal plasma levels of both vWF (85.3, range 53.5-157.0%) and t-PA (6.5, range 2.7-9.3 ng/ml) were observed in primary RP. VWF and t-PA were normal in PAOD patients, compared with age-matched healthy controls (vWF: 143.0, range 57.0-204.0%; t-PA: 7.5, range 3.4-13.6, ng/ml). The platelet content of 5-HT was within the normal range (37.3-99.7 ng/10(8) platelets) in RP patients, but significantly reduced (P < 0.05) in PAOD patients (39.0, range 14.7-91.4). Our data suggest that the different pattern of circulating vWF and t-PA between SSc and arteriosclerotic patients may be related to a different endothelial cell involvement. Whether this increase may reflect active attempts of regeneration and repair, indicating endothelial cell viability rather than damage is a matter of speculation.
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PMID:Tissue-type plasminogen activator and von Willebrand factor plasma levels as markers of endothelial involvement in patients with Raynaud's phenomenon. 145 97

Lipoprotein (a) [Lp(a)] and plasminogen share a high degree of homology as recently evidenced by amino acid and deoxyribonucleic acid analysis. As Lp(a) is enzymatically inactive, it has been suggested that high levels of Lp(a) may suppress the profibrinolytic activity at the cell surface and increase the risk for arteriosclerosis and thrombosis by competitive inhibition of plasminogen. The present study evaluated whether high levels of Lp(a) influence thrombolytic therapy in patients with acute myocardial infarction. Forty-one patients with acute myocardial infarction received a combination low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) and human single-chain urokinase-type plasminogen activator (scu-PA). This regimen did not induce plasminemia or a lytic state as indicated by well-maintained levels of fibrinogen. Coronary patency was assessed angiographically 90 minutes after initiation of treatment. Thrombolysis was successful in 30 and unsuccessful in 11 patients. Patients with high Lp(a) levels (greater than or equal to 25 mg/dl) (n = 9) responded equally well to thrombolytic therapy (8 of 9, patency 89%) as did patients with normal or low levels of Lp(a) (22 of 32, patency 70%, difference greater than 0.1). Lp(a) levels did not differ significantly between patients with successful and unsuccessful thrombolysis. Our results demonstrate that high levels of Lp(a) do not affect thrombolysis in patients with acute myocardial infarction when low-dose pharmacologic concentrations of rt-PA and scu-PA are applied in combination.
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PMID:Effects of lipoprotein (a) on success rate of thrombolytic therapy in acute myocardial infarction. 182 24

Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) and the in vitro ability of platelets to aggregate and of monocytes to express procoagulant (tissue factor) activity (PCA) were evaluated in five patients who are homozygous for familial hypercholesterolemia (FH) before and after a single and a regular 5-month cholesterol removal by low density lipoprotein (LDL) apheresis. The biweekly procedure resulted in a 25% to 30% reduction (approximately 150 mg/dl) in total and LDL cholesterol (both were greater than 550 mg/dl at the beginning of the study). The basal levels of t-PA antigen and fibrinolytic activity before and after 10 minutes of venous stasis, basal PAI activity, and PAI-1 antigen were comparable to controls and were not affected by LDL apheresis. Likewise, regardless of the cholesterol removal, the PCA of freshly isolated monocytes and that of monocytes incubated with lipopolysaccharide did not differ from control values. Finally, the pre-apheresis sensitivity of platelets to adenosine diphosphate, arachidonic acid, and collagen was 1.5 to 2 times the normal value. This ratio was unchanged throughout the 5-month procedure. We conclude that fibrinolysis and monocyte PCA are normal in FH patients, whereas platelet aggregation is abnormally high, and none of these parameters is significantly affected by a 25% to 30% reduction in total and LDL cholesterol by LDL apheresis. Furthermore, our data suggest that removal of cholesterol from plasma by LDL apheresis is important for gaining insight into the mechanisms involved in the ischemic complications of arteriosclerosis in FH patients.
Arteriosclerosis
PMID:Hemostatic variables in homozygous familial hypercholesterolemia. Effect of regular plasma cholesterol removal by low density lipoprotein apheresis. 212 91

Lipoprotein(a) (Lp[a]) is a complex plasma lipoprotein in which apolipoprotein (apo) B-100 is covalently linked by a disulfide bridge to a unique apolipoprotein, apo(a). The cDNA of apo(a) has recently been isolated and sequenced, and a remarkable homology to human plasminogen has been noted. In this report, we demonstrate that, like plasminogen, Lp(a) binds to fibrin. In addition, Lp(a) competes with plasminogen and tissue-type plasminogen activator for fibrin binding. As a functional consequence of these binding properties, we show that Lp(a) attenuates the fibrin-dependent enhancement of tissue-type plasminogen activator activity against the native substrate, and does so as an uncompetitive inhibitor (Ki = 15 nM). Finally, we show that in a plasma milieu, Lp(a) attenuates clot lysis induced by tissue-type plasminogen activator. None of these effects was noted with low density lipoprotein free of apo(a). These data suggest that Lp(a) influences the fibrinolytic system and probably does so by virtue of the fibrin binding properties conferred by the kringle repeats of apo(a).
Arteriosclerosis
PMID:Lipoprotein(a), fibrin binding, and plasminogen activation. 213 52

Parameters of fibrinolysis, including euglobulin fibrinolytic activity, tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PA-inhibitor) activity, and plasmin-alpha 2-antiplasmin complex (PAP) were studied in 62 patients (35 women and 27 men; ages 53 +/- 16 years) with either insulin-dependent (IDDM) or noninsulin-dependent (NIDDM) diabetes mellitus. Compared to a control group of similar age (n = 57), the diabetic patients had a significantly lower mean euglobulin fibrinolytic activity (1.2 +/- 0.7 vs. 1.7 +/- 1.1 ng/ml, p less than 0.01) but significantly higher mean t-PA antigen (15.7 +/- 8.4 vs. 6.6 +/- 2.9 ng/ml, p less than 0.001) and PA-inhibitor activity (2.6 +/- 1.3 vs. 1.5 +/- 0.7 IU/ml, p less than 0.001) levels. Significant univariate correlations were observed between PA-inhibitor activity and age (r = 0.32, p less than 0.05), diastolic blood pressure (r = 0.42, p less than 0.01) and euglobulin fibrinolytic activity (r = -0.40, p less than 0.01). In multivariate analysis, only body mass index (positively) and euglobulin fibrinolytic activity (negatively) remained significantly related to PA-inhibitor activity in the total diabetic population as well as in the NIDDM group. The only parameter in the IDDM group significantly related to PA-inhibitor activity was diastolic blood pressure. These results suggest that PA-inhibitor plays a role in the regulation of fibrinolysis in diabetes patients and that factors like obesity and hypertension may be related to reduced fibrinolysis via PA-inhibitor levels.
Arteriosclerosis
PMID:Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. 244 56

Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of fibrinolysis. It circulates in blood both in free active form and in inactive form complexed with tissue type plasminogen activator (t-PA). Control mechanisms for its synthesis and release from hepatocytes and endothelial cells are important in the pathogenesis of thrombosis. Possible risk factors for myocardial infarction include high insulin and PAI-1 levels, which correlate with one another in healthy subjects, and fibrinogen, which together with PAI-1, is an acute-phase reactant. We therefore studied the interrelationships between PAI-1, plasma insulin, and acute-phase proteins in 67 patients with angina pectoris. Plasma insulin correlated strongly (r = 0.59, p less than 0.001) with PAI activity, free PAI-1 antigen (r = 0.60, p less than 0.001), and total PAI-1 antigen (r = 0.58, p less than 0.001). The acute-phase proteins, fibrinogen and C-reactive protein, correlated significantly with t-PA antigen, total PAI-1 antigen, and PAI-1/t-PA complexes but not with PAI activity or free PAI-1. The results suggest that insulin stimulates synthesis and release of free PAI-1 (probably via hepatocytes as previously shown with cell culture) and that endothelial cell synthesis and release of t-PA, together with PAI-1, reflects a nonspecific acute-phase response to chronic vascular disease. Hyperinsulinemia found in patients with angina pectoris could play a role in the development of myocardial infarction via the induction of high plasma PAI-1 activity.
Arteriosclerosis
PMID:Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute-phase response. 247 Mar 43

Fibrin formed on endothelial cells has previously been shown to have deleterious effects on the cells. Additionally, substances that cause endothelial cell damage have been reported to induce cultured endothelial cells to synthesize prostacyclin and tissue plasminogen activator (t-PA). The present studies were undertaken to determine whether fibrin formed on cultured human umbilical vein endothelial cells would alter synthesis of prostacyclin and t-PA by the cells. Fibrin was found to increase synthesis of both prostacyclin and t-PA in a dose and time dependent manner. Stimulation of prostacyclin synthesis was completely inhibited by indomethacin; partially inhibited by actinomycin D, cycloheximide, and trifluoperazine; and not affected by cytochalasin D or vinblastine. In contrast, stimulation of t-PA synthesis was completely inhibited by actinomycin D and cycloheximide; partially inhibited by cytochalasin D, vinblastine, and trifluoperazine; and not affected by indomethacin. Fibrin I, formed with Reptilase, caused only slight stimulation of t-PA production, but virtually no stimulation of prostacyclin synthesis. Neither collagen polymerization on the cells nor thrombin added in concentrations that did not induce fibrin polymer formation stimulated production of either substance. Furthermore, soluble fibrin II generated in the presence of the fibrin polymerization inhibitor gly-pro-arg-pro also failed to stimulate either prostacyclin or t-PA production. The presence of platelets in the plasma from which the fibrin was formed did not affect the amount of stimulation of the cells. Fibrin-induced stimulation of endothelial cell production of prostacyclin and t-PA could act to limit vascular occlusion in vivo by inhibiting platelet function and by stimulating fibrinolysis via t-PA.
Arteriosclerosis
PMID:Effect of fibrin on endothelial cell production of prostacyclin and tissue plasminogen activator. 249 87

Endothelial cells were isolated from arteries and veins obtained from elderly people at autopsy and propagated for 37 to 69 population doublings. The cells secreted tissue-type plasminogen activator (t-PA) and PA inhibitor-1, and, after subculturing, urokinase-type PA (u-PA) antigen. The following differences between endothelial cells from adult arteries and veins were observed: 1) The cells had the potential to be propagated as a healthy monolayer. The diameter of aortic endothelial cells increased after 8 to 19 population doublings, while a homogeneous population of small diameter vena cava cells was retained for 35 population doublings. 2) The amount of secreted t-PA varied. Vena cava cells produced four times more t-PA than aorta cells, and 20-fold more than umbilical artery or vein endothelial cells. The t-PA mRNA content of vena cava cells did not exceed that of aorta cells, but was fourfold greater than that of umbilical cord endothelial cells. 3) The release of u-PA antigen varied. No u-PA antigen was detectable in conditioned medium of primary cultures of human aorta and vena cava endothelial cells or of early passage vena cava cells. After prolonged subculturing, vena cava cells started to secrete u-PA. Endothelial cells from aorta and other adult arteries, however, started secreting u-PA after one to four passages, parallel to the occurrence of enlarged endothelial cells. u-PA was present as a u-PA/inhibitor complex and as a single-chain u-PA. These differences may be developmentally related to their artery or vein origin or may reflect differences acquired during the "life history" of these blood vessels in vivo. Our data suggest that the release of u-PA antigen by human macrovascular endothelial cells can be used as an indicator of cell senescence.
Arteriosclerosis
PMID:Production of plasminogen activators and inhibitor by serially propagated endothelial cells from adult human blood vessels. 330 Jun 18

The aim of the study was to investigate the long-term chronic effects of smoking on the fibrinolytic enzyme system by comparing two groups of healthy male volunteers (aged 30 to 40 years). One group consisted of 15 habitual smokers who consumed 20 or more cigarettes a day; the other consisted of 15 nonsmokers. Fibrinolysis was studied at rest (baseline) and after infusion of 1-desamino-8-D-arginine vasopressin (DDAVP; 0.4 micrograms/kg body weight). Smokers had significantly lower baseline blood fibrinolytic activity as determined by the overall assays: dilute blood clot lysis (p less than or equal to 0.05) and euglobulin-fibrin plate assay (p less than or equal to 0.05). Further analysis showed that these low activities could be attributed to a lower baseline level of extrinsic tissue-type plasminogen activator (t-PA) activity (p less than or equal to 0.05) in the smokers. There were no significant differences between the groups in various fibrinolytic inhibitors or in the intrinsic fibrinolytic activation pathways. The increased levels of t-PA activity and factor VIII R:Ag in response to DDAVP were also reduced in the smokers (p less than or equal to 0.01). The relative increase (ratio of post-DDAVP activity/baseline activity) for these parameters was not significantly different for the two groups. Smokers also had significantly higher levels of the acute phase reactants, alpha 1-antitrypsin (p less than or equal to 0.02) and plasminogen (p less than or equal to 0.02) and C-reactive protein (p less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Arteriosclerosis
PMID:Effect of chronic smoking on fibrinolysis. 387 92

Tissue-type plasminogen activator (t-PA), purified from the culture fluid of a stable human melanoma cell line, is a serine protease, different from urokinase, with a molecular weight of about 70,000. It is composed of one polypeptide chain, which is converted to a two-chain molecule by limited plasmic action. Activation of plasminogen to plasmin occurs by cleavage of the Arg 560-Val 561 peptide bond. Kinetic analysis has shown that the activation obeys Michaelis-Menten kinetics and that the presence of fibrin strikingly enhances the activation rate by increasing the affinity of plasminogen for fibrin-bound t-PA. The directed action of plasmin toward fibrin in vivo, might be explained by the low Michaelis constant in the presence of fibrin (0.16 microM), which allows efficient plasminogen activation on a fibrin clot, while its high value in the absence of fibrin (65 microM) prevents efficient activation in plasma. Plasmin formed on the fibrin surface would then be protected from rapid inactivation by alpha 2-antiplasmin. An important consequence of this molecular model for physiological fibrinolysis is that specific thrombolysis is only expected with the use of a specific plasminogen activator, which confines activation to the fibrin surface. Studies on the thrombolytic properties of purified t-PA in various animal species and in humans have revealed a higher specific thrombolytic activity than urokinase. Thrombolysis could be achieved without causing significant plasminogen activation, alpha 2-antiplasmin consumption, or fibrinogen breakdown. Alternatively, pro-urokinase, the zymogen precursor of urokinase, also displays a certain degree of fibrin specificity. Its mechanism of action and potential therapeutic value remain to be established.
Arteriosclerosis
PMID:New approaches to thrombolytic therapy. 643 77


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