Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of recombinant vampire bat salivary plasminogen activator (bat-PA) as a thrombolytic agent was compared with that of human tissue-type plasminogen activator (t-PA) in a canine model of arterial thrombosis. An occlusive thrombus was formed in the femoral artery by insertion of a thrombogenic copper coil; femoral arterial blood flow was monitored with a Doppler flow meter. Bat-PA and t-PA, when administered by 5-minute intravenous infusion (14 nmol/kg), reperfused seven out of eight and four out of eight dogs, respectively. The median reperfusion times in the bat-PA and t-PA groups were 24 and greater than or equal to 131 minutes, respectively. The mean reperfusion times (+/- SEM) in the recanalized bat-PA- and t-PA-treated dogs were similar (20 +/- 5 and 11 +/- 2 minutes, respectively, p = NS). Maximal blood flow after reperfusion was greater with bat-PA than with t-PA (80 +/- 10% and 41 +/- 15% of control flow, respectively, p less than 0.05). Furthermore, the median reocclusion time was markedly delayed in the bat-PA group relative to the t-PA group (131 versus 34 minutes, respectively, p less than 0.05). Plasma fibrinogen and plasminogen were not significantly depleted by the administration of t-PA or bat-PA. However, plasma alpha 2-antiplasmin activity was moderately depressed in the t-PA group relative to the bat-PA group (p less than 0.05). The clearance profile for t-PA was monoexponential, with a half-life (t1/2) of 2.4 +/- 0.3 minutes and a mean residence time of 3.5 +/- 0.4 minutes. The clearance profile for bat-PA was biexponential, with a t1/2 alpha of 0.9 +/- 0.2 minutes, a t1/2 beta of 20.2 +/- 2.7 minutes, and a mean residence time of 21.3 +/- 4.3 minutes. The steady-state volume of distribution displayed by bat-PA was 16-fold greater than that of t-PA. Zymography of serial plasma samples from the bat-PA-treated dogs failed to demonstrate the apparent generation of a complex between bat-PA and plasminogen activator inhibitor-1; the corresponding complex with t-PA was observed in plasma samples from the t-PA-treated dogs. The sustained recanalization and improved blood flow in the bat-PA group relative to the t-PA group and the avoidance of fibrinogenolysis by bat-PA, despite its prolonged mean residence time, suggest that bat-PA may be superior to t-PA as a thrombolytic agent.
 ...
PMID:Vampire bat salivary plasminogen activator promotes rapid and sustained reperfusion without concomitant systemic plasminogen activation in a canine model of arterial thrombosis. 137 32

In 29 lean, premenopausal, never-treated hypertensive women (142 +/- 2/93 +/- 1 mmHg, mean +/- SEM) plasminogen activator inhibitor (PAI-1) was elevated (11.0 +/- 1.5 U/ml vs 6.3 +/- 1.0 U/ml, p less than 0.05) compared to healthy, normotensive women (113 +/- 2/71 +/- 2 mmHg). Euglobulin clot lysis time tended to be longer in the hypertensive than in the normotensive women (p = 0.06). PAI-1 was positively correlated to triglycerides (r = 0.60, p less than 0.001), haematocrit (r = 0.45, p less than 0.05), insulin (r = 0.38, p less than 0.05) and body mass index (r = 0.38, p less than 0.05), and inversely correlated to HDL cholesterol (r = -0.43, p less than 0.05) in the hypertensive women. Fibrinogen was not significantly different in the hypertensive and normotensive women, while the hypertensive smokers had higher fibrinogen than the hypertensive non-smokers (3.01 +/- 0.17 g/l vs 2.54 +/- 0.10 g/l, p less than 0.05). All participants were investigated in the same phase of the menstrual cycle. Despite that, oestradiol was significantly lower in the hypertensive than in the normotensive women (0.57 +/- 0.06 vs 0.81 +/- 0.09 nmol l-1, p less than 0.05), while progesterone was similar in the two groups. These results suggest that premenopausal, never-treated hypertensive women are characterized by low oestradiol levels as well as decreased fibrinolytic activity. PAI-1 seems to be associated with other risk factors for cardiovascular disease in hypertensive women.
 ...
PMID:Evidence of decreased fibrinolytic activity in hypertensive premenopausal women. 143 14

Decreased fibrinolytic capacity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. To investigate the potential role of this inhibitor in atherosclerosis, we examined the expression of PAI-1 mRNA in segments of 11 severely diseased and 5 relatively normal human arteries obtained from 16 different patients undergoing reconstructive surgery for aortic occlusive or aneurysmal disease. Densitometric scanning of RNA (Northern) blot autoradiograms revealed significantly increased levels of PAI-1 mRNA in severely atherosclerotic vessels (mean densitometric value, 1.7 +/- 0.28 SEM) compared with normal or mildly affected arteries (mean densitometric value, 0.63 +/- 0.09 SEM; P less than 0.05). In most instances, the level of PAI-1 mRNA was correlated with the degree of atherosclerosis. Analysis of adjacent tissue sections from the same patients by in situ hybridization demonstrated an abundance of PAI-1 mRNA-positive cells within the thickened intima of atherosclerotic arteries, mainly around the base of the plaque. PAI-1 mRNA could also be detected in cells scattered within the necrotic material and in endothelial cells of adventitial vessels. In contrast to these results, PAI-1 mRNA was visualized primarily within luminal endothelial cells of normal-appearing aortic tissue. Our data provide initial evidence for the increased expression of PAI-1 mRNA in severely atherosclerotic human arteries and suggest a role for PAI-1 in the progression of human atherosclerotic disease.
 ...
PMID:Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. 149 92

The hematopoietic growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), enhance the effector functions of mature myeloid cells, including the interaction with vascular endothelium. We examined the direct effect of recombinant human GM-CSF (rhGM-CSF) and recombinant human G-CSF (rhG-CSF) on the growth and function of cultured human umbilical vein endothelial cells (HUVEC). Endothelial cell growth supplement (ECGS) increased the proliferation of passaged and primary cells by 305% +/- 45% (mean +/- SEM, n = 5, P less than .01) over control cells at 4 days; GM-CSF and G-CSF had no effect. Endothelial cell procoagulant activity was increased after 4-hour incubation with recombinant interleukin-1 beta (IL-1 beta) 10 U/mL and recombinant tumor necrosis factor (TNF) 10 U/mL to 1,721% +/- 376% (n = 7, P less than .005) and 247% +/- 71% (n = 4) of control levels, respectively. gamma-Interferon (gamma-IFN) 50 U/mL had no direct effect of its own but was able to prime the response to IL-1 beta. There was no direct or priming effect of GM-CSF (1 ng to 1 microgram/mL) on the expression of procoagulant activity in endothelial cells. GM-CSF and G-CSF (1 ng/mL to 1 microgram/mL) had no effect on the expression of either tissue plasminogen activator (tPA) or plasminogen activator inhibitor-1 (PAI-1) by endothelial cells. The secretion of tPA by endothelial cells was increased, however, after 24-hour incubation with thrombin 4 U/mL (314% +/- 72% of control levels, n = 5, P less than .025). The production of PAI-1 was increased by TNF 200 U/mL (241% +/- 44% of control, n = 3, P less than .005), thrombin 4 U/mL (180% +/- 12% of control, n = 5, P less than .0005) and IL-1 beta 10 U/mL (275% +/- 44% of controls, n = 5, P less than .0005). In four experiments, endothelial cells showed no specific binding of 125I-GM-CSF, whereas peripheral blood (PB) neutrophils demonstrated the presence of 802 +/- 78 high-affinity receptors for GM-CSF. Thus, we found no effect of rhGM-CSF or rhG-CSF on the proliferation activities by these cells. These findings are in accordance with the lack of demonstrable receptors for GM-CSF on cultured HUVEC.
 ...
PMID:Lack of effect of granulocyte-macrophage and granulocyte colony-stimulating factors on cultured human endothelial cells. 193 61

Although the mechanisms involved in the pathophysiology of primary pulmonary hypertension have not yet been delineated, thrombosis has been implicated. This study was designed to determine whether thrombin activity as reflected by plasma concentrations of fibrinopeptide A (FPA), a marker of the action of thrombin on fibrinogen, is increased in patients with primary pulmonary hypertension. To evaluate fibrinolytic activity, we measured plasma concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and cross-linked fibrin degradation products. We studied 31 patients with primary pulmonary hypertension. Plasma FPA concentrations measured by radioimmunoassay, were elevated to 87.4 +/- 36.9 ng/ml (mean +/- SEM). Fifteen minutes after administration of heparin (5,000 U), FPA concentrations decreased to 6.8 +/- 1.4 ng/ml (p less than 0.001 compared with preheparin levels). In 21 of 30 patients (70%), FPA concentrations after heparin administration were less than half the preheparin levels, a response consistent with inhibition of thrombin by heparin and the short half-life of FPA. Despite evidence for marked thrombin activity, plasma concentrations of cross-linked fibrin degradation products were normal in all but four patients. Plasminogen activator inhibitor-1 activity was elevated in 19 of the 27 patients in whom it was measured, potentially limiting the fibrinolytic response. The elevations of FPA indicate that thrombin activity is increased in vivo in patients with primary pulmonary hypertension. Thus, sequential assays of plasma markers of thrombosis and fibrinolysis in vivo may help identify those patients who may benefit from treatment with anticoagulants.
 ...
PMID:Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. 239 5

rt-PA-K, a variant of recombinant tissue-type plasminogen activator (rt-PA) with substitution of amino acids 296 to 299 with alanine (KHRR296-299AAAA) has increased fibrin-specificity and reduced sensitivity to plasminogen activator inhibitor-1; rt-PA-T, with threonine 103 replaced by asparagine has an additional glycosylation site and a reduced clearance; and rt-PA-N, with asparagine 117 mutagenized to glutamine lacks the high mannose carbohydrate side chain. We have investigated whether combination of these properties in a single molecule might yield an improved thrombolytic agent. The thrombolytic potency and fibrin-specificity of the combination mutant rt-PA-TNK was compared with that of rt-PA in a combined venous whole blood clot model and platelet-rich arterial eversion graft thrombosis model in dogs given intravenous heparin and aspirin. Infusion of 0.125 to 1.0 mg/kg over 60 min in groups of 4 to 5 dogs produced dose-dependent fibrin-specific venous clot lysis. The thrombolytic potency (percent lysis per mg compound administered per kg body weight) of rt-PA-TNK was significantly higher than that of rt-PA as evidenced by a higher maximal rate of lysis of 480 +/- 100% versus 140 +/- 40% within the 2 h observation period per mg of compound administered per kg body weight (mean +/- SEM, p = 0.004) and a significantly lower dose of 0.08 +/- 0.01 versus 0.21 +/- 0.04 mg/kg body weight at which the maximal rate of lysis was obtained (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Comparative thrombolytic properties of tissue-type plasminogen activator and of a plasminogen activator inhibitor-1-resistant glycosylation variant, in a combined arterial and venous thrombosis model in the dog. 797 84

Endothelial release of tissue plasminogen activator (t-PA) may initiate fibrinolysis. Fibrinolysis and coagulation were investigated in 12 patients undergoing elective coronary artery bypass surgery. Cardiopulmonary bypass (CPB) was 108 +/- 7 min (mean +/- SEM), the time of cold, crystalloid, retrograde cardioplegia 53 +/- 5 min. Arterial and coronary sinus blood were sampled concomitantly before cardioplegia and after release of the aortic cross-clamp, for measurement of t-PA antigen (Ag) and activity, plasminogen activator inhibitor (PAI-1) Ag and activity, t-PA/PAI-1 complex, single chain urokinase (sc-uPA) and urokinase (uPA) plasminogen activators, the fibrin split product D-dimer, thrombin-antithrombin complex (TAT), and the prothrombin split product F 1 + 2. Cardiopulmonary bypass significantly increased t-PA Ag and activity, t-PA/PAI complex, D-dimer, TAT, and F 1 + 2, and decreased PAI-1 Ag and activity in arterial blood; uPA and sc-uPA were unchanged. The tissue plasminogen activator antigen was higher in coronary sinus than arterial blood after 1 (39 +/- 5 vs 24 +/- 4 ng/ml, P < 0.003), 4 (P < 0.003), and 10 min (P < 0.004) reperfusion. Tissue plasminogen activator activity and t-PA/PAI complex increased, PAI-1 activity decreased, while all other parameters were unchanged across the coronary circulation. In conclusion, CPB induces fibrinolysis and coagulation. Cold cardioplegia induces t-PA release in the coronary circulation, denoting a postischemic antithrombotic function of the coronary endothelium. Tissue plasminogen activator may be used to evaluate endothelial stimulation or injury induced by CPB, or by different regimens of myocardial protection.
 ...
PMID:Fibrinolysis during cardiac surgery. Release of tissue plasminogen activator in arterial and coronary sinus blood. 808 78

Homozygous plasminogen activator inhibitor-1 (PAI-1)-deficient (PAI-1-/-) mice were generated by homologous recombination in D3 embryonic stem cells. Deletion of the genomic sequences encompassing the transcription initiation site and the entire coding regions of murine PAI-1 was demonstrated by Southern blot analysis. A 3.0-kb PAI-1-specific mRNA was identified by Northern blot analysis in liver from PAI-1 wild type (PAI-1+/+) but not from PAI-1-/- mice. Plasma PAI-1 levels, measured 2-4 h after endotoxin (2.0 mg/kg) injection were 63 +/- 2 ng/ml, 30 +/- 10 ng/ml, and undetectable (< 2 ng/ml) in PAI-1+/+, heterozygous (PAI-1+/-) and PAI-1-/- mice, respectively (mean +/- SEM, n = 4-11). PAI-1-specific immunoreactivity was demonstrable in kidneys of PAI-1+/+ but not of PAI-1-/- mice. SDS-gel electrophoresis of plasma incubated with 125I-labeled recombinant human tissue-type plasminogen activator revealed an approximately 115,000-M(r) component with plasma from endotoxin-stimulated (0.5 mg/kg) PAI-1+/+ but not from PAI-1-/- mice, which could be precipitated with a polyclonal anti-PAI-1 antiserum. PAI-1-/- mice were viable, produced similar sizes of litters as PAI-1+/+ mice, and showed no apparent macroscopic or microscopic histological abnormalities.
 ...
PMID:Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. 825 28

Increased plasminogen activator inhibitor-1 (PAI-1) activity has been reported in Type 2 (non-insulin-dependent) diabetes and is a recognized risk factor for coronary artery disease. Fourteen newly diagnosed Type 2 diabetic patients were studied before and 3 months after standard clinical dietary modification. To assess the effect of improved metabolic control on PAI-1 activity, nine Type 2 diabetic patients established on diet therapy and with previous stable glycaemic control served as controls. In the newly diagnosed patients diet therapy resulted in a significant decrease in HbA1c levels (8.3 +/- 0.5 vs 5.2 +/- 0.3% (mean +/- SEM); p < 0.001), and this was accompanied by a fall in fibrinogen (4.3 +/- 0.3 vs 3.0 +/- 0.2 g.l-1; p < 0.01) concentration, and PAI-1 (18.7 +/- 2.3 vs 12.2 +/- 0.9 arbitrary units ml-1; p < 0.02) and factor VIII (147 +/- 17 vs 115 +/- 13%; P < 0.01) activities. PAI-1 activity was correlated with triglyceride levels at the first assessment in the newly diagnosed patients (r = 0.66; p < 0.01), and this was the only independent association by multiple regression analysis when all patients (n = 23) were considered (r = 0.62; p < 0.002). However, there was no association between the changes in PAI-1 activity and the changes in HbA1c BMI, and serum triglyceride levels following treatment in the newly diagnosed patients. Serum triglyceride concentrations, HBA1c, PAI-1 activity, and the coagulation factors remained unchanged in the control group over the same treatment period.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Decreased plasminogen activator inhibitor-1 activity in newly diagnosed type 2 diabetic patients following dietary modification. 828 22

The occurrence of type-1 plasminogen activator inhibitor (PAI-1) in human cerebrospinal fluid (CSF) has not previously been reported. As a member of the serpin superfamily of serine protease inhibitors and an acute phase response component, PAI-1 has powerful potential roles in nervous system homeostasis. We have detected this serpin antigen using a polyclonal anti-PAI-1 antibody in normal human CSF. In Western blotting, PAI-1 in several CSF samples appears as a two-band antigen of Mr = 54 and 35 kDa, presumably the intact and proteolytic fragment, respectively. In vitro complex formation studies confirm that the 54 kDa form of PAI-1 interacts with 125I-urokinase after activation with SDS, but the 35 kDa form does not. Quantification of total PAI-1 antigen in 18 normal human CSF samples by ELISA reveals a mean value of 1.0 +/- 0.07 (SEM) micrograms/dL, indicating that a relatively low concentration of the inhibitor occurs in normal human CSF. This information should now allow comparison of PAI-1 levels and activity in various neurologic disorders.
 ...
PMID:Plasminogen activator inhibitor 1, the primary regulator of fibrinolysis, in normal human cerebrospinal fluid. 845 10


1 2 3 Next >>