Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.68 (tissue plasminogen activator)
11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the relationships between albuminuria, tissue factor-induced coagulation, and endothelial cell dysfunction in 67 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were divided into three groups on the basis of their urinary albumin excretion rate (AER). To assess the early phase of tissue factor-induced coagulation, activated factor VII (FVIIa) levels in plasma were measured by a direct fluorogenic assay. As markers of endothelial cell dysfunction, levels of von Willebrand factor (vWF), tissue-type plasminogen activator-plasminogen activator inhibitor-1 (TPA-PAI-1) complex, PAI-1, and tissue factor pathway inhibitor (TFPI) were measured. FVIIa levels were increased in normoalbuminuric NIDDM patients (AER < 15 micrograms/min) when compared with normal control subjects. This FVIIa increase was accompanied by an increase in thrombin-antithrombin III complex (TAT) levels, indicating increased activation of coagulation even in normoalbuminuric patients. In NIDDM patients with microalbuminuria (AER = 15-200 micrograms/min), the FVIIa level, the FVIIa-FVII antigen (Ag) ratio (an indicator of activation of FVII zymogen to FVIIa), and the TAT level were further increased. This group also had higher levels of endothelial cell-derived factors (vWF, TPA-PAI-1 complex, and PAI-1) than the control group. The levels of endothelial cell-derived factors (including TFPI) were highest in the NIDDM patients with overt albuminuria (AER > 200 micrograms/min). In all 67 diabetic patients, AER showed a strong positive correlation with FVIIa (r = .574, P < .0001) and a weakly but still significant correlation with FVIIa-FVII:Ag (r = .365, P = .01), vWF (r = .315, P < .01), and TAT (r = .323, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of tissue factor-induced coagulation and endothelial cell dysfunction in non-insulin-dependent diabetic patients with microalbuminuria. 762 4

Four group of age- and sex-matched patients were studied: 1. nondiabetic subjects (n = 20) with a body mass index (BMI) < 25 Kg/m2 (lean control subjects); 2. obese non diabetic subjects (n = 22) with a BMI > 30 Kg/m2 (obese control subjects); 3. lean NIDDM subjects (n = 22); and 4. obese NIDDM subjects (n = 24). We determined: total cholesterol, triglycerides, HDL-cholesterol, blood glucose, Apolipoproteins A1 and B, insulin, Lp(a), Factor VII, fibrinogen, plasminogen, t-PA(Ag) pre and post venous occlusion (VO) and PAI activity pre and post VO. In addition to metabolic abnormalities obese non diabetic subjects and lean and obese NIDDM patients displayed significantly higher levels of fibrinogen, Factor VII, plasminogen, PAI pre and post VO and tPA(Ag) pre VO and significantly lower levels of t-PA(Ag) post VO. Our findings demonstrate an impairment of the haemostatic and fibrinolytic mechanisms which may be a key role in the pathogenesis of atherosclerotic vascular complications in obesity and in NIDDM.
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PMID:Blood coagulation and fibrinolysis in obese NIDDM patients. 764 83

Physically active postmenopausal women have a lower incidence of coronary heart disease (CHD) than their more sedentary peers, but little information is available concerning the responsible mechanisms. The primary aim of this study was to test the hypothesis that physically active post-menopausal women demonstrate more favorable levels of hemostatic, metabolic, and androgenic CHD risk factors than less active control subjects. If so, a secondary aim was to determine which of the characteristics associated with a physically active lifestyle, ie, low body fat, a high-carbohydrate/low-fat diet, high maximal aerobic capacity (aerobic fitness), and high levels of physical activity, are most closely related to this lower risk profile. To address these aims, we compared CHD risk factors in physically very active women (n = 14; age, 55 +/- 2 years) with those in healthy, nonobese sedentary control subjects (n = 17; age, 56 +/- 1 years). Maximal aerobic capacity (fitness) was 83% higher (P < .001) in the physically active women. Concentrations of plasminogen activator inhibitor type 1 activity and tissue plasminogen activator antigen were lower (more favorable) (P < .005) in the physically active women versus control subjects, whereas plasma fibrinogen levels did not differ. The physically active women had lower (P < .01) fasting plasma insulin and glucose concentrations as well as smaller responses to an oral glucose challenge. Both total-body and abdominal fat levels were lower (P < .001) and lipid and lipoprotein profiles were generally more favorable (P < .05) in the physically active women.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemostatic, metabolic, and androgenic risk factors for coronary heart disease in physically active and less active postmenopausal women. 774 80

Considering that PAI-1 is an important factor modulating the systemic fibrinolytic activity, the abnormal insulin metabolism frequently seen in end-stage renal disease (ESRD) may cause decreased fibrinolytic activity in concert with PAI-1. To study this possibility, we measured insulin levels and compared it with the fibrinolytic profiles in ESRD patients. Fasting blood sugar, insulin, and C peptide levels were higher in ESRD patients than in the control group. In the ESRD patients, the insulin levels showed a positive correlation with C peptide (r = 0.612, p = 0.0001), fasting blood sugar (r = 0.334, p = 0.044), and PAI-1 antigen (r = 0.474, p = 0.0001) and a reverse correlation with euglobulin fibrinolytic activity (r = 0.5, p = 0.005), but no correlation with t-PA antigen. The euglobulin fibrinolytic activity showed a reverse correlation with PAI-1 antigen (r = 0.289, p = 0.0144), but no correlation with t-PA antigen. Our results suggest that abnormal insulin metabolism and/or insulin resistance, which occur frequently in ESRD, may play an important role in the decrease in systemic fibrinolytic activity by the regulation of the PAI-1 concentration.
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PMID:Insulin levels and fibrinolytic activity in patients with end-stage renal disease. 783 55

This double-blind, randomized parallel group study investigated the effect of 6 months beta-adrenoceptor antagonist therapy with either metoprolol (beta 1-selective without intrinsic sympathomimetic activity [ISA]) or epanolol (beta 1-selective with ISA) on markers of endogenous fibrinolysis in 20 patients with chronic stable angina receiving concurrent treatment with nifedipine. Neither drug had an effect on tissue-type plasminogen activator or plasminogen activator inhibitor type 1 (PAI-1). A significant correlation between fasting insulin and PAI-1 has previously been described and was confirmed in this study. The group treated with metoprolol showed a significant rise in fasting insulin after 6 months with no change in PAI-1. This suggests that the previously described link between these two may not be causal.
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PMID:The long-term effects of metoprolol and epanolol on tissue-type plasminogen activator and plasminogen activator inhibitor 1 in patients with ischaemic heart disease. 791 37

The effects of contraceptive steroids on the expression of endothelial homeostasis were examined by direct and indirect measures in women with insulin-dependent diabetes mellitus (IDDM) in a prospective nonrandomized controlled study. Study subjects were 13 women with uncomplicated IDDM treated with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene for 12 consecutive cycles and 13 women of comparable diabetic status as control. During the study period, none of the participants developed increased renal albumin excretion, which was used as a direct measure of endothelial function. In the indirect assessment of endothelial function, we found a proportionate increase in plasma levels of thrombin-antithrombin III (TAT) complexes and D-dimer during treatment. Hormonal intake was followed by decreased antigen concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (type 1 [PAI-1]), whereas the activities of t-PA and PAI-1 were unchanged. Plasma levels of plasminogen and histidine-rich glycoprotein (HRG) increased and decreased, respectively, whereas an increase in von Willebrand factor was observed in the treatment group. No significant changes in direct or indirect measures were observed in the control group during the observation period of 12 months. In conclusion, no adverse effect on endothelial function was demonstrated by direct measures, but our findings suggest that a procoagulant state, compensated by enhanced activity of the fibrinolytic system, is induced by hormonal treatment. Clinical and metabolic monitoring is recommended if the use of oral contraceptives in women with IDDM is extended.
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PMID:Assessment of endothelial function during oral contraception in women with insulin-dependent diabetes mellitus. 796 93

The aim of this study was to characterize the acute effect of euglycemic (glucose 5.2 +/- 0.6 mmol/l) hyperinsulinemia (mean 118 +/- 32 mU/l) on fibrinolytic variables, free fatty acids (FFA) and counterregulatory hormones. In addition, the effect of chronic treatment with metformin, an oral antidiabetic agent which enhances insulin action, and metoprolol CR, a relatively beta 1-selective adrenergic antagonist, was also evaluated. A randomized, double-blind, placebo-controlled, cross-over study including 18 non-obese men, aged 53 +/- 6 years, was performed. The investigations were performed after each treatment period of 6 weeks in both the postabsorptive state and during a euglycemic, hyperinsulinemic clamp. Compared to the postabsorptive state, plasminogen activator inhibitor (PAI-1) activity and antigen, tissue plasminogen activator (t-PA) antigen and FFA decreased (p < 0.001) after 120 min of euglycemic hyperinsulinemia. In addition, t-PA activity increased (p < 0.01) while blood levels of lipoprotein (a), catecholamines and cortisol remained unchanged. Growth hormone increased during the clamps and this was most pronounced after treatment with metoprolol CR. When the effect of treatment was compared, postabsorptive levels of C-peptide, FFA and t-PA antigen were lower after metformin than after the placebo period (p < 0.05). t-PA antigen also remained lower during the clamp after metformin treatment. No significant effects of metformin or metoprolol CR were seen on insulin-stimulated glucose uptake during the clamps or on postabsorptive levels of counterregulatory hormones, PAI-1 or Lp(a).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of metformin and metoprolol CR on hormones and fibrinolytic variables during a hyperinsulinemic, euglycemic clamp in man. 797 48

Fibrinogen levels predict atherothrombotic disease, and impaired fibrinolysis has been proposed as a risk factor for myocardial infarction. Fibrinolysis is mainly dependent on the activity of tissue plasminogen activator (tPA) and its inhibitor plasminogen activator inhibitor type-1 (PAI-1). Oral glucose tolerance tests were performed in 318 randomly selected healthy men and 324 women aged 25 to 64 years. tPA activity was strongly predicted by fasting insulin in both univariate analysis (r = -.37 and -.34 in men and women, respectively) and multivariate analysis with age, anthropometric measurements, lipids, and blood pressure included. Fasting insulin was the strongest predictor of PAI-1 activity (r = .49 and .51). In women, the influence of fasting insulin level on tPA and PAI-1 activity was consistently stronger after than before menopause, and a threshold effect was seen with distinctly lower fibrinolytic activity in the highest quartile of insulin (> 7.0 mU/L). In men, the relation between insulin and fibrinolytic variables was linear. Fibrinogen levels were not related to insulin or glucose levels after adjustment for age and other risk factors in a multiple regression. Subjects with previously unknown diabetes or impaired glucose tolerance tended to have elevated fibrinogen and PAI-1 activity and decreased tPA activity. Our data support previous findings of a strong correlation between insulin and PAI-1 activity in small highly selected groups, and extend them to randomly selected population samples. The strong inverse relation between endogenous insulin levels and tPA activity has not previously been demonstrated in a healthy population.
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PMID:Hyperinsulinemia predicts low tissue plasminogen activator activity in a healthy population: the Northern Sweden MONICA Study. 799 Jul 15

Recently waist/hip ratio (WHR), a marker of body fat distribution, has been described as a risk factor for cardiovascular disease (CVD). The aim of the present study was to evaluate the influence of body fat distribution on metabolic, haemostatic and haemorheological pattern in premenopausal obese women with different WHR. Fourty premenopausal obese women were subdivided into two groups, matched for age and body mass index (BMI): 20 women with abdominal obesity (WHR = 0.94 +/- 0.02) and 20 women with peripheral obesity (WHR = 0.77 +/- 0.03). Twenty nonobese women were recruited as control group. The abdominal obesity group had significantly higher blood glucose, triglycerides, total cholesterol, Apolipoprotein B and plasma insulin levels and lower high density lipoprotein (HDL) cholesterol and Apolipoprotein A1 levels than the control group. All the haemostatic (figrinogen, Factor VII, plasminogen activator inhibitor (PAI) activity and tissue plasminogen activator (t-PA) antigen (Ag) pre venous occlusion (VO)) and haemorheological parameters (haematocrit, whole blood filterability, blood and plasma viscosity) were significantly higher in the abdominal obesity group as compared to the control group. In contrast, mean values of t-PA (Ag) post VO were significantly lower in abdominal obese women. Moreover positive correlations between WHR and plasma insulin (r = 0.68, p < 0.05), between WHR and fibrinogen (r = 0.63, p < 0.05) and between WHR and PAI pre VO (r = 0.71, p < 0.05) and a negative correlation between WHR and t-PA (Ag) post VO (r = -0.55, p < 0.05) were found.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coagulation, fibrinolysis and haemorheology in premenopausal obese women with different body fat distribution. 799 33

The impact of long-term, heavy exercise on recently established cardiovascular/thromboembolic risk factors of the fibrinolytic system, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) in relation to food composition was studied. Twenty healthy men, aged 18-55 years participated in a 14-day skiing tour through the Swedish mountains, carrying a pack load of 30 kg, and spending each night in self-dug igloos (ambient temp -10 degrees to -25 degrees C), and were randomized to 2 food regimens having 30 or 40 energy percent of fat. Individual records were kept of all consumed food. Citrated plasma was obtained before and after 1 and 2 weeks of exercise: tPA release was assessed by a 10 min venous occlusion (VO) test. At baseline, daily dietary fiber intake correlated negatively with PAI-1 activity. Already after the first week of the skiing tour there were significant drops in PAI-1 activities, cholesterol and triglycerides. The tPA mass concentrations also dropped, both before and after VO, but tPA activities were unchanged, as were von Willebrand factor (vWF) levels. These changes were related mainly to the expenditure of energy, calculated from the food consumption, and appeared to be mediated through changed insulin sensitivity and decreased body fat mass. The energy percent of fat in the food had no differential impact. The effects receded a few weeks after cessation of the endurance exercise. Thus, endurance physical activity improves the fibrinolytic risk factor profile by reducing PAI-1 while leaving tPA activity unaffected, independently of food composition. A low dietary fiber intake appears to be associated with higher PAI-1 activities at baseline.
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PMID:Endurance physical activity, diet and fibrinolysis. 801 8


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