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)

Hypertriglyceridemia is linked to impaired fibrinolytic function, and lipid-lowering treatment with fibric acid derivatives could hypothetically improve fibrinolysis in this condition. We therefore conducted a double-blind, placebo-controlled, crossover study of gemfibrozil treatment on fibrinolytic function in 21 men with combined hyperlipoproteinemia. Measurements were performed at rest and during mental stress and after venous occlusion. The patients had clearly disturbed fibrinolytic function, with elevated plasminogen activator inhibitor-1 (PAI-1) activity at rest ( approximately 25 U/mL; reference, <15 U/mL). Gemfibrozil reduced plasma total and VLDL cholesterol as well as all triglyceride fractions, whereas HDL cholesterol increased (P <.001 for all). Total triglyceride levels were reduced by 57 +/- 4% (from 5.3 to 2.1 mmol/L). Fasting serum insulin levels were not altered by gemfibrozil treatment. Plasma levels of PAI-1 activity and tissue-type plasminogen activator (TPA) activity or antigen were unaffected by gemfibrozil treatment both at rest and during the provocations. The levels of D-dimer, plasmin/antiplasmin complex, and fibrinogen were also uninfluenced by gemfibrozil treatment. Mental stress elevated plasma TPA (P=.0036) and lowered PAI-1 (P=.0012) activity during placebo but not gemfibrozil treatment (P=.28 and P=.17, respectively), but treatment effects did not differ by ANOVA on delta values (ie, stress minus rest). Venous occlusion reduced PAI-1 activity, whereas TPA and plasmin/antiplasmin complex increased during both treatments. Thus, gemfibrozil treatment did not improve fibrinolysis or lower fibrinogen levels in men with combined hyperlipoproteinemia despite marked reduction of plasma triglyceride levels. It seems unlikely that improved fibrinolysis explains the primary preventive effect of gemfibrozil.
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PMID:Gemfibrozil treatment of combined hyperlipoproteinemia. No improvement of fibrinolysis despite marked reduction of plasma triglyceride levels. 862 72

The effect of chronic stress on tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1) antigens was studied in 69 healthy middle-aged men. Chronic stress, defined as feelings of fatigue, lack of energy, increased irritability, and demoralization, was positively associated with plasma concentrations of PAI-1 antigen but was unrelated to TPA. The association remained unaltered after controlling for age, smoking, alcohol consumption, and physical activity but became nonsignificant after further controlling for abdominal obesity, BMI, and serum insulin and triglyceride levels. This attenuated association implies that the relationship between vital exhaustion and PAI-1 may be secondary to the effects of the metabolic variables. Thus, the present study shows that long-term stress affects the fibrinolytic system and suggests that obesity and insulin and triglyceride concentrations, which are closely correlated with the fibrinolytic parameters, may mediate the association. These findings are consistent with the hypothesis that chronic stress causes increased synthesis of PAI-1, thus promoting the risk for atherothrombotic disease by decreasing the likelihood of spontaneous fibrinolysis and increasing the likelihood of fibrin deposition.
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PMID:Association of chronic stress with plasminogen activator inhibitor-1 in healthy middle-aged men. 863 Jun 60

The associations between abdominal visceral fat and the plasma hemostatic system were examined in 38-year-old healthy men (n=52) with a wide range of fatness and fat distribution. Plasma hemostatic factors and metabolic parameters, including glucose tolerance, were measured, and body fatness and adipose tissue distribution were assessed by using computed tomography. The men with more visceral fat (ie, higher than the median value [n=26]) had a less favorable metabolic profile than the men with less visceral fat (n=26). They also had significantly (P<.05) higher plasma fibrinogen, factor VIII clotting activity, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor-1 (PAI-1) activity (19.2+/-2.4 versus 8.5+/-1.6 AU/mL, P<.001) and lower basal tissue-type plasminogen activator activity. After adjustment for plasma insulin, the men with larger abdominal visceral fat area still had significantly higher plasma PAI-1 activity, but no difference was found in any of the other hemostatic factors. In multiple linear regression analysis, abdominal visceral fat area was a positive predictor of plasma PAI-1 activity, but it failed to show any significant association with other hemostatic factors after controlling for plasma insulin. These results suggest the presence of relationships between abdominal visceral fat and several plasma hemostatic factors that are largely mediated by concomitant alterations in plasma insulin concentration. In addition, our results suggest that abdominal accumulation of visceral fat is an independent predictor of plasma PAI-1 activity.
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PMID:Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men. 863 Jun 61

A possible cause of accelerated atherothrombosis in the syndrome of insulin resistance appears to be an elevated blood concentration of plasminogen activator inhibitor type-1 (PAI-1). Insulin resistance occurs with aging, attributable partly to increased adiposity. Scarce information exists regarding the effects of weight loss in elderly, obese individuals on PAI-1 concentrations. Consequently, weight loss (9 +/- 1 kg) was induced by energy intake restriction in 19 elderly, obese individuals, and its effect on fibrinolytic system peptides was measured. Initially elevated PAI-1 concentrations decreased by 50%, with a simultaneous decrease in the concentration of tissue-type plasminogen activator (t-PA)/PAI-1 complexes but no significant change in t-PA suggested a decrease in inhibition of the fibrinolytic system. The concentration of plasmin/antiplasmin complexes (PAP complex) increased by approximately 20%, indicating augmented fibrinolytic system activity. The decline in PAI-1 correlated with that of the decrease in body weight (r = 0.5, P < 0.05) and fat mass losses (r = 0.46, P < 0.05). The increase in PAP complexes correlated with weight and fat mass losses (r = 0.4 and r = 0.46, respectively; P < 0.05 for both). No correlation was seen between fibrinolytic system variables and baseline concentrations of substrates or insulin, but the change in PAI-1 correlated with the change in plasma triacylglycerols (r = 0.58, P < 0.05). Results indicate that energy restriction sufficient to induce moderate weight loss leads to diminution of elevated plasma PAI-1 and relief of inhibition of the fibrinolytic system in elderly, obese subjects. To the extent that these changes are associated with a decrease in the progression of vasculopathy, weight loss in elderly, obese individuals may be a useful means to reduce cardiovascular morbidity and mortality.
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PMID:Amelioration of the inhibition of fibrinolysis in elderly, obese subjects by moderate energy intake restriction. 866 17

In Denmark, clinicians conducted clinical and metabolic evaluations on 17 healthy women, 21-26 years old, within the last 10 days of their menstrual cycle preceding intake with a triphasic oral contraceptive (OC) (ethinyl estradiol + norgestimate) and during the last 7 days of the sixth period of OC treatment. They aimed to examine the effect of proinsulin and insulin on fasting secretion of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA). OCs have a well-defined effect on plasma levels of PAI-1 and t-PA. The clinical researchers also studied the antigen concentrations of PAI-1 and t-PA during slow and fast changes in proinsulin and insulin levels induced by oral and intravenous glucose tolerance tests. They did not find consistent correlations between fasting values of proinsulin, insulin, PAI-1, and t-PA either before or during OC treatment. During the glucose tolerance test induced hyperproinsulinemia and hyperinsulinemia and before OC treatment, PAI-1 and t-PA antigen levels fell (p 0.05). After 6 months of OC treatment, t-PA levels fell only during the oral glucose tolerance test (p 0.05) even though proinsulin and insulin responded similarly to the glucose loads. These findings suggest that neither proinsulin nor insulin regulate plasma levels of PAI-1 and t-PA in young healthy women regardless of OC use status.
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PMID:No influence of proinsulin and insulin on plasma levels of plasminogen activator inhibitor type 1 and tissue plasminogen activator in young women before and during intake of contraceptive steroids. 869 17

Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer.
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PMID:Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. 869 80

Veins used for arterial bypass grafting undergo wall remodeling when exposed to altered flow, which may affect fibrinolytic mechanisms and subsequently the fate of the graft. Our aim was to study the extent of blood coagulation and fibrinolysis activation in 27 patients with patent grafts two years after femoro-distal bypass surgery. The two matched control groups included 10 and 19 conservatively treated patients having similar degree of arterial insufficiency (mean ankle/brachial blood pressure index) as the bypass group pre- and post-operatively, respectively. Plasma samples for coagulation and fibrinolysis activation were determined using ELISA and chromogenic assays. When compared with the control groups circulating tissue-type plasminogen activator antigen, and especially plasminogen activator inhibitor type-1, PAI-1 antigen and activity were significantly increased, the mean increase ranging between 54% and 140% in the bypass group. Thrombin-antithrombin III complex, fibrinogen, and C-reactive protein, did not differ, while triglycerides were elevated in the bypass group. Ten patients in the bypass group were insulin resistant, but this did not explain the differences in the fibrinolytic parameters between the bypassed and control patients. Patients with peripheral vein grafts had upregulation of PAI-1 in their circulation implying reduced fibrinolytic capacity. Increased PAI-1, a risk factor for venous thrombosis, might reflect developing intimal hyperplasia, and it remains to be studied whether upregulation of PAI-1 in venous grafts associates with graft failure.
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PMID:Increased circulating plasminogen activator inhibitor-1 in patients with patent femoro-distal venous bypass. 874 32

We examined the effects of insulin-like growth factor (IGF)-I on follicular growth, oocyte maturation, and ovarian steroidogenesis and plasminogen activator (PA) activity in vitro, using a perfused rabbit ovary preparation in order to determine whether the follicle-stimulating effects of growth hormone (GH) are mediated by IGF-I. The addition of IGF-I to the perfusate stimulated follicular growth and the resumption of meiosis in follicular oocytes in a dose-dependent manner. There was no significant difference in the production of progesterone by perfused rabbit ovaries between IGF-I-treated and control ovaries, whereas IGF-I increased the production of estradiol (E2) by perfused rabbit ovaries in a dose-dependent manner. The concomitant addition of a monoclonal antibody recognizing the type I IGF receptor, alpha IR-3, to the perfusate significantly blocked IGF-I-stimulated follicular growth, oocyte maturation, and E2 production. Intrafollicular PA activity increased significantly 4 h after exposure to 10 or 100 ng/ml of IGF-I and reached maximal levels at 6 h. The percentage increase in follicle diameter at 6 h after exposure to IGF-I was significantly correlated with the intrafollicular PA activity. Treatment with GH resulted in a 2.7-fold increase in intrafollicular levels of IGF-I mRNA. The binding of [125I]-IGF-I to rabbit ovarian membrane preparations was inhibited by unlabeled IGF-I and IGF-II in a concentration-dependent manner. The relative affinity of the IGF-I receptor for IGF-I, IGF-II, and insulin was typical of type I binding (IGF-I > IGF-II > insulin). Affinity cross-linking of ovarian membranes with [125I]-IGF-I revealed a radiolabeled band corresponding to a molecular weight of 135,000, the alpha subunit of the type I IGF receptor. This band was totally displaced by IGF-I and alpha IR-3. It was concluded that IGF-I stimulated follicular development, E2 production, and oocyte maturation by interacting with its specific receptor located in rabbit ovarian membranes.
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PMID:Effects of insulin-like growth factor-I on follicle growth, oocyte maturation, and ovarian steroidogenesis and plasminogen activator activity in the rabbit. 879 70

The relationship between liver steatosis, evaluated by ultrasonography, and various plasma haemostatic factors was examined in 64 apparently healthy males, aged 38 years. Plasma levels of factor VII clotting activity (F-VIIc), plasminogen activator inhibitor-1 (PAI-1) activity and antigen, tissue-type plasminogen activator (t-PA) activity significantly differed in men with liver steatosis (n = 31) as compared with those without steatosis (n = 33). No significant differences were found in t-PA antigen and F-VII antigen. The men with liver steatosis also had significantly higher body mass index (BMI), plasma triglyceride and 2 h post-load insulin concentrations. While the differences in plasma haemostatic factors were substantially unchanged after adjustment for BMI, they totally disappeared when further allowance was made for plasma triglyceride and 2 h insulin concentrations. In conclusion, these results indicate that liver steatosis correlates specifically with increased PAI-1, F-VIIc and decreased t-PA levels, and suggest that such a relation is largely mediated by concomitant alterations in plasma triglyceride and insulin concentrations.
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PMID:Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men--role of the metabolic syndrome. 881 54

Several tissue remodeling events that require extracellular proteolysis are thought to be mediated by plasminogen activators that convert the inactive proenzyme plasminogen to active plasmin. The involvement of plasminogen activator in many biological phenomena reflects the ubiquitous presence of plasminogen and the ability of numerous cell types to synthesize plasminogen activator in a highly regulated manner. Increased plasmin and plasminogen activator in bovine milk are correlated with gradual involution (the declining phase of lactation). Treatment with bST prevented the increase in plasmin during gradual involution, indicating that bST interferes with conversion of plasminogen to plasmin. Concentrations of plasminogen activator in mammary tissue are high after cessation of milking. These results reinforce the association of the plasmin-plasminogen system with gradual involution postlactation. Recently, a role has been proposed for plasminogen activator in cell proliferation in several cellular systems. Insulin and IGF-I increased synthesis of urokinase plasminogen activator and enhanced proliferation of cultured bovine mammary epithelial cells. In contrast, phorbol myristate acetate, which increased expression of urokinase plasminogen activator mRNA by mammary epithelial and myoepithelial cells, stimulated proliferation of myoepithelial cells, but not epithelial cells. Thus, expression of plasminogen activator is not simply related to mitogenesis but is likely to serve multiple functions in bovine mammary epithelial cells.
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PMID:Plasminogen activator system: implications for mammary cell growth and involution. 882 75


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