Plasma Plasma Plasminogen Activator Inhibitor-1 Research Articles

Proneness to Formation of Tight and Rigid Fibrin Gel Structures in Men with Myocardial Infarction at a Young Age

The native fibrin gel structure formed in vitro from plasma samples was examined by liquid permeation of hydrated fibrin gel networks in 38 unselected men who had suffered a myocardial infarction before the age of 45 years and in 88 age-matched population-based control men. Both the fibrin gel porosity (permeability coefficient, Ks) and the calculated fiber mass-length ratio varied considerably within the two groups, but were generally lower in the patients. Ks was 8.3 +/- 5.2 cm2 x 10(9) (mean +/- SD) in the patient group and 12.5 +/- 5.7 cm2 x 10(9) among controls (p < 0.001). The corresponding figures for fiber mass-length ratio were 13.1 +/- 7.7 and 16.5 +/- 7.5 Dalton/ cm x 10(-13), respectively (p < 0.01). Around 50% of the patients had Ks values below the 10th percentile of the control group. A strong inverse correlation was seen between plasma plasminogen activator inhibitor-1 (PAI-1) activity and Ks (r = -0.603, p < 0.001) or fiber mass-length ratio (r = -0.565, p < 0.001) in the patient group. Corresponding weaker associations of PAI-1 with fibrin gel properties were also present in the control group. In addition, inverse relationships of very low density lipoprotein (VLDL) triglyceride concentrations to Ks (r = -0.362, p < 0.001) and fiber mass-length ratio (r = -0.283, p < 0.01) were found among the controls. Proneness to formation of tight and rigid fibrin gel networks with abnormal architecture in vitro is in vivo associated with myocardial infarction at a young age. Impaired fibrinolytic function secondary to a raised plasma PAI-1 activity level is associated with abnormal fibrin gel structure.

Evidence for a relationship between plasminogen activator inhibitor-1 and gamma glutamyl transferase

Plasma plasminogen activator inhibitor-1 (PAI-1) levels are elevated in insulin-resistant obese subjects (1). However, the mechanisms responsible for such elevation are unknown. It has been shown that insulin increases PAI-1 synthesis by the human hepatoma cell line Hep G2 (2) and by freshly isolated human hepatocytes (3). Moreover, a recent study showed that PAI-1 synthesis in presence of insulin was markedly increased in Hep G2 cells down-regulated for insulin receptor (4); these results agree with those found in vivo in insulin-resistant subjects. On the other hand, it has recently been proposed that mild liver abnormalities and steatosis may be among the factors accounting for high plasma PAI-1 levels in hyperlipidemic subjects (5,6). Steatosis and hepatic abnormalities are also a common feature of obese subjects (7,8). Thus the purpose of this investigation was to determine whether plasma PAI-1 levels were correlated with hepatic enzymes in non-hypertriglyceridemic subjects with a wide range of body mass index (BMI) and levels of insulin resistance.

Clinical and biochemical factors associated with prognosis after myocardial infarction at a young age

Objectives. This study examined the effect of metabolic disturbances, hemostatic function, coronary artery disease severity and left ventricular function on the long-term prognosis after myocardial infarction in men <45 years old.Background. Heavy smoking; dyslipoproteinemias involving very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL); a family history of premature coronary artery disease; hyperinsulinemic responses to oral and intravenous glucose challenges; and defective fibrinolytic function characterize the young postinfarction patient, but the influence of these features on the long-term prognosis is virtually unknown.Methods. Measurements of hemostatic function and metabolic and angiographic indicators of risk were included in a prospective cohort study of variables predictive of reinfarction, cardiac death and major coronary events within 6 to 9 years in 108 unselected nondiabetic men with a first myocardial infarction before age 45 years.Results. During follow-up, 20 patients had sudden cardiac death, and 53 had a major coronary event (reinfarction, sudden cardiac death, bypass surgery or intervention by catheterization). In multivariate analysis, VLDL and global coronary atherosclerosis score predicted reinfarction; plasma plasminogen activator inhibitor-1 (PAI-1) activity and global coronary stenosis score predicted cardiac death; and VLDL triglyceride levels, global coronary atherosclerosis score and age predicted any major coronary event.Conclusions. This prospective cohort study shows that hypertriglyceridemia, impaired fibrinolytic capacity secondary to plasma PAI-1 activity elevation and extensive coronary artery disease increase the risk of recurrences in men with a first myocardial infarction before age 45 and contribute to the relatively poor long-term prognosis in this patient group.

Insulin sensitivity is not an independent determinant of plasma plasminogen activator inhibitor-1 activity.

It recently has been hypothesized that increased plasma plasminogen activator inhibitor-1 (PAI-1) activity could be a possible link between insulin resistance and coronary heart disease. However, it is not known whether insulin sensitivity per se is a determinant of plasma PAI-1 activity or whether other intermediates could explain this association. We investigated the relationship between plasma PAI-1 activity and insulin sensitivity, obesity, distribution of body fat, blood pressure, plasma insulin concentration, and serum lipid levels in normoglycemic men (n = 61) and women (n = 77) 53 to 61 years old who participated in a previous population-based study. Insulin sensitivity was estimated by the minimal model from a frequently sampled intravenous glucose tolerance test. In univariate analyses, PAI-1 correlated positively with body mass index, waist-to-hip ratio (WHR), fasting and 2-hour insulin levels, and triglyceride level in both men and women. Furthermore, in women PAI-1 correlated inversely with high-density lipoprotein (HDL) cholesterol level. There was an inverse relationship between PAI-1 and insulin sensitivity (r = -.39, P < .01 in men; r = -.38, P < .001 in women). In multivariate analyses in men, insulin sensitivity failed to show any significant association with PAI-1. In contrast, triglyceride level and body mass index were independently associated with PAI-1. Also in women, insulin sensitivity was not independently associated with PAI-1. In women, WHR and HDL cholesterol concentration or WHR and 2-hour insulin concentration were independently related to PAI-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin.

High plasma plasminogen activator inhibitor-1 (PAI-1) activity is associated with insulin resistance and is correlated with hyperinsulinemia. The cellular origin of plasma PAI-1 in insulin resistance is not known. The hepatoma cell line Hep G2 has been shown to synthesize PAI-1 in response to insulin. The aim of this study was to analyze the insulin-mediated response of PAI-1 and lipid synthesis in Hep G2 cells after producing an insulin-resistant state by decreasing insulin receptor numbers. The effect of metformin, a dimethyl-substituted biguanide, known to lower plasma insulin and PAI-1 levels in vivo was concomitantly evaluated. Preincubation by an 18-h exposure of Hep G2 cells to 10(-7) M insulin aimed at reducing the number of insulin receptors, was followed by a subsequent 24-h stimulation with 10(-9) M insulin. The decrease in insulin receptors was accompanied as expected, by a reduction in [14C]acetate incorporation, an index of lipid synthesis, whereas PAI-1 secretion and PAI-1 mRNA expression were enhanced. The addition of metformin did not modify the effect of insulin on insulin receptors or [14C]acetate incorporation. In contrast, the drug (10(-4) M) inhibited insulin-mediated PAI-1 synthesis. The results indicate that PAI-1 synthesis in presence of insulin is markedly increased in down-regulated cells, and that metformin inhibits this effect by acting at the cellular level. These in vitro data are relevant with those found in vivo in insulin-resistant patients. Hep G2 cells may be a suitable model to study PAI-1 regulation in response to hyperinsulinemia.

Effect of single oral dose of aspirin on human platelet functions and plasma plasminogen activator inhibitor-1.

Previous reports documented the inhibitory efficacy of different doses of aspirin on arachidonic acid (AA)-induced platelet aggregation, however, the sensitivity of platelets toward other agonists as well as the effects of aspirin on platelet and plasma plasminogen activator inhibitor-1 (PAI-1) release and levels were not investigated. Hence, the present study was undertaken to investigate the effect and duration of action of a single oral dose (650 mg) of aspirin on human platelet functions (n = 34, normal healthy male and female volunteers) including aggregation, fibrinogen binding and PAI-1 release, and on the plasma level of PAI-1. Aspirin demonstrated a rapid onset of action (at 2 h after ingestion) in specifically inhibiting ex vivo AA-mediated functions including (a) fibrinogen binding to gel-purified platelets, (b) platelet aggregation, and (c) platelet PAI-1 release. A peak reduction of plasma PAI-1 level at 2 h was demonstrated as well. The effect of aspirin on the ex vivo AA-mediated effects (a-c) was shown to last for up to 4 days. However, aspirin treatment resulted in a rebound effect in platelet function (a-c) to other platelet agonists such as adenosine diphosphate or the combination of agonists including adenosine diphosphate, epinephrine, and AA. In conclusion, a single oral dose of aspirin has long-acting effects on AA-induced platelet activation and reduces plasma levels of PAI-1 as well.(ABSTRACT TRUNCATED AT 250 WORDS)