Association of mortality in the surgical ICU with plasma concentrations of plasminogen activator inhibitor-1 and soluble E-selectin

SummaryFibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of fibrates on fibrinogen, PAI-1 and apo A-I synthesis and the underlying regulatory mechanisms in primary monkey hepatocytes.We show that fibrates time- and dose-dependently increase fibrinogen and apo A-I expression and decrease PAI-1 expression in cultured cynomolgus monkey hepatocytes, the effects demonstrating different potency for different fibrates. After three consecutive periods of 24 h the most effective fibrate, ciprofibrate (at 1 mmol/l), increased fibrinogen and apo A-I synthesis to 356% and 322% of control levels, respectively. Maximum inhibition of PAI-1 synthesis was about 50% of control levels and was reached by 1 mmol/l gemfibrozil or ciprofibrate after 48 h. A ligand for the retinoid-X-receptor (RXR), 9-cis retinoic acid, and specific activators of the peroxisome proliferator-activated receptor-α (PPARα), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARα/RXRα heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARα trans-activation activity as determined in a PPARα-sensitive reporter gene system and the ability of the compounds to affect fibrinogen, PAI-1 and apo A-I antigen production, a good correlation (r = 0.80; p <0.01) between PPARα transactivation and fibrinogen expression was found. Apo A-I expression correlated only weakly with PPARα transactivation activity (r = 0.47; p = 0.24), whereas such a correlation was absent for PAI-1 (r = 0.03; p = 0.95). These results strongly suggest an involvement of PPARα in the regulation of fibrinogen gene expression.

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Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice

Blood ◽

10.1182/blood.v96.1.153.013k11_153_160 ◽

2000 ◽

Vol 96 (1) ◽

pp. 153-160

Author(s):

Tomihisa Kawasaki ◽

Mieke Dewerchin ◽

Henri R. Lijnen ◽

Jos Vermylen ◽

Marc F. Hoylaerts

Keyword(s):

Carotid Artery ◽

Plasminogen Activator ◽

Thrombus Formation ◽

Blood Platelets ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Deficient Mice ◽

Activator Inhibitor ◽

Pai 1

The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice. Photochemically induced thrombosis in the carotid artery was analyzed via transillumination. In comparison to thrombosis in C57BL/6J wild-type (wt) mice (113 ± 19 × 106 arbitrary light units [AU] n = 15, mean ± SEM), thrombosis in PAI-1−/− mice (40 ± 10 × 106 AU, n = 13) was inhibited (P < .01), indicating that PAI-1 controls fibrinolysis during thrombus formation. Systemic administration of murine PAI-1 into PAI-1−/− mice led to a full recovery of thrombotic response. Occurrence of fibrinolytic activity was confirmed in 2-antiplasmin (2-AP)–deficient mice. The sizes of thrombi developing in wt mice, in 2-AP+/− and 2-AP−/− mice were 102 ± 35, 65 ± 8.1, and 13 ± 6.1 × 106 AU, respectively (n = 6 each) (P < .05), compatible with functional plasmin inhibition by 2-AP. In contrast, thrombi in wt mice, t-PA−/− and u-PA−/−mice were comparable, substantiating efficient inhibition of fibrinolysis by the combined PAI-1/2-AP action. Platelet depletion and reconstitution confirmed a normal thrombotic response in wt mice, reconstituted with PAI-1−/− platelets, but weak thrombosis in PAI-1−/− mice reconstituted with wt platelets. Accordingly, murine (wt) PAI-1 levels in platelet lysates and releasates were 0.43 ± 0.09 ng/109 platelets and plasma concentrations equaled 0.73 ± 0.13 ng/mL. After photochemical injury, plasma PAI-1 rose to 2.9 ± 0.7 ng/mL (n = 9, P < .01). The plasma rise was prevented by ligating the carotid artery. Hence, during acute thrombosis, fibrinolysis is efficiently prevented by plasma 2-AP, but also by vascular PAI-1, locally released into the circulation after endothelial injury.

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Short-Term Infusions of Insulin, Triacylglycerol and Glucose do not Cause Acute Increases in Plasminogen Activator Inhibitor-1 Concentrations in Man

Clinical Science ◽

10.1042/cs0790513 ◽

1990 ◽

Vol 79 (5) ◽

pp. 513-516 ◽

Cited By ~ 57

Author(s):

P. J. Grant ◽

E. K. O. Kruithof ◽

C. P. Felley ◽

J. P. Felber ◽

F. Bachmann

Keyword(s):

Plasminogen Activator ◽

Glucose Concentration ◽

Plasma Insulin ◽

Insulin Infusion ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Short Term ◽

Mean Glucose ◽

Activator Inhibitor

1. To investigate the acute effects of insulin and triacylglycerol (‘triglyceride’) on circulating plasminogen activator inhibitor-1 concentrations, seven healthy volunteers were studied during hyperinsulinaemic clamps in the presence of euglycaemia (mean glucose concentration 5 mmol/l) and hyperglycaemia (mean glucose concentration 9 mmol/l) with and without triacylglycerol infusions. 2. During euglycaemia, plasma insulin levels rose from baseline values [median (range)] of 13 (6.6–20.6) m-units/l to 89 (74–105) m-units/l and 99 (74–109) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 fell from 27.5 (10–47) ng/ml to 25.0 (14.5–55) ng/ml and 15.5 (11.5–28.5) ng/ml (P < 0.02) over the same time. 3. During hyperglycaemia, plasma insulin concentrations were 12.1 (9.3–17.1) m-units/l at the run-in period and rose to 87 (73–112) m-units/l and 91 (84–97) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 again showed a gradual fall from 24.7 (22–50) ng/ml to 14 (8.3–25.5) ng/ml and 13 (6.0–35.0) ng/ml (P < 0.02) over the same period. 4. Infusion of Intralipid in the presence of hyperinsulinaemia with either euglycaemia or hyperglycaemia was associated with a similar fall in concentrations of plasminogen activator inhibitor-1 over the study period. 5. The results from this study indicate that short-term increases in insulin, glucose or triacylglycerol do not cause acute increases in plasma concentrations of plasminogen activator inhibitor-1.

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Functional Stability of Plasminogen Activator Inhibitor-1

The Scientific World JOURNAL ◽

10.1155/2014/858293 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 39

Author(s):

Songul Yasar Yildiz ◽

Pinar Kuru ◽

Ebru Toksoy Oner ◽

Mehmet Agirbasli

Keyword(s):

Plasminogen Activator ◽

Biological Effects ◽

Critical Role ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Plasminogen Activator Inhibitor 1 ◽

Type Plasminogen Activator ◽

Activator Inhibitor ◽

Pai 1

Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and a major regulator of the fibrinolytic system. PAI-1 plays a pivotal role in acute thrombotic events such as deep vein thrombosis (DVT) and myocardial infarction (MI). The biological effects of PAI-1 extend far beyond thrombosis including its critical role in fibrotic disorders, atherosclerosis, renal and pulmonary fibrosis, type-2 diabetes, and cancer. The conversion of PAI-1 from the active to the latent conformation appears to be unique among serpins in that it occurs spontaneously at a relatively rapid rate. Latency transition is believed to represent a regulatory mechanism, reducing the risk of thrombosis from a prolonged antifibrinolytic action of PAI-1. Thus, relying solely on plasma concentrations of PAI-1 without assessing its function may be misleading in interpreting the role of PAI-1 in many complex diseases. Environmental conditions, interaction with other proteins, mutations, and glycosylation are the main factors that have a significant impact on the stability of the PAI-1 structure. This review provides an overview on the current knowledge on PAI-1 especially importance of PAI-1 level and stability and highlights the potential use of PAI-1 inhibitors for treating cardiovascular disease.

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Association between plasma concentrations of plasminogen activator inhibitor-1 and survival in patients with colorectal cancer

BMJ ◽

10.1136/bmj.316.7134.829 ◽

1998 ◽

Vol 316 (7134) ◽

pp. 829-830 ◽

Cited By ~ 53

Author(s):

H. J. Nielsen ◽

H. Pappot ◽

I. J. Christensen ◽

N. Brunner ◽

O. Thorlacius-Ussing ◽

...

Keyword(s):

Colorectal Cancer ◽

Plasminogen Activator ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor

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Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice

Blood ◽

10.1182/blood.v96.1.153 ◽

2000 ◽

Vol 96 (1) ◽

pp. 153-160 ◽

Cited By ~ 46

Author(s):

Tomihisa Kawasaki ◽

Mieke Dewerchin ◽

Henri R. Lijnen ◽

Jos Vermylen ◽

Marc F. Hoylaerts

Keyword(s):

Carotid Artery ◽

Plasminogen Activator ◽

Thrombus Formation ◽

Blood Platelets ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Deficient Mice ◽

Activator Inhibitor ◽

Pai 1

Abstract The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice. Photochemically induced thrombosis in the carotid artery was analyzed via transillumination. In comparison to thrombosis in C57BL/6J wild-type (wt) mice (113 ± 19 × 106 arbitrary light units [AU] n = 15, mean ± SEM), thrombosis in PAI-1−/− mice (40 ± 10 × 106 AU, n = 13) was inhibited (P < .01), indicating that PAI-1 controls fibrinolysis during thrombus formation. Systemic administration of murine PAI-1 into PAI-1−/− mice led to a full recovery of thrombotic response. Occurrence of fibrinolytic activity was confirmed in 2-antiplasmin (2-AP)–deficient mice. The sizes of thrombi developing in wt mice, in 2-AP+/− and 2-AP−/− mice were 102 ± 35, 65 ± 8.1, and 13 ± 6.1 × 106 AU, respectively (n = 6 each) (P < .05), compatible with functional plasmin inhibition by 2-AP. In contrast, thrombi in wt mice, t-PA−/− and u-PA−/−mice were comparable, substantiating efficient inhibition of fibrinolysis by the combined PAI-1/2-AP action. Platelet depletion and reconstitution confirmed a normal thrombotic response in wt mice, reconstituted with PAI-1−/− platelets, but weak thrombosis in PAI-1−/− mice reconstituted with wt platelets. Accordingly, murine (wt) PAI-1 levels in platelet lysates and releasates were 0.43 ± 0.09 ng/109 platelets and plasma concentrations equaled 0.73 ± 0.13 ng/mL. After photochemical injury, plasma PAI-1 rose to 2.9 ± 0.7 ng/mL (n = 9, P < .01). The plasma rise was prevented by ligating the carotid artery. Hence, during acute thrombosis, fibrinolysis is efficiently prevented by plasma 2-AP, but also by vascular PAI-1, locally released into the circulation after endothelial injury.

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Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins

Twin Research and Human Genetics ◽

10.1017/thg.2017.36 ◽

2017 ◽

Vol 20 (4) ◽

pp. 338-348 ◽

Cited By ~ 1

Author(s):

Anna Janina Engstler ◽

Turid Frahnow ◽

Michael Kruse ◽

Andreas Friedrich Hermann Pfeiffer ◽

Ina Bergheim

Keyword(s):

Adipose Tissue ◽

Mrna Expression ◽

Plasminogen Activator ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Fatty Tissue ◽

Plasminogen Activator Inhibitor 1 ◽

The Impact ◽

Activator Inhibitor ◽

Pai 1

In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18–70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p< .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients — for example, a switch to a fat-rich diet — affects PAI-1 concentrations in humans and that this is highly heritable.

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943: Plasminogen Activator Inhibitor 1 (PAI-1) is Increased in Human Peyronie's Disease

The Journal of Urology ◽

10.1016/s0022-5347(18)35099-7 ◽

2005 ◽

Vol 173 (4S) ◽

pp. 255-255 ◽

Cited By ~ 1

Author(s):

Hugo H. Davila ◽

Thomas R. Magee ◽

Freddy Zuniga ◽

Jacob Rajfer ◽

Nestor F. GonzalezCadavid

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Peyronie’S Disease ◽

Plasminogen Activator Inhibitor 1 ◽

Peyronie's Disease ◽

Activator Inhibitor ◽

Pai 1

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Relationship of Plasminogen Activator Inhibitor-1 Levels following Thrombolytic Therapy with rt-PA as Compared to Streptokinase and Patency of Infarct Related Coronary Artery

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614637 ◽

1999 ◽

Vol 82 (07) ◽

pp. 104-108 ◽

Cited By ~ 13

Author(s):

Franck Paganelli ◽

Marie Christine Alessi ◽

Pierre Morange ◽

Jean Michel Maixent ◽

Samuel Lévy ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Thrombolytic Therapy ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Control Group ◽

Plasminogen Activator Inhibitor 1 ◽

Vessel Patency ◽

Activator Inhibitor ◽

Pai 1

Summary Background: Type 1 plasminogen activator inhibitor (PAI-1) is considered to be risk factor for acute myocardial infarction (AMI). A rebound of circulating PAI-1 has been reported after rt-PA administration. We investigated the relationships between PAI-1 levels before and after thrombolytic therapy with streptokinase (SK) as compared to rt-PA and the patency of infarct-related arteries. Methods and Results: Fifty five consecutive patients with acute MI were randomized to strep-tokinase or rt-PA. The plasma PAI-1 levels were studied before and serially within 24 h after thrombolytic administration. Vessel patency was assessed by an angiogram at 5 ± 1days. The PAI-1 levels increased significantly with both rt-PA and SK as shown by the levels obtained from a control group of 10 patients treated with coronary angioplasty alone. However, the area under the PAI-1 curve was significantly higher with SK than with rt-PA (p <0.01) and the plasma PAI-1 levels peaked later with SK than with rt-PA (18 h versus 3 h respectively). Conversely to PAI-1 levels on admission, the PAI-1 levels after thrombolysis were related to vessel patency. Plasma PAI-1 levels 6 and 18 h after SK therapy and the area under the PAI-1 curve were significantly higher in patients with occluded arteries (p <0.002, p <0.04 and p <0.05 respectively).The same tendency was observed in the t-PA group without reaching significance. Conclusions: This study showed that the PAI-1 level increase is more pronounced after SK treatment than after t-PA treatment. There is a relationship between increased PAI-1 levels after thrombolytic therapy and poor patency. Therapeutic approaches aimed at quenching PAI-1 activity after thrombolysis might be of interest to improve the efficacy of thrombolytic therapy for acute myocardial infarction.

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