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

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

Critical Care ◽

10.1186/cc6428 ◽

2008 ◽

Vol 12 (Suppl 2) ◽

pp. P207

Author(s):

T Yasuda ◽

M Nakahara ◽

Y Kakihana ◽

Y Kanmura

Keyword(s):

Plasminogen Activator ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Surgical Icu ◽

Activator Inhibitor ◽

Soluble E Selectin

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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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D-dimer, plasminogen activator inhibitor-1, prothrombin fragments and protein C – role in prothrombotic state of colorectal cancer.

Neoplasma ◽

10.4149/neo_2011_03_235 ◽

2011 ◽

Vol 58 (3) ◽

pp. 235-238 ◽

Cited By ~ 9

Author(s):

M. MYTNIK ◽

J. STASKO

Keyword(s):

Colorectal Cancer ◽

Plasminogen Activator ◽

Protein C ◽

Plasminogen Activator Inhibitor ◽

Prothrombotic State ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor ◽

D Dimer

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Plasminogen activator inhibitor-1 values predict survival in colorectal cancer

BMJ ◽

10.1136/bmj.316.7134.0f ◽

1998 ◽

Vol 316 (7134) ◽

Keyword(s):

Colorectal Cancer ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor

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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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Association between Five Common Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms and Colorectal Cancer Susceptibility

International Journal of Molecular Sciences ◽

10.3390/ijms21124334 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4334 ◽

Cited By ~ 1

Author(s):

Jisu Oh ◽

Hui Jeong An ◽

Jung Oh Kim ◽

Hak Hoon Jun ◽

Woo Ram Kim ◽

...

Keyword(s):

Colorectal Cancer ◽

Plasminogen Activator ◽

Gene Polymorphisms ◽

Cancer Susceptibility ◽

Plasminogen Activator Inhibitor ◽

Cell Types ◽

Plasminogen Activator Inhibitor 1 ◽

Polymerase Chain ◽

Activator Inhibitor ◽

Pai 1

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (−844G > A [rs2227631], −675 4G > 5G [rs1799889], +43G > A [rs6092], +9785G > A [rs2227694], and +11053T > G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 −675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556; 95% confidence interval (CI): 1.012–2.391; p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620; 95% CI: 0.413–0.932; p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662; 95% CI: 0.469–0.933; p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.

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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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