Plasminogen Activator Inhibitor 1 and Plasminogen Activator Inhibitor 2 in Various Disease States

Kruithof, Egbert K. O.; Gudinchet, Annelise; Bachmann, Fédor

doi:10.1055/s-0038-1642556

Cited by 165 publications

(65 citation statements)

References 48 publications

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“…Our findings might explain the apparently paradoxical clinical findings of a strong relationship between the levels of this protease inhibitor, high metastasis rate and poor survival [12][13][14] . (Fig.…”

Section: Discussionmentioning

confidence: 91%

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Bajou

Noël

Gerard

et al. 1998

Nat Med

623

474

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Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angio-genesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.Tumor cell invasion and metastatic processes require the coordinated and temporal regulation of a series of adhesive, proteolytic and migratory events 1 . The plasminogen activator (PA)-plasmin proteolytic system has been implicated in these processes. Urokinase-type (uPA) and tissue-type (tPA) plasminogen activators are serine proteases that catalyze the conversion of inactive plasminogen into plasmin, a broadly acting enzyme able to degrade a variety of extracellular matrix proteins and to activate metalloproteinases and growth factors 2,3 . Plasminogen and uPA bind to their specific receptors directing plasmin activity to the migrating tumor cell surface. The activities of PA are directly controlled by specific inhibitors, the PA inhibitors 1 and 2 (PAI1 and PAI2) (ref. 4).Many studies have focused on the role of uPA in cellular invasion and metastasis. Much of the data supporting the role of uPA in these events derives from in vitro and in vivo experiments demonstrating a correlation between uPA expression and cell invasion and metastasis as well as reduction of metastatic potential by using natural or synthetic serine protease inhibitors, neutralizing antibodies to uPA or antisense oligonucleotides 5,6 . PAI1 may also be directly involved in cancer progression. Both tumor cells and capillary endothelial cells express higher levels of PAI1 than other cell types [7][8][9] . Surprisingly, this inhibitor is necessary for optimal invasion of cultured lung cancer cells 10 , and an increasing number of clinical studies have demonstrated that high PAI1 levels indicate a poor prognosis for the survival of patients suffering from a variety of cancers [11][12][13] . However, as PAI1 is an acute-phase reactant 14 , it remains undetermined whether the increased PAI1 levels causally contribute to, or rather are the consequence of, the malignancy.Various observations indicate that the PA system may provide both surface-associated protease activity and an adhesion mechanism for cells through interaction with vitronectin. Deng et al. suggested that the balance between cell adhesion and cell detachment is governed by PAI1 (ref. 15). The PAI1-mediated release of cells attached to vitronectin seems to occur independently of the abili...

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Section: Discussionmentioning

confidence: 91%

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Bajou

Noël

Gerard

et al. 1998

Nat Med

623

474

View full text Add to dashboard Cite

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“…These factors share 3 characteristics: ( 1) undetectable serum concentrations in normal subjects, (2) rapid and marked increase in serum concentration in response to an in- sult, and (3) return to normal serum concentrations with resolution of tissue injury.29 Plasma PAI-1 activity responds similarly to acute insults such as surgery, and has been considered an acute phase reactant in people. 30 The increase in PAI-1 activity that occurs in people after surgery has been termed the postoperative "fibrinolytic shut down"; this response predisposes patients to develop venous thrombosis and pulmonary embolism.31 Human plasma PAI-I activity is increased 18 to 24 hours after surgery, and the PAI-I activity profile over the ensuing 7 days mirrors that of C-reactive protein. 32 The stimulus for the rapid, transient postoperative increase in plasma PAl-1 activity is different from that mediating other inflammatory responses in that it does not appear to be either tumor necrosis factor-a or interleukin-1, but a distinct, as yet uncharacterized plasma factor.…”

Section: Discussionmentioning

confidence: 99%

Fibrinolytic Activity in Plasma From Horses With Gastrointestinal Diseases: Changes Associated With Diagnosis, Surgery, and Outcome

Collatos

Barton

Moore

1995

Veterinary Internal Medicne

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Plasma fibrinolytic activity was evaluated over 5 consecutive days in 59 horses admitted to the Large Animal Teaching Hospital with acute gastrointestinal diseases. Only horses hospitalized for at least 5 days were included in the study. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) were quantitated using standard chromogenic activity assays. Statistical analyses were performed using analysis of variance; differences were considered significant when P I .05. Activity of PAI-1, the primary endogenous inhibitor of fibrinolysis, was significantly increased on hospital days 2, 4, and 5 in horses that died, when compared with those that were discharged from the hospital. Plasma PAL1 activity was not different at admission, but was significantly increased on hospital days 2 and 3 in horses that underwent surgery, when compared with those that did not, suggesting an acute phase response to surgical intervention.ndotoxin, a lipopolysaccharide component of the

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“…urokinase, factor XIa, activated protein C) has led to the classification of this inhibitor in the serine protease inhibitor (serpin) superfamily (1,2). The role of PAI-1 as a primary regulator of fibrinolysis was initially raised by the association of elevated blood PAI-1 and a number of physiological and pathological processes that carry an increased risk of thrombotic complications, including pregnancy (4,5), severe trauma (6), major surgery (7), and a wide spectrum of other disease states (8). This concept is further supported by the correlation of bleeding disorders in a number of patients with a deficiency in blood PAI-1 activity (9 -13).…”

Section: Type 1 Plasminogen Activator Inhibitor (Pai-1)mentioning

confidence: 99%

Calcium-dependent Stabilization of Type I Plasminogen Activator Inhibitor within Plateletα-Granules

Lang

Schleef

1996

Journal of Biological Chemistry

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Type 1 plasminogen activator inhibitor (PAI-1) is known to be synthesized in an active conformation but it is rapidly converted into an inactive conformation (t1 ⁄2 1 h) upon incubation at 37°C. This study was initiated to investigate the mechanism that account for the presence of active PAI-1 in anucleated platelets that have a mean life span of 9 -12 days in the circulation. Stabilization experiments with a functional immunoassay indicated that the activity of PAI-1 in both platelets and in isolated ␣-granules was prolonged in comparison to the rapid inactivation of this molecule in their lysates (t1 ⁄2 1 h). Although combined ligand blot/immunoblot analysis revealed that vitronectin was the major PAI-1 binding protein in platelets, vitronectin/PAI-1 complexes were not detected in ␣-granules using a two-site immunoassay. Co-incubation of ␣-granules with a number of agents that disrupt pH gradients (e.g. ionophores) had no effect on the stability of PAI-1 activity, whereas incubation of ␣-granules with the calcium ionophore A23187 reduced the half-life of PAI-1 to the levels observed for PAI-1 in solution. Addition of calcium ions to intact ␣-granules was an effective means of neutralizing the ionophore's effect on PAI-1 activity. Fractionation of ␣-granule proteins on molecular sieving columns using conditions known to be present within storage granules (e.g. a high calcium concentration) revealed the presence of PAI-1 in fractions with a molecular mass of >10 6 daltons. Immunoabsorption of PAI-1 from these column fractions followed by negative staining revealed 25-nm diameter complexes of ␣-granule proteins under the electron microscope. PAI-1 activity associated with these complexes was prolonged in the presence of calcium ions and these high M r complexes were shown to be composed of a defined set of proteins that can be dissociated from PAI-1 by chelation of calcium ions. These data indicate that PAI-1 is stabilized by its packaging with other ␣-granule proteins in a calcium-dependent manner.Type 1 plasminogen activator inhibitor (PAI-1) 1 is the primary physiological inhibitor of vascular tissue-type plasminogen activator with rate constants greater than 10 7 (mol/liter) Ϫ1

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Plasminogen Activator Inhibitor 1 and Plasminogen Activator Inhibitor 2 in Various Disease States

Cited by 165 publications

References 48 publications

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Fibrinolytic Activity in Plasma From Horses With Gastrointestinal Diseases: Changes Associated With Diagnosis, Surgery, and Outcome

Calcium-dependent Stabilization of Type I Plasminogen Activator Inhibitor within Plateletα-Granules

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