Plasminogen activator release during venous stasis and exercise as determined by a new specific assay

Wiman, Björn; Mellbring, G; Rånby, Mats

doi:10.1016/s0009-8981(83)80012-6

Cited by 244 publications

(82 citation statements)

References 13 publications

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“…1 A , left ). Because PAI-1 can circulate in both active and latent forms (24), plasma PAI-1 activity was measured using a microtiter system which monitors PAI-1-mediated inhibition of plasminogen-activator activity (16,17). These experiments demonstrated a time-dependent increase in plasma PAI-1 activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Plasminogen activator inhibitor activity was determined by a functional rate assay described by Ranby et al (16), and its adaptation to plasma samples, as described by Wiman et al (17). In brief, samples from normoxic or hypoxic conditions were added to reaction mixture containing a known quantity of tPA, soluble fibrin (Desafib; American Diagnostica), and a plasmin substrate (Spectrozyme PL; American Diagnostica).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Pinsky¹,

Liao²,

Lawson³

et al. 1998

J. Clin. Invest.

182

109

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Oxygen deprivation, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. To investigate the effects of low ambient oxygen tension on the fibrinolytic system, mice were placed in a hypoxic environment with pO 2 Ͻ 40 Torr. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) antigen, detected by ELISA, increased in a time-dependent fashion after hypoxic exposure (increased as early as 4 h, P Ͻ 0.05 vs. normoxic controls), and were accompanied by an increase in plasma PAI-1 activity by 4 h ( P Ͻ 0.05 vs. normoxic controls). Northern analysis of hypoxic murine lung demonstrated an increase in PAI-1 mRNA compared with normoxic controls; in contrast, transcripts for both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) decreased under hypoxic conditions. Immunocolocalization studies identified macrophages as the predominant source of increased PAI-1 within hypoxic lung. Using a transformed murine macrophage line, striking induction of PAI-1 transcripts occurred under hypoxic conditions, due to both increased de novo transcription as well as increased mRNA stability. Consistent with an important role of the fibrinolytic system in hypoxia-induced fibrin accumulation, PAI-1 ϩ / ϩ mice exposed to hypoxia exhibited increased pulmonary fibrin deposition based upon a fibrin immunoblot, intravascular fibrin identified by immunostaining, and increased accumulation of 125 I-fibrinogen/fibrin in hypoxic tissue. In contrast, mice deficient for the PAI-1 gene (PAI-1 Ϫ / Ϫ ) similarly exposed to hypoxic conditions did not display increased fibrin accumulation compared with normoxic PAI-1 ϩ / ϩ controls. Furthermore, homozygous null uPA (uPA Ϫ / Ϫ ) and tPA (tPA Ϫ / Ϫ ) mice subjected to oxygen deprivation showed increased fibrin deposition compared with wildtype controls. These studies identify enhanced expression of PAI-1 as an important mechanism suppressing fibrinolysis under conditions of low oxygen tension, a response which may be further amplified by decreased expression of plasminogen activators. Taken together, these data provide insight into an important potential role of macrophages and the fibrinolytic system in ischemia-induced thrombosis.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Pinsky¹,

Liao²,

Lawson³

et al. 1998

J. Clin. Invest.

182

109

View full text Add to dashboard Cite

show abstract

“…33 Plasma was separated within 1 h by centrifugation for 20 min at 3000 Â g and stored at À701C until assay. Plasma t-PA activity 34 was determined with a parabolic rate assay based on fibrin stimulation of the t-PA-catalysed conversion of Glu-plasminogen to plasmin, which subsequently cleaves the chromogenic substrate. The t-PA activity was expressed in IU/ml by reference to the World Health Organization First International Standard for t-PA coded 86/670 from the National Institute for Biological Standard and Control, Potters Bar, England.…”

Section: Methodsmentioning

confidence: 99%

Effect of delapril–manidipine combination vs irbesartan–hydrochlorothiazide combination on fibrinolytic function in hypertensive patients with type II diabetes mellitus

et al. 2004

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The aim of this double-blind, double-dummy, parallel group study was to compare the effects of delaprilmanidipine combination vs a irbesartan-hydrochlorothiazide combination on plasma tissue plasminogen activator (t-PA) and plasmogen activator inhibitor type I (PAI-l) activities in hypertensive patients with type II diabetes mellitus. After a 4-week run-in placebo period, 80 patients (37 male and 43 female), aged 41-65 years, were randomly allocated to an 8-week treatment with delapril 30 mg once daily or irbesartan 150 mg once daily. Thereafter, manidipine l0 mg once daily was added to delapril treatment and hydrochlorothiazide 12.5 mg to irbesartan treatment for a further 8 weeks. Blood pressure (BP), plasma t-PA and PAI-l activities were evaluated at the end of the run-in period, after 4-week monotherapy treatments, and at the end of the combination treatment periods. Both combination treatments, delapril-manidipine and irbesartan-hydrochlorothiazide, produced a greater reduction in systolic BP/diastolic BP (SBP/DBP) values (À27.6/21.8 mmHg and À26.4/20.2 mmHg, respectively) than the respective monotherapies (À15.2/ 11.7 mmHg with delapril and À16.3/11.3 mmHg with irbesartan). Delapril monotherapy significantly decreased plasma PAI-l activity (À10.4 IU/mI; Po0.05). The addition of manidipine produced a significant increase in t-PA activity ( þ 0.27 IU/mI); Po0.05). Irbesartan monotherapy did not significantly affect the fibrinolytic balance, whereas the addition of hydrochlorothiazide worsened it, producing a significant increase in PAI-l activity ( þ 9.5 IU/ml; Po0.05). In hypertensive patients with type II diabetes mellitus, the combination delapril-manidipine may determine a greater improvement of the fibrinolytic function than the respective monotherapy, while the association irbesartan-hydrochlorothiazide may worsen it.

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“…The serine protease t-PA, the predominant plasminogen activator in blood, is synthesized and secreted by endothelial cells and circulates in a single-chain form (6)(7)(8). This form is cleaved by plasmin into the double-chain form, consisting of an amino-terminal "heavy" (H) chain and a carboxy-terminal "light" (L) chain held together by a disulfide bond (9,10).…”

Section: Introductionmentioning

confidence: 99%

Interaction between plasminogen activator inhibitor type 1 (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Binding of t-PA/PAI-1 complexes to fibrin mediated by both the finger and the kringle-2 domain of t-PA.

Wagner¹,

Vries²,

Hohmann³

et al. 1989

J. Clin. Invest.

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Plasminogen activation is catalyzed both by tissue-type-(t-PA) and by urokinase-type plasminogen activator (u-PA). This reaction is controlled by plasminogen activator inhibitor type 1 (PAI-1) that is either present in plasma or bound to fibrin, present in a thrombus. We studied the mechanism of in vitro inhibition of both t-PA and u-PA activity by PAI-1 bound to fibrin. It is shown that activation of latent PAI-1 unmasks a specific fibrin-binding site that is distinct from its reactive site. This reactive site of activated PAI-1 bound to fibrin is fully exposed to form complexes with t-PA and u-PA, that are unable to activate plasminogen. Upon complex formation with either one of the plasminogen activators, PAI-1 apparently undergoes a conformational change and loses its affinity for fibrin. Consequently, complexes of u-PA and PAI-1 dissociate from the fibrin matrix and are encountered in the fluid phase. In contrast, t-PA/PAI-1 complexes remain bound to fibrin. By employing recombinant t-PA deletion-mutant proteins, that precisely lack domains involved in fibrin binding, we demonstrate that binding of t-PA/PAI-1 complexes is mediated by both the "finger" (F) and the "kringle-2" (K2) domain of t-PA. A model is proposed that explains inhibition of the fibrinolytic process, at the level of plasminogen activation by t-PA, directed by PAI-1 bound to fibrin. An implication of the proposed model is that t-PA/PAI-1 complexes and free t-PA compete for the same binding sites on fibrin.

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Plasminogen activator release during venous stasis and exercise as determined by a new specific assay

Cited by 244 publications

References 13 publications

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Effect of delapril–manidipine combination vs irbesartan–hydrochlorothiazide combination on fibrinolytic function in hypertensive patients with type II diabetes mellitus

Interaction between plasminogen activator inhibitor type 1 (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Binding of t-PA/PAI-1 complexes to fibrin mediated by both the finger and the kringle-2 domain of t-PA.

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