A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?

Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics.

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A Specific Immunologic Assay for Functional Plasminogen Activator Inhibitor 1 in Plasma – Standardized Measurements of the Inhibitor and Related Parameters in Patients with Venous Thromboembolic Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646305 ◽

1992 ◽

Vol 68 (05) ◽

pp. 486-494 ◽

Cited By ~ 15

Author(s):

Malou Philips ◽

Anne-Grethe Juul ◽

Johan Selmer ◽

Bent Lind ◽

Sixtus Thorsen

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Normal Subjects ◽

Tissue Type ◽

Blood Collection ◽

Plasminogen Activator Inhibitor 1 ◽

Type Plasminogen Activator ◽

Significant Difference ◽

Activator Inhibitor ◽

Pai 1

SummaryA new assay for functional plasminogen activator inhibitor 1 (PAI-1) in plasma was developed. The assay is based on the quantitative conversion of PAI-1 to urokinase-type plasminogen activator (u-PA)-PAI-l complex the concentration of which is then determined by an ELISA employing monoclonal anti-PAI-1 as catching antibody and monoclonal anti-u-PA as detecting antibody. The assay exhibits high sensitivity, specificity, accuracy, and precision. The level of functional PAI-1, tissue-type plasminogen activator (t-PA) activity and t-PA-PAI-1 complex was measured in normal subjects and in patients with venous thromboembolism in a silent phase. Blood collection procedures and calibration of the respective assays were rigorously standardized. It was found that the patients had a decreased fibrinolytic capacity. This could be ascribed to high plasma levels of PAI-1. The release of t-PA during venous occlusion of an arm for 10 min expressed as the increase in t-PA + t-PA-PAI-1 complex exhibited great variation and no significant difference could be demonstrated between the patients with a thrombotic tendency and the normal subjects.

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Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients

Scientific Reports ◽

10.1038/s41598-020-80010-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yu Zuo ◽

Mark Warnock ◽

Alyssa Harbaugh ◽

Srilakshmi Yalavarthi ◽

Kelsey Gockman ◽

...

Keyword(s):

Plasminogen Activator ◽

Ex Vivo ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Bleeding Complications ◽

Clot Lysis ◽

Thrombosis Prophylaxis ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor ◽

Pai 1

AbstractPatients with coronavirus disease-19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. However, bleeding complications have also been observed in some patients. Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies. 118 hospitalized COVID-19 patients and 30 healthy controls were included in the study. We measured plasma antigen levels of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) and performed spontaneous clot-lysis assays. We found markedly elevated tPA and PAI-1 levels in patients hospitalized with COVID-19. Both factors demonstrated strong correlations with neutrophil counts and markers of neutrophil activation. High levels of tPA and PAI-1 were associated with worse respiratory status. High levels of tPA, in particular, were strongly correlated with mortality and a significant enhancement in spontaneous ex vivo clot-lysis. While both tPA and PAI-1 are elevated among COVID-19 patients, extremely high levels of tPA enhance spontaneous fibrinolysis and are significantly associated with mortality in some patients. These data indicate that fibrinolytic homeostasis in COVID-19 is complex with a subset of patients expressing a balance of factors that may favor fibrinolysis. Further study of tPA as a biomarker is warranted.

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Abstract T P75: Temporal Profiles of Plasminogen Activator Inhibitor-1 Concentration and Activity Changes in Circulation after Focal Stroke and Tissue Type Plasminogen Activator Administration in Rats

Stroke ◽

10.1161/str.45.suppl_1.tp75 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Qi Liu ◽

Xiang Fan ◽

Helen Brogren ◽

Ming-Ming Ning ◽

Eng H Lo ◽

...

Keyword(s):

Endothelial Cells ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Plasminogen Activator Inhibitor 1 ◽

Type Plasminogen Activator ◽

Temporal Profiles ◽

Activator Inhibitor ◽

Pai 1

Aims: Plasminogen activator inhibitor-1 (PAI-1) is the main and potent endogenous tissue-type plasminogen activator (tPA) inhibitor, but an important question on whether PAI-1 in blood stream responds and interferes with the exogenously administered tPA remains unexplored. We for the first time investigated temporal profiles of PAI-1 concentration and activity in circulation after stroke and tPA administration in rats. Methods: Permanent MCAO focal stroke of rats were treated with saline or 10mg/kg tPA at 3 hours after stroke (n=10 per group). Plasma (platelet free) PAI-1 antigen and activity levels were measured by ELISA at before stroke, 3, 4.5 (1.5 hours after saline or tPA treatments) and 24 hours after stroke. Since vascular endothelial cells and platelets are two major cellular sources for PAI-1 in circulation, we measured releases of PAI-1 from cultured endothelial cells and isolated platelets after direct tPA (4 μg/ml) exposures for 60 min in vitro by ELISA (n=4 per group). Results: At 3 hours after stroke, both plasma PAI-1 antigen and activity were significantly increased (3.09±0.67, and 3.42±0.57 fold of before stroke baseline, respectively, all data are expressed as mean±SE). At 4.5 hours after stroke, intravenous tPA administration significantly further elevated PAI-1 antigen levels (5.26±1.24), while as expected that tPA neutralized most elevated PAI-1 activity (0.33±0.05). At 24 hours after stroke, PAI-1 antigen levels returned to the before baseline level, however, there was a significantly higher PAI-1 activity (2.51±0.53) in tPA treated rats. In vitro tPA exposures significantly increased PAI-1 releases into culture medium in cultured endothelial cells (1.65±0.08) and platelets (2.02±0.17). Conclution: Our experimental results suggest that tPA administration may further elevate stroke-increased blood PAI-1 concentration, but also increase PAI-1 activity at late 24 hours after stroke. The increased PAI-1 releases after tPA exposures in vitro suggest tPA may directly stimulate PAI-1 secretions from vascular walls and circulation platelets, which partially contributes to the PAI-1 elevation observed in focal stroke rats. The underlying regulation mechanisms and pathological consequence need further investigation.

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Plasminogen activator inhibitor-1 rises after hemorrhage in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.268.6.e1065 ◽

1995 ◽

Vol 268 (6) ◽

pp. E1065-E1069 ◽

Cited By ~ 2

Author(s):

M. Yamashita ◽

D. N. Darlington ◽

E. J. Weeks ◽

R. O. Jones ◽

D. S. Gann

Keyword(s):

Plasminogen Activator ◽

High Performance ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Sprague Dawley ◽

Plasminogen Activator Inhibitor 1 ◽

Sprague Dawley Rats ◽

Type Plasminogen Activator ◽

Activator Inhibitor ◽

Pai 1

Large hemorrhage leads to hypercoagulability, a phenomenon that has never been well explained. Because an elevation of plasminogen activator inhibitor (PAI)-1 increases procoagulant activity, we have determined whether plasma PAI activity and tissue PAI-1 mRNA are elevated after hemorrhage. Sprague-Dawley rats were bled (20 or 15 ml/kg) 4 days after cannulation. Plasma PAI activity was determined by the capacity of plasma to inhibit tissue-type plasminogen activator activity. Changes of PAI-1 mRNA in various tissues were detected by high-performance liquid chromatography after reverse transcription and polymerase chain reaction. Hemorrhage (20 ml/kg) significantly elevated plasma PAI activity at 0.5, 1, 2, 4, 6, and 8 h after hemorrhage and PAI-1 mRNA in liver at 1, 2, 4, and 6 h after hemorrhage. The PAI-1 message was also significantly elevated in lung, heart, and kidney at 4 h after hemorrhage. The increases of PAI-1 mRNA after 20 ml/kg hemorrhage were significantly greater than those after 15 ml/kg hemorrhage. These findings indicate that large hemorrhage can induce the increases in PAI activity and PAI-1 message and suggest that induction of PAI-1 may be involved in the thrombogenic responses observed after large hemorrhage.

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Spironolactone Abolishes the Relationship between Aldosterone and Plasminogen Activator Inhibitor-1 in Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.2.7980 ◽

2002 ◽

Vol 87 (2) ◽

pp. 448-452 ◽

Cited By ~ 41

Author(s):

Pairunyar Sawathiparnich ◽

Sandeep Kumar ◽

Douglas E. Vaughan ◽

Nancy J. Brown

Keyword(s):

Angiotensin Ii ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Plasminogen Activator Inhibitor 1 ◽

Type Plasminogen Activator ◽

Serum Aldosterone ◽

The Relationship ◽

Activator Inhibitor ◽

Pai 1

Recent studies have defined a link between the renin-angiotensin-aldosterone system and fibrinolysis. The present study tests the hypothesis that endogenous aldosterone regulates plasminogen activator inhibitor-1 (PAI-1) production in humans. Hemodynamic parameters, PAI-1 and tissue-type plasminogen activator (t-PA) antigen, potassium, PRA, angiotensin II, and aldosterone were measured in nine male hypertensive subjects after a 3-wk washout, after 2 wk of hydrochlorothiazide (HCTZ; 25 mg plus 20 mmol KCl/d), and after 2 wk of spironolactone (100 mg/d plus KCl placebo). Spironolactone (P = 0.04), but not HCTZ (P = 0.57 vs. baseline; P = 0.1 vs. spironolactone), significantly lowered systolic blood pressure. Angiotensin II increased from baseline during both HCTZ (P = 0.02) and spironolactone (P = 0.02 vs. baseline; P = 0.19 vs. HCTZ) treatments. Although both HCTZ (P = 0.004) and spironolactone (P < 0.001 vs. baseline) increased aldosterone, the effect was greater with spironolactone (P < 0.001 vs. HCTZ). HCTZ increased PAI-1 antigen (P = 0.02), but did not alter t-PA antigen. In contrast, there was no effect of spironolactone on PAI-1 antigen (P = 0.28), whereas t-PA antigen was increased (P = 0.01). There was a significant correlation between PAI-1 antigen and serum aldosterone during both baseline and HCTZ study days (r2 = 0.57; P = 0.0003); however, treatment with spironolactone abolished this correlation (r2 = 0.13; P = 0.33). This study provides evidence that endogenous aldosterone influences PAI-1 production in humans.

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Inactivation of Plasminogen Activator Inhibitor-1 Accelerates Thrombolysis of a Platelet-rich Thrombus in Rat Mesenteric Arterioles

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616758 ◽

2001 ◽

Vol 86 (12) ◽

pp. 1528-1531 ◽

Cited By ~ 18

Author(s):

Alain Rupin ◽

Frédéric Martin ◽

Marie-Odile Vallez ◽

Edith Bonhomme ◽

Tony Verbeuren

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Cerebral Stroke ◽

Plasminogen Activator Inhibitor 1 ◽

Thrombosis Model ◽

Rat Mesentery ◽

Student’S T ◽

Activator Inhibitor ◽

Pai 1

SummaryTo investigate the role of active plasminogen activator inhibitor 1 (PAI-1) in the evolution of a microthrombus generated in the arteriolar microcirculation, the monoclonal antibody, 33H1F7, which transforms active PAI-1 to a tissue type plasminogen activator (t-PA) substrate, was evaluated in an arteriolar thrombosis model in the rat mesentery. Arterioles (200-300 μm) were stimulated electrically to create an endothelial lesion; ADP was then perfused for 2 min to induce the formation of a platelet-rich thrombus which lysed spontaneously in 140 ± 24 s. Two successive ADP superfusions produced comparable thrombi which lysed in comparable times. Different doses of 33H1F7 were infused to rats for 30 min and the dose which inactivates rapidly and totally active rat PAI-1 (300 μg/kg/min) was selected to be tested on the thrombosis model. Infusion of 33H1F7 beginning 10 min before the ADP application significantly reduced the lysis time in comparison to the control (123 ± 30 s versus 169 ± 33 s, P < 0.05, paired Student’s t-test) and the cumulative thrombus area during the lysis period was decreased by 56 ± 7%. These results demonstrate that inactivation of PAI-1 is able to accelerate lysis of a platelet-rich clot in a mesenteric arteriole of the rat. Thus active PAI-1 most likely participates to the resistance to thrombolysis in the arteriolar microcirculation and its inactivation may shorten ischemic periods after microvascular obstruction such as e.g. during cerebral stroke.

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The interaction of plasminogen activator inhibitor 1 with plasminogen activators (tissue-type and urokinase-type) and fibrin: localization of interaction sites and physiologic relevance

Blood ◽

10.1182/blood.v78.2.401.401 ◽

1991 ◽

Vol 78 (2) ◽

pp. 401-409 ◽

Cited By ~ 78

Author(s):

J Keijer ◽

M Linders ◽

AJ van Zonneveld ◽

HJ Ehrlich ◽

JP de Boer ◽

...

Keyword(s):

Plasminogen Activator ◽

Regulatory Protein ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activators ◽

Tissue Type ◽

Clot Lysis ◽

Plasminogen Activator Inhibitor 1 ◽

Interaction Sites ◽

Activator Inhibitor ◽

Pai 1

Abstract Plasminogen activator inhibitor 1 (PAI-1), an essential regulatory protein of the fibrinolytic system, harbors interaction sites for plasminogen activators (tissue-type [t-PA] and urokinase-type [u-PA]) and for fibrin. In this study, anti-PAI-1 monoclonal antibodies (MoAbs) were used to identify interaction sites of PAI-1 with these components. The binding sites of 18 different MoAbs were established and are located on five distinct “linear” areas of PAI-1. MoAbs, binding to two distinct areas of PAI-1, are able to prevent the inhibition of t-PA by PAI-1. In addition, two interaction sites for fibrin were identified on PAI-1. The area located between amino acids 110 and 145 of PAI-1 contains a binding site for both components and its significance is discussed in the context of the t-PA inhibition by fibrin-bound PAI-1. Subsequently, the MoAbs were used to assess the role of platelet-PAI-1 in clot-lysis. An in vitro clot-lysis system was used to demonstrate that clot-lysis resistance is dependent on the presence of activated platelets and that PAI-1 is a major determinant for lysis-resistance. We propose that, upon activation of platelets, PAI-1 is fixed within the clot by binding to fibrin and retains its full capacity to inhibit t-PA and u-PA.

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Cell-Free mRNA Concentrations of Plasminogen Activator Inhibitor-1 and Tissue-Type Plasminogen Activator Are Increased in the Plasma of Pregnant Women with Preeclampsia

Clinical Chemistry ◽

10.1373/clinchem.2006.081372 ◽

2007 ◽

Vol 53 (3) ◽

pp. 399-404 ◽

Cited By ~ 42

Author(s):

Yuditiya Purwosunu ◽

Akihiko Sekizawa ◽

Keiko Koide ◽

Antonio Farina ◽

Noroyono Wibowo ◽

...

Keyword(s):

Pregnant Women ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Maternal Plasma ◽

Tissue Type ◽

Plasminogen Activator Inhibitor 1 ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Activator Inhibitor ◽

Pai 1

Abstract Background: Detection of placental mRNA in maternal plasma has been reported in high-risk pregnancies. We attempted to investigate the concentrations of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) mRNA in maternal plasma in preeclampsia. Methods: Peripheral blood samples were obtained from healthy pregnant women before and after delivery and also from women with or without preeclampsia. Plasma was isolated from these samples, and RNA was extracted. Plasma PAI-1 and tPA mRNA concentrations were then measured by use of reverse transcription PCR assays. The concentrations were converted into multiples of the median (MoM) of the controls adjusted for gestational age. Data were stratified and analyzed according to the clinical severity of preeclampsia and quantitative distribution of blood pressure and proteinuria. Results: The median (minimum–maximum) PAI-1 mRNA MoM values for women with preeclampsia and controls were 2.48 (0.82–8.53) and 1.00 (0.41–2.33), respectively, whereas the median (minimum–maximum) tPA mRNA MoM values were 3.33 (1.01–10.58) and 1.00 (0.95–1.20), respectively. The concentrations of both PAI-1 and tPA mRNA were significantly increased in cases of preeclampsia, compared with controls (P <0.0001). The MoM values of both mRNA species were directly correlated with the severity of preeclampsia and were greatest among a subgroup of hemolysis, increased liver enzymes, and low platelets pregnancies. Conclusion: Maternal plasma PAI-1 and tPA mRNAs are significantly increased in patients with preeclampsia and are positively correlated with the severity of preeclampsia.

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Endocytosis and lysosomal delivery of tissue plasminogen activator- inhibitor 1 complexes in Hep G2 cells

Blood ◽

10.1182/blood.v80.11.2746.2746 ◽

1992 ◽

Vol 80 (11) ◽

pp. 2746-2754 ◽

Cited By ~ 11

Author(s):

DM Underhill ◽

DA Owensby ◽

PA Morton ◽

AL Schwartz

Keyword(s):

Plasminogen Activator ◽

Culture Media ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Hep G2 ◽

Hep G2 Cells ◽

Plasminogen Activator Inhibitor 1 ◽

G2 Cells ◽

Activator Inhibitor ◽

Pai 1

Abstract Receptor-mediated endocytosis of tissue-type plasminogen activator (t- PA)-plasminogen activator inhibitor type 1 (PAI-1) complexes results in their clearance by Hep G2 cells. After complexes are internalized, the t-PA component is degraded. However, neither the locus of intracellular catabolism nor the fate of PAI-1 has been elucidated. To characterize these aspects of t-PA-PAI-1 catabolism, the subcellular distribution of a prebound cohort of ligand molecules was delineated after internalization at 37 degrees C. 125I-t-PA.PAI-1 and t-PA.125I-PAI-1 were compared in separate experiments. After ligand uptake, intracellular vesicles were separated on density gradients. Internalized 125I-t-PA.PAI-1 concentrated initially in endosomes. After 20 minutes of uptake, the complex began to appear in lysosomes. Subsequently, low molecular weight labeled ligand fragments were detected in culture media. A panel of lysosomotropic agents, including primaquine, chloroquine, ammonium chloride, and a combination of leupeptin and pepstatin A, inhibited degradation. When t-PA.125I-PAI-1 rather than 125I-t-PA.PAI-1 was internalized, strikingly different results were observed. Although the kinetics of internalization and the intracellular itinerary were indistinguishable for the differently labeled complexes, the 125I-PAI-1 component of t-PA.125I-PAI-1 resisted rapid degradation. After a rapid loss of t-PA, the 125I-PAI-1 moiety persisted in lysosomes for up to 180 minutes. Thus, internalized t- PA.PAI-1 is targeted to lysosomes in which PAI-1 is relatively more stable than t-PA.

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Endocytosis and lysosomal delivery of tissue plasminogen activator- inhibitor 1 complexes in Hep G2 cells

Blood ◽

10.1182/blood.v80.11.2746.bloodjournal80112746 ◽

1992 ◽

Vol 80 (11) ◽

pp. 2746-2754

Author(s):

DM Underhill ◽

DA Owensby ◽

PA Morton ◽

AL Schwartz

Keyword(s):

Plasminogen Activator ◽

Culture Media ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Hep G2 ◽

Hep G2 Cells ◽

Plasminogen Activator Inhibitor 1 ◽

G2 Cells ◽

Activator Inhibitor ◽

Pai 1

Receptor-mediated endocytosis of tissue-type plasminogen activator (t- PA)-plasminogen activator inhibitor type 1 (PAI-1) complexes results in their clearance by Hep G2 cells. After complexes are internalized, the t-PA component is degraded. However, neither the locus of intracellular catabolism nor the fate of PAI-1 has been elucidated. To characterize these aspects of t-PA-PAI-1 catabolism, the subcellular distribution of a prebound cohort of ligand molecules was delineated after internalization at 37 degrees C. 125I-t-PA.PAI-1 and t-PA.125I-PAI-1 were compared in separate experiments. After ligand uptake, intracellular vesicles were separated on density gradients. Internalized 125I-t-PA.PAI-1 concentrated initially in endosomes. After 20 minutes of uptake, the complex began to appear in lysosomes. Subsequently, low molecular weight labeled ligand fragments were detected in culture media. A panel of lysosomotropic agents, including primaquine, chloroquine, ammonium chloride, and a combination of leupeptin and pepstatin A, inhibited degradation. When t-PA.125I-PAI-1 rather than 125I-t-PA.PAI-1 was internalized, strikingly different results were observed. Although the kinetics of internalization and the intracellular itinerary were indistinguishable for the differently labeled complexes, the 125I-PAI-1 component of t-PA.125I-PAI-1 resisted rapid degradation. After a rapid loss of t-PA, the 125I-PAI-1 moiety persisted in lysosomes for up to 180 minutes. Thus, internalized t- PA.PAI-1 is targeted to lysosomes in which PAI-1 is relatively more stable than t-PA.

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