On the interaction of fibrin-bound plasminogen activator inhibitor type 1(PAI-1) with tissue-type (t-PA) and urokinase type (u-PA) plasminogen activator: Potential implications for reocclusion upon thrombolytic therapy with t-PA

Abstract A 36-year-old patient was investigated for a lifelong history of epistaxis and delayed bleeding after minor surgeries. Deficiencies or abnormalities of the coagulation system, of platelet function, or of factor XIII and alpha-2-antiplasmin were excluded. Consistently, however, over a period of 7 years, a high basal euglobulin fibrinolytic activity was observed that was characterized by a high tissue-type plasminogen activator (t-PA) activity, normal t-PA antigen, and undetectable plasminogen activator inhibitor type-1 (PAI-1) antigen and activity. The high specific activity of t-PA (640,000 IU/mg) and the minimal amounts of t-PA/PAI-1 complexes detected by fibrin zymography suggest that in this patient all t-PA was active. This is in striking contrast to normal plasma, where the majority of t-PA is complexed to PAI-1. Thus, in this patient, a severe deficiency of PAI-1 is associated with a delayed type bleeding tendency. Our observation underscores the importance of plasma PAI-1 for the stabilization of the hemostatic plug.

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PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1: STUDIES ON STRUCTURE AND REGULATION

10.1055/s-0038-1642810 ◽

1987 ◽

Author(s):

P A Andreasen ◽

A Riccio ◽

L R Lund ◽

K G Welinder ◽

F Blasi ◽

...

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Amino Terminal ◽

Plasminogen Activator Inhibitor Type ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Activator Inhibitor ◽

Pai 1

Human plasminogen activator inhibitor type-1 is an Mr∼54,000 protein which specifically inhibits urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activators. During inhibition, u-PA and t-PA convert PAI-1 to an inactive form with Mr∼50,000. We have determined the amino-terminal amino acid sequence of native and converted PAI-1, and isolated and partly sequenced PAI-1 cDNA. The data show that the conversion of PAI-1 consists of cleavage of an Arg-Met bond 33 residues from the carboxy-terminus, thus localizing the reactive center of the inhibitor to that position, and identifying PAI-1 as an "arg-serpin". PAI-1 activity is known to be influenced by a number of agents; we have studied the mechanisms of the stimulation of PAI-1 activity by transforming growth factor-β (TGF-β) and the synthetic glucocorticoid dexame-thasone in human WI-38 lung fibroblasts and HT-1080 fibrosarcoma cells. Bytheuse of PAI-1 cDNA, TGF-β was found to course a rapid increase in PAI-1 mRNA level in WI-38 cells, reaching a maximal 50-fold enhancement after 8 hours. Dexamethasone caused a 10-fold increase in PAI-1 mRNA in HT-1080 cells, which was detectable after 4 hours and became maximal after 16 hours. In both cases, the 3.4 as well as the 2.4 Kb-PAI-1-mRNA species were increased. Quantitative studies on the effect of these agents on PAI-1 protein levels in cell extracts and culture media by ELISA gave results consistent with the effects on PAI-1 mRNA. These studies suggest that TGF-β and glucocorticoids may exert important controls over plasminogen activation-mediated extracellular proteolysis through an enhancement of PAI-1 gene transcription.

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A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1

Blood ◽

10.1182/blood.v77.3.528.bloodjournal773528 ◽

1991 ◽

Vol 77 (3) ◽

pp. 528-532 ◽

Cited By ~ 1

Author(s):

J Dieval ◽

G Nguyen ◽

S Gross ◽

J Delobel ◽

EK Kruithof

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Bleeding Tendency ◽

Plasminogen Activator Inhibitor Type ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Activator Inhibitor ◽

Pai 1

A 36-year-old patient was investigated for a lifelong history of epistaxis and delayed bleeding after minor surgeries. Deficiencies or abnormalities of the coagulation system, of platelet function, or of factor XIII and alpha-2-antiplasmin were excluded. Consistently, however, over a period of 7 years, a high basal euglobulin fibrinolytic activity was observed that was characterized by a high tissue-type plasminogen activator (t-PA) activity, normal t-PA antigen, and undetectable plasminogen activator inhibitor type-1 (PAI-1) antigen and activity. The high specific activity of t-PA (640,000 IU/mg) and the minimal amounts of t-PA/PAI-1 complexes detected by fibrin zymography suggest that in this patient all t-PA was active. This is in striking contrast to normal plasma, where the majority of t-PA is complexed to PAI-1. Thus, in this patient, a severe deficiency of PAI-1 is associated with a delayed type bleeding tendency. Our observation underscores the importance of plasma PAI-1 for the stabilization of the hemostatic plug.

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Induction of Plasminogen Activator Inhibitor Type-1 (PAI-1) by Proinsulin and Insulin In Vivo

Circulation ◽

10.1161/01.cir.91.3.764 ◽

1995 ◽

Vol 91 (3) ◽

pp. 764-770 ◽

Cited By ~ 116

Author(s):

Thomas K. Nordt ◽

Hirofumi Sawa ◽

Satoshi Fujii ◽

Burton E. Sobel

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor Type ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Activator Inhibitor ◽

Pai 1

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C-reactive protein is directly related to plasminogen activator inhibitor type 1 (PAI-1) levels in diabetic subjects with the 4G allele at position −675 of the PAI-1 gene

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/j.numecd.2006.10.001 ◽

2008 ◽

Vol 18 (3) ◽

pp. 220-226 ◽

Cited By ~ 8

Author(s):

R. Testa ◽

A.R. Bonfigli ◽

C. Sirolla ◽

M. Marra ◽

M. Boemi ◽

...

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

C Reactive Protein ◽

Reactive Protein ◽

Plasminogen Activator Inhibitor Type ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Activator Inhibitor ◽

Pai 1

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Adiponectin is inversely related to plasminogen activator inhibitor type 1 in patients with stable exertional angina

Thrombosis and Haemostasis ◽

10.1160/th03-12-0731 ◽

2004 ◽

Vol 91 (05) ◽

pp. 1026-1030 ◽

Cited By ~ 24

Author(s):

Hidetomo Maruyoshi ◽

Tohru Funahashi ◽

Shinzo Miyamoto ◽

Jun Hokamaki ◽

Hirofumi Soejima ◽

...

Keyword(s):

Plasminogen Activator ◽

Plasma Levels ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor Type ◽

Exertional Angina ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Activator Inhibitor ◽

Pai 1

SummaryAdipose tissue is a secretory organ producing a variety of bioactive substances, such as adiponectin. Adiponectin has antiatherogenic properties while plasminogen activator inhibitor type 1 (PAI-1) is closely involved in the development of atherosclerosis. The relationship between adiponectin and PAI-1 in patients with coronary artery disease (CAD) has not been clarified. This study examined plasma levels of adiponectin and PAI-1 in 64 patients with stable exertional angina (SEA) and 65 patients with the chest pain syndrome (CPS). Plasma logadiponectin levels were significantly lower in patients with SEA (0.62±0.08 µg/dL) compared to those with CPS (0.86± 0.05 µg/dL) (p<0.0001). The plasma levels of log-PAI-1 were significantly higher in patients with SEA (1.23±0.18 ng/mL) compared to those with CPS (1.15±0.22 ng/mL) (p<0.05). Plasma log-adiponectin levels correlated negatively with diabetes mellitus (DM), body mass index (BMI), log-PAI-1 (r=−0.284, p<0.001), triglyceride (TG), and remnant-like particles cholesterol (RLP-C), and positively with high-density lipoprotein cholesterol (HDL-C) levels. Plasma levels of log-PAI-1 correlated positively with DM, BMI, TG and RLP-C levels, and negatively with HDL-C levels. Multiple logistic regression analysis identified sex, angina pectoris, and PAI-1 as independent determinants of hyperadiponectinemia (p<0.05). Adiponectin is inversely related to PAI-1. DM, BMI, TG, HDL-C, and RLP-C are common mediators between adiponectin and PAI-1, and treatment for common mediators may prevent the development of CAD by reducing PAI-1 and increasing adiponectin levels.

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