scholarly journals The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in fibrinolysis

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1056-1061 ◽  
Author(s):  
K Wu ◽  
T Urano ◽  
H Ihara ◽  
Y Takada ◽  
M Fujie ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Plasminogen Activator Inhibitor ◽  
Clot Lysis ◽  
Lysis Time ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Clot Lysis Time

Abstract The effect of the proteolytic cleavage of plasminogen activator inhibitor type 1 (PAI-1) by human neutrophil elastase (HNE) on fibrinolysis was investigated. HNE cleaved active PAI-1 and produced low molecular weight forms of inactive PAI-1, as previously reported. Latent PAI-1 was resistant to HNE treatment. Vitronectin (VN) partially protected the cleavage. NH2-terminal sequence analysis indicated that the cleavage site was Val355-Ser356 (P4-P3). The effects of PAI-1 cleavage by HNE on clot lysis was studied in a purified system. Clot lysis time without PAI-1 was 20.0 +/- 5.0 minutes and was prolonged to 86.7 +/- 2.9 minutes by 68 nmol/L of PAI-1. It was shortened when HNE (from 0.6 nmol/L to 80 nmol/L) was added and returned to the value obtained without PAI-1 by 80 nmol/L of HNE (20.0 +/- 5.8 minutes). However, in the absence of PAI-1, elastase did not enhance clot lysis at all. Euglobulin clot lysis time was also shortened after HNE treatment. The cleavage and inactivation of PAI-1 by HNE was shown to be a novel pathway to enhance fibrinolysis.

scholarly journals The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in fibrinolysis

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1056-1061
Author(s):  
K Wu ◽  
T Urano ◽  
H Ihara ◽  
Y Takada ◽  
M Fujie ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Plasminogen Activator Inhibitor ◽  
Clot Lysis ◽  
Lysis Time ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Clot Lysis Time

The effect of the proteolytic cleavage of plasminogen activator inhibitor type 1 (PAI-1) by human neutrophil elastase (HNE) on fibrinolysis was investigated. HNE cleaved active PAI-1 and produced low molecular weight forms of inactive PAI-1, as previously reported. Latent PAI-1 was resistant to HNE treatment. Vitronectin (VN) partially protected the cleavage. NH2-terminal sequence analysis indicated that the cleavage site was Val355-Ser356 (P4-P3). The effects of PAI-1 cleavage by HNE on clot lysis was studied in a purified system. Clot lysis time without PAI-1 was 20.0 +/- 5.0 minutes and was prolonged to 86.7 +/- 2.9 minutes by 68 nmol/L of PAI-1. It was shortened when HNE (from 0.6 nmol/L to 80 nmol/L) was added and returned to the value obtained without PAI-1 by 80 nmol/L of HNE (20.0 +/- 5.8 minutes). However, in the absence of PAI-1, elastase did not enhance clot lysis at all. Euglobulin clot lysis time was also shortened after HNE treatment. The cleavage and inactivation of PAI-1 by HNE was shown to be a novel pathway to enhance fibrinolysis.

Human Thrombin and Calcium Bound Factor Xa Significantly Shorten tPA-Induced Fibrin Clot Lysis Time via Neutralization of Plasminogen Activator Inhibitor Type 1 Activity

1998 ◽  
Vol 80 (07) ◽  
pp. 161-166 ◽  
Author(s):  
Tetsumei Urano ◽  
Nobuo Nagai ◽  
Megumi Matsuura ◽  
Hayato Ihara ◽  
Yumiko Takada ◽  
...  
Keyword(s):  
Factor Xa ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Lysis Time ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor ◽  
Pai 1

SummaryEmploying a fibrin clot lysis assay, we reassessed the significance of the neutralization of plasminogen activator inhibitor type 1 (PAI-1) activity by thrombin and factor-Xa in fibrinolysis. When PAI-1 enriched fibrin clots were formed using increasing concentrations of thrombin (0.1, 0.5, 1.0 IU/ml), their lysis times became shorter (43.8 ± 4.9, 25.7 ± 3.7, 13.9 ± 0.8 h respectively). Times were shortened further by either heparin (43.9 ± 11.0, 12.1 ± 2.6, 3.6 ± 0.2 h respectively) or vitronectin (17.0 ± 1.6, 1.9 ± 0.7, 0.9 ± 0.0 h respectively). Factor-Xa together with Ca++ shortened the clot lysis time further. Fibrin autography revealed that both enzymes dose dependently interfered with complex formation between tPA and PAI-1, making large amounts of tPA remaining to be free form. The mechanism seems to play a role in the coagulation associated enhancement of fibrinolysis.

Limited Proteolysis of Vitronectin by Plasmin Destroys Heparin Binding Activity

1991 ◽  
Vol 66 (03) ◽  
pp. 310-314 ◽  
Author(s):  
David C Sane ◽  
Tammy L Moser ◽  
Charles S Greenberg
Keyword(s):  
Limited Proteolysis ◽  
Plasminogen Activator Inhibitor ◽  
Binding Activity ◽  
Binding Domain ◽  
Heparin Binding ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor ◽  
Pai 1

SummaryVitronectin (VN) stabilizes plasminogen activator inhibitor type 1 (PAI-1) activity and prevents the fibrin(ogen)-induced acceleration of plasminogen activation by t-PA. These antifibrinolytic activities as well as other functions are mediated by the glycosaminoglycan (GAG) binding domain of VN. Since the GAG binding region is rich in arginyl and lysyl residues, it is a potential target for enzymes such as plasmin. In this paper, the dose and time-dependent proteolysis of VN by plasmin is demonstrated. The addition of urokinase or streptokinase (200 units/ml) to plasma also produced proteolysis of VN. With minimal proteolysis, the 75 kDa band was degraded to a 62-65 kDa form of VN. This minimal proteolysis destroyed the binding of [3H]-heparin to VN and reversed the neutralization of heparin by VN.Thus, the plasmin-mediated proteolysis of the GAG binding activity of VN could destroy the antifibrinolytic activity of VN during physiologic conditions and during thrombolytic therapy. Furthermore, other functions of VN in complement and coagulation systems that are mediated by the GAG binding domain may be destroyed by plasmin proteolysis.

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

2004 ◽  
Vol 91 (05) ◽  
pp. 1026-1030 ◽  
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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