The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in fibrinolysis.
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.
Wu
K
K
Department of Physiology, Hamamatsu University, School of Medicine, Shizuoka, Japan.
Urano
T
T
Ihara
H
H
Takada
Y
Y
Fujie
M
M
Shikimori
M
M
Hashimoto
K
K
Takada
A
A
D000595:Amino Acid Sequence; D005342:Fibrinolysis; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000378:metabolism*; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase