title: The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in fibrinolysis.
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.
authors.affiliation: Department of Physiology, Hamamatsu University, School of Medicine, Shizuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Wu
authors.forename: T
authors.initials: T
authors.lastname: Urano
authors.forename: H
authors.initials: H
authors.lastname: Ihara
authors.forename: Y
authors.initials: Y
authors.lastname: Takada
authors.forename: M
authors.initials: M
authors.lastname: Fujie
authors.forename: M
authors.initials: M
authors.lastname: Shikimori
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
authors.forename: A
authors.initials: A
authors.lastname: Takada
mesh_terms: 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
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase