Enhancement of plasminogen activation by surfactin C: augmentation of fibrinolysis in vitro and in vivo.
The reciprocal activation of plasminogen and prourokinase (pro-u-PA) is an important mechanism in the initiation and propagation of local fibrinolytic activity. We have found that a bacterial lipopeptide compound, surfactin C (3-20 microM), enhances the activation of pro-u-PA in the presence of plasminogen. This effect accompanied increased conversions of both pro-u-PA and plasminogen to their two-chain forms. Surfactin C also elevated the rate of plasminogen activation by two-chain urokinase (tcu-PA) while not affecting plasmin-catalyzed pro-u-PA activation and amidolytic activities of tcu-PA and plasmin. The intrinsic fluorescence of plasminogen was increased, and molecular elution time of plasminogen in size-exclusion chromatography was shortened in the presence of surfactin C. These results suggested that surfactin C induced a relaxation of plasminogen conformation, thus leading to enhancement of u-PA-catalyzed plasminogen activation, which in turn caused feedback pro-u-PA activation. Surfactin C was active in enhancing [125I]fibrin degradation both by pro-u-PA/plasminogen and tcu-PA/plasminogen systems. In a rat pulmonary embolism model, surfactin C (1 mg/kg, i.v.) elevated 125I plasma clot lysis when injected in combination with pro-u-PA. The present results provide first evidence that pharmacological relaxation of plasminogen conformation leads to enhanced fibrinolysis in vivo.
Kikuchi
Tadashi
T
Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwaicho, Fuchu, 183-8509, Tokyo, Japan.
Hasumi
Keiji
K
D000818:Animals; D001407:Bacillus; D005337:Fibrin / Q000737:chemistry; D005342:Fibrinolysis / Q000187:drug effects*; D055666:Lipopeptides; D008074:Lipoproteins / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010958:Plasminogen / Q000737:chemistry; D011487:Protein Conformation; D011655:Pulmonary Embolism / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage / Q000737:chemistry
D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C009365:surfactin peptide; D005337:Fibrin; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase