A comparative study of amyloid-beta (1-42) as a cofactor for plasminogen activation by vampire bat plasminogen activator and recombinant human tissue-type plasminogen activator.
The activity of both human tissue-type plasminogen activator (t-PA) and the PA from the saliva of the vampire bat, Desmodus rotundus, (DSPA) is critically dependent on the presence of a cofactor. The most efficient cofactor for both PAs is fibrin, but fibrinogen and amyloid beta peptides also have cofactor activities for human t-PA. Compared to t-PA, DSPA has a more stringent requirement for fibrin as a cofactor. The present study was undertaken to compare cofactor activities of amyloid beta 1-42 (Abeta1-42) for plasminogen activation by DSPA-alpha1 or by t-PA. The two PAs were incubated with different concentrations of glu-plasminogen, a chromogenic substrate for plasmin and 100 micro g mL (-1) of Abeta1-42, fibrinogen or fibrin as cofactor. Using the kinetic parameters directly determined from the chromogenic substrate conversion curves, we derived the relative efficacies of DSPA or t-PA in the presence of cofactor at the physiological plasminogen concentration of 2 micro M. In the presence of fibrin, the activity of DSPA was comparable to that of t-PA and 23,270-fold higher than its activity without cofactor, whereas fibrin induced only a 248-fold increase in t-PA activity. The activity of DSPA with Abeta1-42 or fibrinogen as cofactor was 485-fold lower than its activity in the presence of fibrin, while for t-PA this difference was only 26-fold. The much lower activity of DSPA as compared to t-PA with Abeta1-42 or fibrinogen might lead to fewer side effects when used for the thrombolytic therapy of stroke.
Kruithof
Egbert K O
EK
Division of Angiology and Hemostasis, University Hospital of Geneva, 24, Rue Micheli-du-Crest CH-1211 Geneva, Switzerland. Egbert.Kruithof@hcuge.ch
Schleuning
Wolf-Dieter
WD
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002685:Chiroptera; D005337:Fibrin / Q000494:pharmacology; D005341:Fibrinolysin / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000494:pharmacology*; D010958:Plasminogen / Q000187:drug effects / Q000378:metabolism*; D010960:Plasminogen Activators / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D005343:Fibrinolytic Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D005337:Fibrin; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin