Inhibitory action of amyloid precursor protein against human Hageman factor (factor XII).
Amyloid precursor protein forms that contain Kunitz protease inhibitor domains are released from activated platelets, T-lymphocytes, and leukocytes and inhibit trypsin, plasmin, and activated factor XI. We investigated the effects of amyloid precursor protein isoforms on activated Hageman factor (factor XII), activated factor X (Stuart factor), and thrombin. Recombinant amyloid precursor proteins with or without the Kunitz domain, 770 and 695 amino acids, respectively, were produced in insect cells by Baculovirus expression (BAC770 and BAC695). Neither BAC695 nor BAC770 inhibited human alpha-thrombin or activated factor X. The partial thromboplastin time was prolonged by both amyloid precursor proteins, only one of which, BAC770, contains the Kunitz protease inhibitor domain. Both forms of amyloid precursor proteins inhibited ellagic acid-induced activation of Hageman factor but did not inhibit activated Hageman factor. Bismuth subgallate, which is an insoluble analog of ellagic acid, lost its ability to activate Hageman factor on being exposed to BAC770. Inhibition of ellagic acid-induced activation of Hageman factor by both forms of amyloid precursor protein was enhanced by heparin. These findings suggested that the heparin-binding domain of amyloid precursor proteins is not in the Kunitz domain. This heparin-binding domain may block the activation of Hageman factor by negatively charged agents. Thus, amyloid precursor proteins may be involved in the control of hemostasis, properties not all dependent on the Kunitz domain.
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH.
H
H
Niwano
P B
PB
Embury
B D
BD
Greenberg
O D
OD
Ratnoff
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D004610:Ellagic Acid / Q000494:pharmacology; D005174:Factor XII / Q000037:antagonists & inhibitors*; D065427:Factor Xa Inhibitors; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007313:Insecta; D009942:Organometallic Compounds / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors
D016564:Amyloid beta-Protein Precursor; D065427:Factor Xa Inhibitors; D009942:Organometallic Compounds; D011994:Recombinant Proteins; D004610:Ellagic Acid; D005707:Gallic Acid; D005174:Factor XII; D006493:Heparin; D013917:Thrombin; C002170:bismuth subgallate