IV. Anticoagulant activity of compound 48/80: inhibition of factor VII activation in leukemia THP-1 monocytes.
Our previous study described a novel biologic function of compound 48/80 (48/80) in the downregulation of monocytic tissue factor (TF)-initiated hypercoagulation in response to bacterial endotoxin (lipopolysaccharide; LPS). The inhibition was not due to the blockade of LPS cell signaling, as evidenced by the unaffected LPS-induced TF synthesis. We herein determined the mechanism by which 48/80 inhibits the extrinsic coagulation in agonist-challenged THP-1 monocytes. LPS as well as A23187 substantially induced TF activity. TF synthesis was enhanced by LPS but not by A23187. However, the elevated FVII binding to monocytes accompanying the upregulation of factor VII (FVII) activation was uniformly observed in both cases. A 5-min preincubation of the cells with a sheep anti-humanTF antibody (anti-hTF Ab) showed the downregulation of FVII activation, indicating a regulatory role of FVII binding in the modulation of the extrinsic coagulation. The 48/80 blocked FVII binding to monocytes, leading to the preferential inhibition of FVII activation. As the result of the diminished FVIIa formation, monocytic TF-initiated extrinsic coagulation was downregulated in agonist-challenged THP-1 monocytes.
Chu
A J
AJ
Department of Surgery, School of Medicine, Wayne State University, Detroit, Michigan, USA. ad5742@wayne.edu
Wang
Z G
ZG
Raphael
U O
UO
D001777:Blood Coagulation / Q000187:drug effects; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology; D005167:Factor VII / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007938:Leukemia; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D013925:Thromboplastin / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology*
D004731:Endotoxins; D008070:Lipopolysaccharides; D003189:p-Methoxy-N-methylphenethylamine; D005167:Factor VII; D013925:Thromboplastin