Thrombin downregulates thrombomodulin expression and activity in primary human endothelial cells.
Thrombomodulin (TM) is a cell surface anticoagulant glycoprotein that plays a key role in the protein C pathway. TM expression in endothelial cells may be modulated by a variety of extracellular signals. Most notably, TM has been shown to be downregulated by inflammatory mediators, such as tumor necrosis factor-alpha and lipopolysaccharide. The objective of this study was to determine the effect of thrombin on TM expression and activity. Thrombin resulted in reduced TM in primary cultures of human endothelial cells by approximately 40% at the level of mRNA, protein, and activity. These effects were blocked by the thrombin inhibitor hirudin. These results suggest that activation of the coagulation cascade may result in a positive-feedback loop consisting of thrombin-mediated repression of TM-dependent protein C activation.
Division of Molecular and Vascular Medicine and The Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. seguin@muhc. mcgill.ca
Chantal
C
Séguin
Md Ruhul
MR
Abid
Katherine C
KC
Spokes
William C
WC
Aird
D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018180:Thrombomodulin / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology
D006629:Hirudins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D018180:Thrombomodulin; D013917:Thrombin