Transcellular signaling and pharmacological modulation of thrombin-induced production of plasminogen activator inhibitor-1 in vascular smooth muscle cells.
Thrombin formation is increased at the sites of vascular injury. Previous studies by our group and other groups indicated that the generation of plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor for plasminogen activators, from cultured vascular smooth muscle cells (SMC) is elicited by thrombin. The present study demonstrates that the thrombin receptor, pertussis toxin-sensitive G protein, genistein-sensitive tyrosine kinase, phospholipase C, and protein kinase C may be involved in thrombin-induced PAI-1 production in cultured baboon aortic SMC. Forskolin and 8-bromo-cyclic AMP inhibited thrombin-induced PAI-1 production in cultured SMC. Treatment with hirulog-1, a synthetic thrombin receptor inhibitor, suppressed thrombin-induced PAI-1 generation at mRNA and protein levels in SMC. The results of the present study suggest that transmembrane receptor and multiple signal transduction systems are involved in thrombin-induced increase in PAI-1 transcription in vascular SMC. The production of PAI-1 stimulated by thrombin in vascular SMC may be pharmacologically modulated by thrombin receptor inhibitor.
Shen
G X
GX
Department of Internal Medicine, The University of Manitoba, Winnipeg, Canada.
Ren
S
S
Fenton
J W
JW
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006629:Hirudins / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010215:Papio; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D006629:Hirudins; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018179:Receptors, Thrombin; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; C082835:thrombin receptor peptide (42-47); D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D037342:Pertussis Toxin; D013917:Thrombin; D019204:GTP-Binding Proteins; C074619:bivalirudin