G proteins and phospholipase C mediate thrombin-induced generation of plasminogen activator inhibitor-1 from vascular smooth muscle cells.
The present study investigated transcellular signalling mechanism involved in thrombin-induced production of plasminogen activator inhibitor-1 (PAI-1) in cultured vascular baboon aortic smooth muscle cells (BASMC). Treatments with thrombin dose-dependently increased the steady state levels of PAI-1 mRNA and the generation of PAI-1 antigen from BASMC. Thrombin receptor-activating peptide mimicked the effect of thrombin on the generation of PAI-1. Sodium fluoride (1 mM) stimulated PAI-1 generation from BASMC. Pertussis toxin dose-dependently suppressed thrombin-induced increase of PAI-1 generation. Treatment with 5 mM neomycin, 10 microM U73122 or 1 microM calphostin C blocked thrombin-induced PAI-1 generation. Phorbol myristate acetate at 10 nM for 3 h strongly stimulated the generation of PAI-1 from BASMC. Forskolin (100 microM) or 8-bromo-cAMP (100 microM) suppressed thrombin-induced PAI-1 generation. The responses of quiescent BASMC to thrombin or the inhibitors on PAI-1 generation were comparable to that of growing cells. The results of the present study suggest that pertussis toxin-sensitive G proteins and a phospholipase C are involved in thrombin-induced generation of PAI-1 in BASMC, which may transmit signals from occupied thrombin receptor to protein kinase C and thereby increase the generation of PAI-1. Elevated levels of intracellular cAMP may negatively regulate the generation of PAI-1 from vascular SMC.
Ren
S
S
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Cockell
K A
KA
Fenton
J W
JW
Angel
A
A
Shen
G X
GX
D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D010215:Papio; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000819:agonists; D015290:Second Messenger Systems; D015398:Signal Transduction; D012969:Sodium Fluoride / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007375:Interleukin-1; D009281:Naphthalenes; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D018179:Receptors, Thrombin; D010566:Virulence Factors, Bordetella; C076901:thrombin receptor-activating peptide (P508-530); D005576:Colforsin; D012969:Sodium Fluoride; D000242:Cyclic AMP; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D013917:Thrombin; D019204:GTP-Binding Proteins; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate