Tissue-type plasminogen activator is a potent mitogen for human aortic smooth muscle cells.
Tissue-type plasminogen activator (t-PA) is a potent and efficacious mitogen for growth-arrested cultured human aortic smooth muscle cells, stimulating an increase in cell number at 0.3-30 nM concentration. Double-chain t-PA is as efficient as single-chain t-PA in stimulating smooth muscle cell mitogenesis, whereas single-chain urokinase-type plasminogen activator (u-PA) or u-PA and plasmin or plasminogen are ineffective. Plasminogen activator inhibitor-1, Pefabloc-TPA, diisopropyl fluorophosphate or alpha 1-anti-trypsin inhibit the mitogenic effect of t-PA for smooth muscle cells in a dose-dependent manner, showing that it is dependent on the enzymatic activity. t-PA activated phosphoinositide turnover in smooth muscle cells through a pertussis toxin-insensitive pathway and stimulated proto-oncogene c-fos and c-jun mRNA levels. These findings indicate that t-PA stimulates vascular human smooth muscle cell proliferation and suggest for the first time that it may contribute to intimal smooth muscle cell proliferation after vascular injury as a result of angioplasty or vascular compromise during atherogenesis.
Herbert
J M
JM
Hemobiology Research Department, Sanofi Recherche, Toulouse, France.
Lamarche
I
I
Prabonnaud
V
V
Dol
F
F
Gauthier
T
T
D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007531:Isoflurophate / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D007295:Inositol Phosphates; C000715470:MAS1 protein, human; D008934:Mitogens; D010716:Phosphatidylinositols; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D010566:Virulence Factors, Bordetella; D000515:alpha 1-Antitrypsin; D007531:Isoflurophate; D037342:Pertussis Toxin; D010959:Tissue Plasminogen Activator