Regulation of plasminogen activator inhibitor-1 secretion by urokinase and tissue plasminogen activator in rat epithelioid-type smooth muscle cells.
Tissue plasminogen activator (tPA) and urokinase (uPA) are targets of plasminogen activator inhibitor-1 (PAI-1) inhibition. We have previously shown that both proteases can also induce PAI-1 secretion in rat smooth muscle cells (SMCs). We now report that both proteases appear to use very similar cellular mechanisms for signal transduction. They induced PAI-1 secretion using a pathway(s) involving protein kinase C (PKC). They also activated the Raf/Mek/mitogen-activated protein kinase (MAPK) pathway, which lies downstream of PKC activation. Activation of protein kinase A (PKA), however, lowered PAI-1 secretion induced by uPA and tPA, as a result of an inhibition of the PKC pathway and inhibition of Raf, Mek and MAPK phosphorylations. Src and syk family non-receptor tyrosine kinases (TK) were also involved in PAI-1 induction. The mechanisms of interaction of these tyrosine kinases with other pathways appeared to be quite different: src appeared to act within the PKC and PKA pathways, while syk operated independently of these pathways. Furthermore, whereas src inhibition resulted in inhibition of Raf/Mek/Erk phosphorylations, syk inhibition could only inhibit Mek and Erk phosphorylations but not the phosphorylation of Raf. These multiple pathways utilized by uPA and tPA to modulate PAI-1 secretion might be involved in determining the proteolytic or antiproteolytic potential of the SMCs under different pathophysiological conditions.
Lau
Herbert K F
HK
Division of Hematology, Department of Medicine, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada. lauh@smh.toronto.on.ca
Ho
Joanne
J
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002227:Carbazoles; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002227:Carbazoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D011758:Pyrroles; D013267:Stilbenes; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; C057416:KT 5720; D003994:Bucladesine; C041525:3,3',4,5'-tetrahydroxystilbene; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D015056:1-Methyl-3-isobutylxanthine