kt-5720 and 3-3--4-5--tetrahydroxystilbene

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.

Topics: 1-Methyl-3-isobutylxanthine; 8-Bromo Cyclic Adenosine Monophosphate; Animals; Bucladesine; Carbazoles; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; Flavonoids; Genistein; Indoles; Isoquinolines; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Phosphodiesterase Inhibitors; Phosphorylation; Plasminogen Activator Inhibitor 1; Protein Kinase C; Protein-Tyrosine Kinases; Pyrroles; Rats; Signal Transduction; src-Family Kinases; Stilbenes; Sulfonamides; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator