Regulation of plasminogen activator inhibitor-1 secretion by growth factors in smooth muscle cells.
Epithelioid-type vascular smooth muscle cells are metabolically active and secrete many proteases and protease inhibitors. We have previously cloned epithelioid-type smooth muscle cells from rat carotid arteries, and showed that polypeptide growth factors basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) could dose-dependently induce plasminogen activator inhibitor-1 (PAI-1) secretion from these cells. In the present study, we have used these cells to investigate the growth factor-induced signal transduction pathways leading to PAI-1 secretion. We report here that PAI-1 induction was dependent on protein kinase C (PKC) and tyrosine kinase but not on protein kinase A (PKA), ras and phosphoinositol-3-kinase inhibitor. Induction of PAI-1 by bFGF and PDGF was also accompanied by activation of a mitogen-activated protein kinase pathway involving Raf/Mek/Erk1/2, and the family non-receptor tyrosine kinases., another non-receptor tyrosine kinase, on the contrary, behaved differently from in that it was part of a pathway leading to PAI-1 induction by bFGF, but not when PDGF was used as the stimulating reagent. Activation of a PKA-dependent pathway(s) opposed PAI-1 induction. One mechanism for PKA activators to inhibit PAI-1 secretion was that they markedly inhibited the phosphorylations of Mek and mitogen-activated protein kinase that were up-regulated in the presence of bFGF and PDGF.
Division of Hematology, Department of Medicine, St Michael's and University of Toronto, Ontario, Canada. lauh@smh.toronto.on.ca
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D000818:Animals; D002339:Carotid Arteries / Q000166:cytology; D004792:Enzyme Precursors; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase
D004792:Enzyme Precursors; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D010982:Platelet-Derived Growth Factor; D016222:Fibroblast Growth Factor 2; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat