Thrombin stimulates syndecan-1 promotor activity and expression of a form of syndecan-1 that binds antithrombin III in vascular smooth muscle cells.
Vascular smooth muscle (VSM) cells express transmembrane proteoglycans of the syndecan gene family. We reported previously that the expression of syndecans by VSM cells is regulated by mitogens such as serum, platelet-derived growth factor, and basic fibroblast growth factor and that syndecan expression is induced after balloon injury in vivo. We now show that thrombin is a potent inducer of syndecan-1 expression in VSM cells. Transient transfection experiments with a rat syndecan-1 promoter construct demonstrated that thrombin stimulates transcription of the syndecan-1 gene. Syndecan expression in response to thrombin was not inhibited by downregulation of protein kinase C. Thrombin-induced syndecan-1 expression was dependent on tyrosine kinase activity. Calcium was necessary for syndecan-1 expression, but increasing the intracellular calcium levels was not sufficient to induce syndecan-1 expression. Analysis of antithrombin III (AT III) binding activity revealed that thrombin caused an increase in the synthesis of syndecan-1 molecules that exhibited high-affinity AT III binding. These results suggest that VSM cells could play an important role in controlling local thrombus formation subsequent to vascular injury, via a feedback mechanism that involves thrombin-induced stimulation of an inhibitor of thrombin activity.
Cizmeci-Smith
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Henry Hood MD Research Program, Sigfried, Pa., USA.
Carey
D J
DJ
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism*; D001483:Base Sequence; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011493:Protein Kinase C / Q000502:physiology; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1; D053667:Syndecans; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D014162:Transfection
D002614:Chelating Agents; D008562:Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C508242:Sdc1 protein, mouse; C508243:Sdc1 protein, rat; D053668:Syndecan-1; D053667:Syndecans; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D000990:Antithrombin III; D011493:Protein Kinase C; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium