THROMBIN INDUCES THROMBOMODULIN MESSENGER-RNA EXPRESSION VIA THE PROTEOLYTICALLY ACTIVATED THROMBIN RECEPTOR IN CULTURED BOVINE SMOOTH-MUSCLE CELLS

Thrombin, an important mitogen governing smooth muscle cell proliferat ion, binds to cultured bovine aortic smooth muscle cells (BASMCs) via both the proteolytically activated thrombin receptor (PATR) and thromb omodulin (TM). Although TM mRNA expression and functional activity is regulated by thrombin in human endothelial cells and mouse hemangioma cells, it remains unclear in those models whether the increased TM mRN A expression observed upon thrombin stimulation is mediated through th e activation of PATR or via TM occupancy, We observed in cultured BASM Cs that TM mRNA is increased threefold to sixfold by either thrombin, basic fibroblast growth factor (bFGF), or platelet-derived growth fact or (PDGF). The increase in TM mRNA with thrombin is time dependent (ma ximal at 3 hours), a consequence of increased mRNA stability, and acco mpanied by increases in cell surface TM functional activity. Thrombin- induced TM mRNA was reproduced by the hexameric thrombin receptor-acti vating peptide (TRAP(6)) and augmented by a TM-specific antibody, Toge ther, these data suggest that up-regulation of TM mRNA by thrombin is mediated via the PATR. We speculate that increases in BASMC TM mRNA an d activity after thrombin may contribute to the impaired thrombus form ation observed after atherosclerotic vascular injury.