ALPHA-THROMBIN INDUCES TRANSFORMING GROWTH FACTOR-BETA(1) MESSENGER-RNA AND PROTEIN IN CULTURED VASCULAR SMOOTH-MUSCLE CELLS VIA A PROTEOLYTICALLY ACTIVATED RECEPTOR

The potent growth factors and chemoattractants alpha-thrombin and tran sforming growth factor-beta(1) (TGF-beta(1)) have both been identified at sites of arterial injury, however the interaction between these tw o factors has not been defined. By Northern hybridization analyses, ac cumulation of both a 1.9- and a 2.4-kb transcript of TGF-beta(1) were detected and occurred in a time- and dose-dependent fashion following alpha-thrombin stimulation of cultured vascular smooth muscle cells (V SMC). This induction of TGF-beta(1) mRNA required the proteolytic acti vity of thrombin and was mimicked by a thrombin-receptor-(TR)-activati ng peptide or TRAP (SFFLRNP). Increases in alpha-thrombin-induced TGF- beta(1) message expression were insensitive to cycloheximide, but sens itive to actinomycin D. Furthermore, the induction of TGF-beta(1) mRNA expression correlated with the production of latent TGF-beta(1) prote in in alpha-thrombin-conditioned media. In summary, alpha-thrombin sti mulation of VSMC induces transcriptional activation of the TGF-beta(1) gene through proteolytic activation of the cloned seven-transmembrane TR resulting in the formation of latent TGF-beta(1) protein. These re sults demonstrate a potential mechanism whereby alpha-thrombin may mod ulate the vascular response to injury through TGF-beta(1)-dependent me chanisms.