Transcellular Signaling and Pharmacological Modulation of Thrombin-Induced Production of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cells

Abstract

Thrombin formation is increased at the sites of vascular injury. Previous studies by our group and other groups indicated that the generation of plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor for plasminogen activators, from cultured vascular smooth muscle cells (SMC) is elicited by thrombin. The present study demonstrates that the thrombin receptor, pertussis toxin-sensitive G protein, genistein-sensitive tyrosine kinase, phospholipase C, and protein kinase C may be involved in thrombin-induced PAI-1 production in cultured baboon aortic SMC. Forskolin and 8-bromo-cyclic AMP inhibited thrombin-induced PAI-1 production in cultured SMC. Treatment with hirulog-1, a synthetic thrombin receptor inhibitor, suppressed thrombin-induced PAI-1 generation at mRNA and protein levels in SMC. The results of the present study suggest that transmembrane receptor and multiple signal transduction systems are involved in thrombin-induced increase in PAI-1 transcription in vascular SMC. The production of PAI-1 stimulated by thrombin in vascular SMC may be pharmacologically modulated by thrombin receptor inhibitor.