INHIBITION BY HIRULOG-1 OF GENERATION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 FROM VASCULAR SMOOTH-MUSCLE CELLS INDUCED BY THROMBIN

Hirulog-1 effectively prevents thrombosis in coronary artery disease a nd is associated with a low incidence of bleeding complications. Our s tudy characterized the effect of Hirulog-1 on thrombin-induced product ion of plasminogen activator inhibitor-1 (PAI-1) in cultured baboon ao rtic smooth-muscle cells (BASMCs). Thrombin increased the steady-state levels of PAI-1 messenger RNA (mRNA) and the release of PAI-1 antigen from BASMCs. Treatments with 10-20 mg/L of Hirulog-1 inhibited >80% o f thrombin-induced PAI-I generation from BASMCs. Hirulog-1 alone did n ot significantly alter PAI-1 production in the absence of thrombin. Si gnificant reduction of thrombin-induced PAI-1 release was observed in cultures treated with Hirulog-1 for 1 h. The maximal effect of Hirulog -1 on thrombin-induced PAI-1 release was achieved in cultures treated with thrombin plus Hirulog-1 for 3 to 6 h, associated with the normali zation of PAI-1 mRNA levels induced by thrombin treatment. Strong inhi bition by Hirulog-1 on thrombin-induced PAI-1 release remained in cult ures with 8 h of the treatment, but the effect was attenuated 16 h aft er a single addition of the inhibitor. Our study demonstrates that Hir ulog-1 effectively inhibited thrombin-induced PAI-1 production in cult ured vascular SMCs at mRNA and protein levels. Vascular SMCs may be ex posed to high concentrations of thrombin when endothelium is injured. The information generated from this study suggests that Hirulog-1 pote ntially prevents intravascular thrombogenesis through inhibiting throm bin-induced PAI-1 production in vascular SMCs, especially when hyperco agulation and endothelial injury occurs.