Abstract 19616: Plasminogen Activator Inhibitor-1 Inhibits Thrombin Activity in Vein Grafts
Introduction: Thrombin activates vascular smooth muscle cells (SMC) and promotes adverse remodeling in vein grafts (VG) after bypass surgery. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-PA, also inhibits thrombin, though the functional significance of this interaction is unknown. We tested the hypothesis that PAI-1 expressed by venous cells inhibits thrombin under physiological conditions.
Methods and Results: We isolated SMC from inferior vena cava (IVC) of wild-type (WT) and PAI-1-deficient (Pai1−/−) mice. Thrombin-induced proliferation of Pai1−/− SMC was greater than that of WT SMC (210±7 vs. 140±6 % of unstimulated cells, respectively, P<0.05), while no significant difference was observed between groups in the presence of hirudin, a specific thrombin inhibitor. Thrombin-induced migration did not differ between WT and Pai1−/− SMC. To determine if PAI-1 inhibits thrombin in VG, we grafted IVC segments into carotid arteries of recipient mice. After 5 days, VG were harvested and protein extracts were assayed for thrombin activity in the presence and absence of hirudin. Thrombin specific activity was greater in VG of Pai1−/−graft/Pai1−/−recipient mice (2.3±1.5 mOD/μg protein; n=4) than in VG of WTgraft/WTrecipient mice (1.1±0.9 mOD/μg protein; n=4; P<0.05). At 28 days after vein grafting, mean intima area (0.20±0.01 vs. 0.11±0.01 mm2, respectively, n=7–9/group, P<0.01) and cell proliferation (53±2.9 vs. 25±2.1 % PCNA-positive cells, respectively, n=6/group, P<0.05) were greater in VG from Pai1−/−graft/WTrecipient mice than in VG from WTgraft/WTrecipient mice, while plasma PAI-1 did not differ between groups, suggesting that PAI-1 deficiency in VG increases cell proliferation and intimal hyperplasia.
Conclusions: The proliferative effect of thrombin is inhibited by PAI-1 expressed by SMC. PAI-1 functions as a physiological thrombin inhibitor in vivo in VG. These data suggest that within the VG wall, an environment inaccessible to plasma antithrombin, PAI-1 inhibits thrombin and its proliferative properties.
- © 2010 by American Heart Association, Inc.