PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN NEOINTIMA OF VEIN GRAFTS - ITS ROLE IN REDUCED FIBRINOLYTIC POTENTIAL AND GRAFT FAILURE

Background Intimal smooth muscle cell proliferation is an underlying p athogenetic mechanism for neointimal hyperplasia and consequent vein g raft failure. This study characterizes the expression of tissue-type p lasminogen activator (TPA), urokinase-type plasminogen activator (UPA) , and plasminogen activator inhibitor-1 (PAI-1) in hyperplastic vein g rafts and normal venous tissue. Methods and Results Failing graft and control vein specimens from 14 donors were homogenized, and TPA and PA I-1 were quantified with ELISA. The amount of PAI-1 was seven times hi gher (4.2 +/- 2.1 versus 0.6 +/- 0.6 ng/mg protein, P<.005), but the T PA antigen content was markedly lower (3.1 +/- 2.1 versus 8.1 +/- 3.7 ng/mg protein, P<.OO5) in the stenosed grafts compared with the contro l veins. Strong immunohistochemical PAI-1 reactivity and in situ hybri dization signals for PAI-1 and UPA mRNA were associated with the smoot h muscle cells of the thickened intima of the grafts. Functional assay s of the graft specimens showed an increased UPA/TPA ratio and a decre ased total fibrinolytic activity in comparison with normal veins. Conc lusions Upregulation of PAI-1 mRNA expression and markedly increased a mounts of PAI-1 antigen were detected in the vein grafts after the dev elopment of neointima. Furthermore, augmented UPA activity was found i n the graft wall, but TPA was clearly depleted. Altogether, our findin gs imply decreased fibrinolytic potential in the stenosed graft, which may contribute to the graft occlusion.