Prolonged hypercholesterolemia-induced tissue factor expression in rabbit vein grafts: a potential mechanism for graft failure

Abstract

To evaluate tissue factor (TF) expression in vein grafts interposed in the arterial circulation of hypercholesterolemic rabbits. Veins implanted in the arterial circulation of normocholesterolemic rabbits respond by inflammation and infiltration by monocytes with transient TF expression. In a hypercholesterolemic milieu these monocytes may differentiate into macrophages capable of enhanced TF synthesis, which may facilitate hyperplasia and thrombosis. Autologous jugular veins interposed in the carotid artery of hypercholesterolemic rabbits were harvested at 1, 2, 4, 6, and 8 weeks after surgery and examined for presence and localization of rabbit TF antigen. Protein extracted from vein segments was evaluated for procoagulant activity by bioassay and for TF protein content by western blotting. Rabbit TF antigen was observed mostly in the subendothelium of vein grafts. Peak TF procoagulant activity observed at 1-2 weeks postsurgery (2.3+/-1.8 pg/mg, P<0.006) declined to 0.9+/-0.5, 0.2+/-0.1, and 0.15+/-0.06 pg/mg at 4, 6, and 8 weeks, respectively (P<0.03). Western blotting showed a time-dependent pattern for rabbit TF protein with prolonged expression peaking at 6 weeks. Prolonged expression of biologically active rabbit TF and TF protein were shown within jugular vein grafts of hypercholesterolemic rabbits. This response, reported for the first time and attributed to increased cholesterol levels, may possibly contribute to enhanced hyperplasia. These results suggest that TF expression could serve as another mechanism underlying vein graft failure and that hypercholesterolemia in bypass patients should be treated aggressively beginning within the weeks after surgery.