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Updated: Aug 14, 2026
Orthotopic Aortic Transplantation: A Rat Model to Study the Development of Chronic Vasculopathy
Published on: December 5, 2010
Hirudin reduces tissue factor expression and attenuates graft arteriosclerosis in rat cardiac allografts
H Hölschermann1, R M Bohle, H Schmidt
1Departments of Internal Medicine , Justus-Liebig-University, Giessen, Germany. hans.f.hoelschermann@innere.med.uni-giessen.de
Insights
Recombinant hirudin treatment significantly reduced cardiac allograft vasculopathy (CAV) in a rat model by inhibiting tissue factor (TF) expression and neointimal hyperplasia, suggesting a potential therapeutic strategy for preventing CAV.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Coagulation Biology
Background:
- Cardiac allograft vasculopathy (CAV) is a significant complication following heart transplantation.
- Intravascular clotting, initiated by tissue factor (TF), is implicated in CAV pathogenesis.
- Previous studies linked coronary intima TF expression to neointimal thickening.
Purpose of the Study:
- To evaluate the efficacy of recombinant hirudin in preventing CAV.
- To assess hirudin's effect on tissue factor (TF) expression in cardiac allografts.
Main Methods:
- Lewis to Fisher rat heterotopic cardiac allografts were used.
- Recipients were randomized to control or hirudin-treated groups (2 mg/kg/day SC).
- Histological analysis, TF staining, and quantitative TF mRNA analysis (real-time PCR) were performed.
Main Results:
- Hirudin significantly suppressed CAV development in graft microvessels (P<0.05).
- Hirudin treatment markedly reduced TF protein and mRNA expression (P<0.001).
- TF gene transcription upregulation in graft intimal cells was prevented by hirudin (P<0.01).
Conclusions:
- Hirudin treatment inhibited TF expression and decreased neointimal hyperplasia in this rat cardiac transplant model.
- Hirudin may attenuate hypercoagulable states and prevent CAV development, particularly in graft coronary vasculature.
- TF inhibition by hirudin offers a potential therapeutic avenue for managing CAV.
Abstract:
BACKGROUND-Intravascular clotting has been implicated in the pathogenesis of cardiac allograft vasculopathy (CAV). We previously identified the expression of tissue factor (TF), the primary cellular initiator of blood coagulation, within the coronary intima, which was associated with neointimal thickening. In the present study, the effect of recombinant hirudin on CAV was assessed in Lewis to Fisher rat heterotopic cardiac allografts. METHODS AND RESULTS-Transplant recipients were randomized to a control group (n=10) and a hirudin-treated group (n=12; 2 mg. kg(-1). d(-1) SC). Histological evaluations of rejection, CAV, and TF staining were performed 120 days after transplantation. No significant differences were observed between the 2 groups with respect to the degree of rejection. Hirudin significantly (P<0.05) suppressed the development of CAV in the graft microvessels, but it was less effective in large coronary arteries. Graft intimal cells, isolated by laser-assisted cell picking, showed a marked upregulation of TF gene transcription, which was prevented by hirudin (P<0.01). As demonstrated by immunohistochemistry and quantitative analyses of TF mRNA levels by real-time polymerase chain reaction, hirudin treatment resulted in a significant reduction of TF protein and mRNA expression (P<0.001). CONCLUSIONS-Treatment with hirudin in this rat cardiac transplant model inhibited TF expression and decreased neointimal hyperplasia. These results suggest that TF inhibition by hirudin, in addition to its direct effect on thrombin, may attenuate the hypercoagulable state and prevent the development of CAV at least in restricted sites of the graft coronary vasculature.
