Hirudin reduces tissue factor expression and attenuates graft arteriosclerosis in rat cardiac allografts.
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.
Hölschermann
H
H
Departments of Internal Medicine , Justus-Liebig-University, Giessen, Germany. hans.f.hoelschermann@innere.med.uni-giessen.de
Bohle
R M
RM
Schmidt
H
H
Zeller
H
H
Fink
L
L
Stahl
U
U
Grimm
H
H
Tillmanns
H
H
Haberbosch
W
W
D000818:Animals; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology*; D003331:Coronary Vessels / Q000378:metabolism; D016027:Heart Transplantation; D006629:Hirudins / Q000494:pharmacology*; D008297:Male; D011184:Postoperative Period; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014184:Transplantation, Homologous
D006629:Hirudins; D013925:Thromboplastin