Hirudin Reduces Tissue Factor Expression and Attenuates Graft Arteriosclerosis in Rat Cardiac Allografts

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 (nϭ10) and a hirudin-treated group (nϭ12; 2 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 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 (PϽ0.05) 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 (PϽ0.01). 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 (PϽ0.001). 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.

Targeting complement component 5a promotes vascular integrity and limits airway remodeling

“…The histological specificity of vascular thrombin deposition is confirmed by hirudin, a specific thrombin inhibitor, blocking the staining with antithrombin antibody. Of note, it has been previously demonstrated that systemic hirudin administration to rat cardiac allograft recipients attenuates graft arteriosclerosis in close association with reduced tissue factor expression in transplant vasculature; tissue factor being necessary for thrombin formation (21). The current study extends these observations by showing that thrombin itself colocalizes with the microvasculature: a finding that is, to our knowledge, a unique observation in transplant biology.…”

Inhibition of Thrombin Receptor Signaling on α-Smooth Muscle Actin + CD34 + Progenitors Leads to Repair After Murine Immune Vascular Injury

“…19 -21 Moreover, a potent thrombin inhibitor, hirudin, has been shown to attenuate experimental TA in rat cardiac allografts. 22 Our data now provide a mechanistic explanation for the link between TF and IH, through thrombin/PAR-1 signaling on circulating CD34 ϩ cells. PAR-1 is the archetypal member of a family of G-proteincoupled, 7 transmembrane-domain cell surface receptors, designated PAR-1 to PAR-4, [23][24][25][26] through which coagulation proteases mediate many of their proinflammatory effects.…”

The role of tissue factor in normal pregnancy and in the development of preeclampsia: A review

“…estrogen, in cigarette smokers and in hyperhomocysteinemia [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] .…”