Abstract 5671: The Effects of Pharmacological PAI-1 Inhibition in Acute and Chronic Rejection in Murine Cardiac Allografts

Abstract

Backgrounds: Acute rejection and graft arterial disease (GAD) in cardiac transplantation are enhanced by inflammation and thrombus formation. However, little is known about the effect of plasminogen activator inhibitor-1 (PAI-1) in heart transplantation. Thus, the objective was to clarify the role of PAI-1 in the progression of rejection. Methods and Results: Murine hearts were heterotopically transplanted using major mismatch combinations for evaluation of acute rejection and class II mismatch combinations for the GAD. We performed administration of the specific PAI-1 inhibitor (IMD-1622) into murine recipients of cardiac allografts. Nontreated allografts of the major mismatch group were acutely rejected (n=6; 7.3±0.2 days), while the PAI-1 inhibitor prolonged their survival (n=6; 13.7±2.4 days, P < 0.05). Pathologically, severe myocardial cell infiltration (40.8±3.3 %) and fibrosis (44.5±2.8 %) were observed in untreated allografts, the PAI-1 inhibitor attenuated infiltration (25.8±1.9 %, p<0.05) and fibrosis (25.8±3.1 % p<0.05) in the class II mismatch group on day 60. Although severe GAD (luminal occlusion 28.6±6.4 %) was observed in untreated allografts, the PAI-1 inhibitor suppressed the development of neointimal formation (8.1±3.5 %, p<0.05). Immunohistochemically, CD8 and ICAM-1 were enhanced in nontreated allografts, while the PAI-1 inhibitor markedly attenuated expression of these factors. Zymography showed that increased gelatinase activity was observed in the non-treated allograft group, however, the PAI-1 inhibitor decreased the activity. RNAse protection assay revealed that PAI-1 inhibitor suppressed IFN-gamma compared with that of non-treated group. Conclusion: The PAI-1 inhibitor is potent in the suppression of both allograft rejection and arterial disease because they are critically involved in the development of rejection through the suppression of inflammation.