Abstract 18529: Protease-Activated Receptor-1 Deficiency Reduces Doxorubicin-Induced Cardiotoxicity

Abstract

Objective: The administration of doxorubicin (Dox), a potent effective anti-cancer anthracycline drug, is limited by its cardiotoxicity and coagulation activation. This study was conducted to investigate whether there is a direct connection between the increased thrombin-mediated signaling via the protease-activated receptor 1 (PAR-1) and the cardiotoxicity after Dox administration. Methods and Results: PAR-1-/- mice and wild-type (WT) littermates were subjected to a single injection of Dox (20mg/kg) or a weekly injection of Dox (5mg/kg) for 5 weeks. Changes in heart size, heart function and cardiotoxicity were measured by echocardiography 5 days or 5 weeks after injection (p.i.). Direct effects of thrombin during Dox stimulation was analyzed on neonatal cardiomyocytes and fibroblasts in vitro. PAR-1-/- mice were protected from Dox-induced cardiac injury and had preserved left ventricular function 5 days p.i. compared to WT littermates (fractional shortening: 53.7±1.8% vs. 43.9±2.0%; P<0.05). The hearts of PAR-1-/- mice had less cardiac expression of 3-Nitrotyrosine, KC and MPO compared to WT mice 5 days p.i.. Furthermore, the hearts of Dox-treated PAR-1-/- mice exhibited increased activation of pro-survival AKT and less acetylation of pro-apoptotic p53 compared to treated WT mice. In addition, PAR-1-/- mice had improved heart function compared WT mice at the 5 weeks’ time point (Dox cumulative dose 25mg/kg). In vitro experiments confirmed the deleterious effects of a thrombin-mediated PAR-1 activation during Dox incubation. Rat cardiomyocytes exhibited increased release of cardiac troponin I which was associated with increased levels of p53 acetylation. Furthermore, Dox-induced p53 accumulation in mouse fibroblast was enhanced by thrombin. Conclusion: These results indicate that PAR-1 activation contributes to Dox-induced cardiotoxicity by enhancing inflammatory response and apoptosis. These findings suggest that PAR-1 antagonist may be useful in preventing Dox-induced heart failure in cancer patients.