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Antoniak Lab published a study investigating the role of thrombin-PAR1 signaling in chemotherapy induced heart failure.

UNC Blood Research Center researchers Drs Grover, Bharathi, Mackman and Antoniak in collaboration with Drs. Posma, Griffin and Palumbo published in Blood Advances “Thrombin mediated activation of PAR1 enhances doxorubicin induced cardiac injury in mice”.

Dr. Antoniak was the senior author on this multi-institutional experimental study into the role of thrombin-dependent protease-activated receptor 1 (PAR1) signaling on doxorubicin-induced cardiotoxicity. The chemotherapeutic drug doxorubicin is known for its cardiotoxicity (DoxTox) and can cause irreversible heart failure. In addition, doxorubicin can cause activation of coagulation. In the study we determined the effect of thrombin-mediated activation of PAR1 on DoxTox. Our study showed that doxorubicin leads to Tissue Factor-dependent coagulation activation. In addition, PAR1 on cardiomyocytes and fibroblast contribute to DoxTox in mice. Using transgenic mice insensitive to thrombin (Par1R41Q) or to activated protein C (Par1R46Q) we showed that PAR1-dendent contribution to DoxTox was mediated through thrombin-mediated cleavage of PAR1 at R41. Mice lacking Par1 or Par1R41Q were both protected against DoxTox compared to their controls. Importantly, using a selective PAR1 inhibitor Q94, which blocks PAR1-Galphaq signaling, we observed that Q94 protected mice against DoxTox. Our data suggest that thrombin-mediated activation of PAR1 contributes to DoxTox. The study was supported by a NIH NHLBI R01HL.148432 to Dr. Antoniak.

Click here to read the paper.