Thioredoxin-2 Inhibits Mitochondrial Ros Generation And Ask1 Activity To Maintain Cardiac Function

Background: Increasing evidence indicates that mitochondrial-derived reactive oxygen species (ROS) and cellular apoptosis contribute to the pathogenesis of cardiac dysfunction. Mitochondrial thioredoxin (Trx2) is a key protein regulating cellular redox and survival, However, but its role in normal cardiac growth has not been determined. Methods and Results: We have generated cardiac-specific Trx2 knockout mice (Trx2-cKO) to determine the physiological importance of the Trx2 system in the heart. Trx2-cKO mice developed a spontaneous dilated cardiomyopathy at 1 month of age with increased heart size, fibrosis, reduced ventricular wall thickness, and progressive contractile dysfunction, resulting in death due to heart failure by 4 months of age. Cardiac changes in Trx2-cKO mice were accompanied by disruption of mitochondrial integrity and function, as evident by alterations in mitochondrial number, ultrastructure, membrane potential and ATP production. Increases in ASK1 signaling and ROS production preceded mitochondrial damage, cellular apoptosis and contractile dysfunction in both Trx2-cKO hearts and isolated cardiomyocytes. Moreover, deletion of ASK1 attenuates ROS production, mitochondrial dysfunction and cellular apoptosis in Trx2-deficient cardiomyocytes. These data indicate that ASK1 is a major target of Trx2 and that activation of ASK1 is causally associated with mitochondrial dysfunction, ROS production and cellular apoptosis. We also detected reduced Trx2 expression and increased ASK1 activity in human hearts from patients with cardiomyopathy, suggesting that this mechanism is clinically important. Conclusion: Our data support an essential role for mitochondrial Trx2 in preserving cardiac function by suppressing mitochondrial ROS production and ASK1-dependent apoptosis. These results suggest that pharmacological inhibition of ASK1 may provide a therapeutic strategy for the treatment of dilated cardiomyopathy and heart failure.