Abstract 597: Targeted Deletion of Thioredoxin-Interacting Protein Prevents Cardiac Dysfunction in Response to Pressure Overload
Biomechanical overload induces left ventricular (LV) hypertrophy and failure, and reactive oxygen species (ROS) play a role in both processes. We previously identified Thioredoxin-Interacting Protein (Txnip) as a mechanically regulated gene that controls cell growth and apoptosis in part through the inhibition of the endogenous dithiol antioxidant thioredoxin. Here we show in mice that Txnip is a critical regulator of the cardiac response to pressure overload, potentially through regulation of myocardium glucose utilization. We generated cardiac-specific and systemic Txnip null mice (Txnip-KO) using Flp/frt and Cre/lox technology. Epitope-mapped monoclonal antibodies demonstrated complete absence of Txnip protein in targeted tissues. Compared with wild-type littermates (WT), Txnip-KO hearts had reduced LV mass (Δ%LV mass/ tibial length from baseline to TAC −50±20%, n=14), myocyte cross-sectional area (−16±6%, n=11, P<0.05), and percent fibrosis area (−54±19%, n=11, P< 0.05) in response to pressure overload by transverse aortic constriction. Echocardiography and catheterization revealed that Txnip-KO hearts had preserved fractional shortening (Δ%FS +41±18% from baseline to TAC, n=17, P<0.05), stroke volume (+43±20%, n=4, P<0.05), and LV developed pressure (dP/dt max: +19±10%; dP/dt min: +64±22%, n=6, P<0.05) after TAC compared with wild-type littermates. Surprisingly, the beneficial effects of Txnip deletion on cardiac performance were not associated with increased myocardial thioredoxin activity or reduced levels of ROS. Since the systemic Txnip-KO mice were hypoglycemic, we measured myocardial 2-deoxyglucose uptake (2-DG) using 31P NMR spectroscopy. Txnip-KO hearts showed a robust increase in 2-DG uptake in an insulin-independent manner (3.2±0.5-fold over WT, n=6, P<0.01). LV developed pressure was preserved during 2-DG uptake in Txnip-KO hearts (2.3±0.3-fold over WT; n=6, P<0.01). These data demonstrate that deletion of Txnip prevents cardiac dysfunction in response to pressure overload in vivo, but the benefits of Txnip deletion may be due to an unanticipated role in myocardial glucose metabolism rather than inhibition of thioredoxin activity.