Abstract 16269: Targeted Deletion of Thioredoxin-Interacting Protein (Txnip) Enhances Anaerobic Metabolism and Mitochondrial Thioredoxin Activity and Protects the Heart from Ischemia Reperfusion Injury
Thioredoxin-Interacting Protein (Txnip) is a regulator of metabolism and an inhibitor of the antioxidant thioredoxin, but little is known about roles of Txnip in the myocardium. We previously showed that Txnip deletion leads to a robust increase in myocardial glucose uptake and maladaptive LV remodeling following prolonged pressure overload. To gain more insight into Txnip's physiological role, we examined Txnip-KO hearts by Polony Multiplex Analysis of Gene Expression and proteomic analysis; both techniques identified a coordinated downregulation of genes participating in mitochondrial oxidative phosphorylation relative to wildtype controls (WT). Mitochondrial O2 consumption measured by polarography was significantly reduced in Txnip-KO hearts (69±7% of WT, p<0.01). Txnip-KO mitochondria were structurally normal by electron microscopy, but exhibited more matrix granules and perimitochondrial lipid droplets. Given the central role that mitochondria serve during hypoxia, we hypothesized that Txnip deletion amplifies deleterious effects during ischemia-reperfusion injury. Surprisingly, cardiomyocyte-specific Txnip KO mice had reduced infarct size (50±13% of control, p<0.01) after ischemia-reperfusion, demonstrating improved ischemic tolerance in vivo. Independent ex vivo experiments also demonstrated that Txnip-KO hearts had greater recovery of LV function following ischemia-reperfusion (104±8% improvement of WT, p<0.01). Interestingly, whereas the mitochondrial production of ATP was minimally decreased in Txnip-KO hearts, cytosolic ATP production was 5-times higher in Txnip-KO hearts after ischemic injury, suggesting enhanced anaerobic glycolysis by Txnip deletion. Mitochondrial, but not cytosolic, thioredoxin activity was increased by 20% in Txnip-KO hearts, associated with decreased global ROS levels in the myocardium assessed by lipid peroxides. These results suggest that genetic deletion of Txnip suppresses mitochondrial oxidative phosphorylation, directing cardiomyocytes towards enhanced anaerobic metabolism and increased mitochondrial thioredoxin activity. Thus, even though Txnip deletion impairs mitochondrial respiration, it acutely protects the heart during ischemia-reperfusion injury.
- © 2010 by American Heart Association, Inc.