Abstract 16442: Positive Feedback Regulation Between AMP-Activated Protein Kinase and Thioredoxin-1 Maintains Energy- and Redox-Homeostasis During Myocardial Ischemia
Thioredoxin-1 (Trx1) is upregulated by myocardial ischemia and protects the heart against cell death. We hypothesized that AMP-activated protein kinase (AMPK), a sensor for energy deprivation, plays an essential role in mediating upregulation of Trx1 during ischemia. Expression of Trx1 was increased by prolonged (3h) ischemia (PI) in the mouse heart (3.1 fold, p<0.01 vs sham), an effect which was attenuated in dominant negative (DN)-AMPK mice (Tg-DN-AMPK) (1.0 fold, p<0.01 vs control). Phosphorylation of AMPK was increased by PI (2.2 fold, p<0.01 vs sham) and this was inhibited in DN-Trx1 mice (Tg-DN-Trx1) (1.1 fold, p<0.01 vs control). Thus, AMPK and Trx1 mediate upregulation/activation of one another during PI. The size of myocardial infarction (MI)/area at risk after PI was significantly greater in Tg-DN-AMPK (72% vs 53% p<0.05) and Tg-DN-Trx1 (62% vs 39% p<0.05) than in respective controls, suggesting that both AMPK and Trx1 are protective against PI. Glucose deprivation (GD) upregulated Trx1 in cardiomyocytes (CMs) (2.0 fold, p<0.05), which was accompanied by 2.7 fold activation of AMPK (p<0.05). AICAR, an activator of AMPK, upregulated Trx1 (2.8 fold, p<0.05). Inhibition of AMPK by DN-AMPK attenuated upregulation of Trx1 in response to GD or AICAR (0.6 and 0.5fold, p<0.05). Phosphorylation of AMPK and ACC, a downstream substrate of AMPK, during GD was also significantly attenuated (0.6 and 0.7fold, p<0.05) by downregulation of Trx1. GD-induced cell death was enhanced by inhibition of AMPK (68%vs 55%, p<0.05) or downregulation of Trx1 (60% vs 37% p<0.05). Downregulation of Trx1 inhibited GD-induced Glut4 translocation and glucose uptake (0.3 fold, p<0.05). Phosphorylation of phospho-fructose kinase 2 induced by GD was also attenuated and the increased glycolysis rate (4 fold, p<0.05) was also completely inhibited by sh-Trx1. Decreases in ATP content during GD were enhanced by inhibition of AMPK (1.9 fold, p<0.05) and downregulation of Trx1 (1.5 fold, p<0.05) due to impaired glucose metabolism. These results suggest that AMPK and Trx1form a positive feedback loop during myocardial ischemia, thereby enhancing each other's function against energy starvation-induced damage to maintain the energy and redox balance in the heart.
- © 2011 by American Heart Association, Inc.