Abstract 18277: Positive Feedback Regulation Between Amp Activated Protein Kinase and Thioredoxin-1 During Ischemia
Thioredoxin-1 (Trx1) is upregulated by stress and protects the heart against oxidative stress, inflammation and cell death. The mechanism mediating upregulation of Trx1 by stress is not well understood. Glucose deprivation (GD) upregulated Trx1 in cardiomyocytes (CMs) (2.0 fold, p<0.05), which was accompanied by activation of AMP activated protein kinase (AMPK) by 2.7 fold (p<0.05). AICAR, an activator of AMPK, upregulated Trx1 (2.8 fold, p<0.05). Inhibition of AMPK by dominant negative (DN) AMPK attenuated upregulation of Trx1 in response to GD or AICAR (0.6 and 0.5fold, p<0.05). Expression of Trx1 was increased by ischemia in mouse heart (3.1 fold, p<0.01), an effect which was attenuated in DN-AMPK mice (Tg-DN-AMPK). These results suggest that AMPK plays an important role in mediating upregulation of Trx1 during GD/ischemia. Interestingly, phosphorylation of AMPK and downstream target ACC during GD was also significantly attenuated (0.6 and 0.7fold, p<0.05) by downregulation of Trx1, indicating that AMPK and Trx1 stimulate one another. GD-induced cell death was enhanced by inhibition of AMPK (0.4fold, p<0.05) and downregulation of Trx1 (0.5fold, p<0.05). 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). These results suggest that AMPK and Trx1 coordinately mediate protection against GD. The size of myocardial infarction (MI) after 3 hours of prolonged ischemia (PI) was significantly greater in Tg-DN-AMPK (72% vs 53% p<0.05 n=4) and Tg-DN-Trx1 (62% vs 39% p<0.05 n=4) than in respective control mice, indicating that both endogenous AMPK and Trx1 are protective against PI. Importantly, the increase in the MI size was normalized when Tg-DN-AMPK mice were crossed with Trx1 transgenic mice (41% vs 72% p<0.05 n=4). Decreases in the intracellular ATP content and the aconitase activity after PI were also normalized in the bigenic mice, suggesting that the lack of Trx1 upregulation is responsible for the enhanced myocardial injury in Tg-DN-AMPK mice during PI. In conclusion, AMPK and Trx1form a positive feedback loop during GD and PI, thereby enhancing the function of one another and preserving ATP and mitochondrial function in the heart in a coordinated manner.
- © 2010 by American Heart Association, Inc.