AMPK and the Atrial Response to Metabolic Inhibition.

SEE PAGE 47 A MP-activated protein kinase (AMPK) is a molecular energy sensor that is essential to the stress response in the heart (1). AMPK is activated during energy imbalance, when the ADPor AMP-toATP ratio increases. Because few proteins have adenine nucleotide binding domains, the activation of a protein kinase, which phosphorylates numerous downstream proteins, amplifies the energy stress response. AMP and ADP binding to AMPK enhances the phosphorylation of the critical Thr172-activating site by promoting the activity of the upstream kinase liver kinase B1 (LKB1), which is also present in the heart. When activated, AMPK signals the cell to generate ATP through substrate metabolism and to conserve energy by limiting anabolic pathways (1). The LKB1-AMPK axis has emerged as a master metabolic regulator with pleiotropic actions in the heart. During ischemia, there is rapid and robust activation of endogenous left ventricular (LV) AMPK, which limits energy depletion by stimulating glucose uptake and glycolysis and increases autophagy and inhibits protein synthesis (1). Mice with genetically inactivated AMPK are predisposed to ischemiareperfusion injury with exaggerated necrosis and apoptosis (2,3). Conversely, small-molecule AMPK activators prevent myocardial injury during ischemiareperfusion (4). Furthermore, agents that activate AMPK may also have benefit in experimental heart failure (5).