Congestive heart failure causes a switch from adult isoforms of contractile and regulatory proteins to more fetal forms of the proteins. In addition, there is a switch to a """"""""fetal"""""""" metabolic pattern in which carbohydrates become the preferred substrate over fatty acids. However, the effect of increased glucose uptake and decreased fatty acid uptake on substrate energy metabolism is not know. Furthermore, the signaling pathway responsible for this switch is unclear. The studies outlined in this proposal will focus on the mechanisms responsible for the switch in substrate preferences as well as the metabolic consequences of that switch in a rat model of heart failure. The proposed studies will test the novel hypothesis that the changes in the high energy phosphates (ATP, AMP, and phosphocreatine) that occur in the setting of heart failure regulate the switch from fatty acid oxidation to carbohydrate utilization through chronic activation of the metabolic stress protein. AMP- activated protein kinase (AMPK). Specifically, the studies will address three major aspects of cardiac metabolism in the setting of heart failure: 1) changes in the uptake and utilization of carbohydrate and fatty acid and their contribution to the citric acid cycle, 2) changes in the expression of key regulatory proteins in carbohydrate (the glucose transporters GLUT1 and GLUT4, hexokinase, phosphofructokinase-2, pyruvate dehydrogenase, and pyruvate dehydrogenase kinase), fatty acid metabolism (fatty acid binding protein, acetyl-CoA carboxylase, carnitine palmitoyltransferase I, and long chain acyl- CoA dehydrogenase), citric acid cycle flux (citrate synthase and alpha- ketoglutarate dehydrogenase), and oxidative phosphorylation (uncoupling protein (UCP)-2 and UCP-3) the role of AMPK activation in regulating metabolism in the failing heart. The findings of these studies will help to characterize the defects in energy metabolism in the failing heart and aid in the design of therapies that improve energy transduction in the failing human heart.
| Russell 3rd, Raymond (2006) Stress signaling in the heart by AMP-activated protein kinase. Curr Hypertens Rep 8:446-50 |
| Baron, Suzanne J; Li, Ji; Russell 3rd, Raymond R et al. (2005) Dual mechanisms regulating AMPK kinase action in the ischemic heart. Circ Res 96:337-45 |
| Russell 3rd, Raymond (2003) The Role of AMP-activated protein kinase in fuel selection by the stressed heart. Curr Hypertens Rep 5:459-65 |
