Role of cardiac energy deprivation in type 1 and type 2 diabetes

Previously we determined that delta protein kinase C (dPKC) interacts with the 'd' subunit of the F1Fo ATP synthase (dF1Fo) to inhibit F1Fo function in cardiac myocytes. We hypothesize that this contributes to compromised ATP production and cardiac injury in diabetes. Our first Aim is therefore: To determine if the dPKC-dF1Fo interaction contributes to, energy depletion, mitochondrial dysfunction and cardiac injury in rodent models of type 1 and type 2 diabetes. We will use streptozotocin (STZ)-treated rats and db/db mice to monitor the dPKC-dF1Fo interaction, F1Fo ATPase activities, oxidative stress, cell death or infarction, and cell/tissue ATP levels. We further hypothesize that the dPKC-dF1Fo interaction in diabetes increases susceptibility to cardiac IR injury in diabetes. Our second aim is therefore: To determine the role of the dPKC-dF1Fo interaction in type 1 and type 2 diabetes-induced exacerbation of cardiac IR injury. STZ-treated rats and 5, 8 and 15 week old db/db mice, will be subjected to IR injury using an open chest coronary ligation model. The dPKC-dF1Fo interaction, F1Fo ATPase activities and dimer formation, cristae structure, ATP levels and infarction will be monitored. In addition, we will use proteomic and native gel techniques to monitor which F1Fo subunits are phosphorylated following diabetic and IR injuries and determine the role of dPKC in F1Fo ATP synthase subunit phosphorylation, dimer/oligomer formation and cristae development. To facilitate these studies, we have developed 2 novel, cell-permeable, mitochondrially-targeted peptides which facilitate and antagonize the dPKC-dF1Fo interaction. These compounds may reveal a novel cardioprotective therapy diabetic injury. (AHA Program: Grant-in-Aid)