Modulating delta protein kinase C interaction with the F1Fo ATP synthase d subunit to reduce cardiac ischemia/reperfusio

Under normal conditions over 90% of cardiac energy needs are met by the F1Fo adenosine triphosphate (ATP) synthase. In myocardial ischemia, the enzyme is inhibited and eventually functions in reverse as an ATPase to destroy ATP. This loss of ATP contributes heavily to cardiac dysfunction and death following a heart attack. We have identified a potent inhibitory effect on the F1Fo enzyme complex mediated by a selective binding interaction between delta protein kinase C (dPKC) and the 'd' subunit of F1Fo ATP synthase. We believe this interaction plays a major role in the pathology of cardiac ischemia reperfusion injury. We have therefore developed cell-permeable mitochondrial-targeted modulatory peptides of the dPKC-dF1Fo interaction and in the current proposal will test their ability to minimize the cell death and oxidative damage occurring in cardiac IR injury. One of the peptides disrupts the interaction and a second peptide induces it. These peptides are derived from the dF1Fo protein and are readily targeted to subsarcolemmal and interfibrillar mitochondria when injected intraveneously into rats. In this proposal we will focus on determining the translational research potential of these peptides by monitoring their effects to reduce cardiac infarct size, oxidative stress and mitochondrial dysfunction in adult Sprague-Dawley rat and Yorkshire pig in vivo coronary occlusion models. If successful, these studies may provide the foundation for clinical testing of these compounds in humans. (AHA Program: Grant-in-Aid)