The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated, irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of this Program Project application is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will be accomplished by utilizing a combined approach by integrative and basic scientists. There are 4 projects and 5 cores, with major interactions among projects and cores. All the projects include cellular and molecular studies as well as integrative whole animal physiology. All Projects use all the Cores, which is the glue that binds the Projects and provides the synergy characteristic of a Program Project. One unique aspect of this Program Project is the use of the large mammalian model, which is central to Projects 1 and 2. Project 1, "Effects of Cardiac Denervation on Ischemic Protection", involves the study of the mechanisms of cardiac protection in the second window of ischemic protection in chronically instrumented conscious swine. The project is based, in part, on the novel observation that either regional cardiac denervation or adrenergic receptor blockade abrogates the second window of protection. Project 2, "Molecular Mechanisms in Chronically Stunned Myocardium", parallels Project 1 in that it also uses the conscious, chronically instrumented swine model, but focuses on the chronic, repetitive stunning model developed in this project in the last funding period. This model recapitulates many of the features of hibernating myocardium in patients with chronic coronary artery disease, and also exhibits myocardial protection, potentially through a third window of protection. Project 3, "Cell Death Promoting Mechanisms of Mst 1", also involves the study of cell survival and cell death with special emphasis on the molecule Mst 1, mammalian sterile kinase. This project is based on findings during the current funding period that Mst 1, belonging to a recently identified evolutionary conserved protein kinase cascade activated by myocardial ischemia, has unexpected and diverse functions not limited to pro-apoptosis but which contributes to cardiac dysfunction. Project 4, "Survival Role of H11 Kinase during Myocardial Ischemia", is a new project which focuses on cardioprotection mechanisms invoked by H11 kinase. This project is based on work completed during the initial funding period, where one of the novel molecular mechanisms involved in myocardial stunning and hibernation discovered was H11 kinase, a molecule not previously studied in the heart, and found to afford powerful protection against myocardial ischemia. The Program Project approach is exemplified by the interactions among Projects and Cores, which strengthens each individual project and is designed to improve our understanding and delineate new therapies for patients with coronary artery disease.