The most common form of heart disease is myocardial ischemia, which is characterized by an insufficientsupply 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 the Projectis to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which willbe accomplished by utilizing an integrative approach including cellular and molecular studies as well asintegrative whole animal physiology. This Project is based on a model of repetitive stunning in the swine,developed in the current funding period, that reproduces the chronic myocardial dysfunction with maintainedviability that characterizes the human hibernating myocardium. We show in the Preliminary Data that the welldefined cardioprotective mechanisms attributed to the first and second window of preconditioning are notactivated in the model of repetitive stunning. Rather, in this model, cardiac protection results from theactivation of a different gene/protein program of cell survival, and also from the regulation of specificintracellular pathways, including autophagy. Accordingly, this may represent a third window of protection.The goal of this proposal is to better define the mechanisms of cardioprotection activated in this model ofrepetitive stunning, to determine their durability, to compare those mechanisms with those activated duringpreconditioning, and to determine whether the repetition of ischemia extends this cardioprotection to theremote, normal myocardium. Importantly, the swine model of repetitive stunning resembles pathophysiologyin humans more closely than rodents, lacks preformed coronary collateral vessels, and the heart issufficiently large to provide measurements of regional function, blood flow, biochemistry, molecular biologyand pathology from the same animals in both the ischemic zone and a contralateral, remote, non-ischemiczone. This project is tied closely to the other projects and cores, as well as to the major themes of theProgram Project: 1)Mechanisms of myocardial ischemia and reperfusion; 2)Molecular signaling;3)Myocardial protection and cell survival vs. cell death; 4)lntegrative cardiovascular research. This project islinked closely to Project 1, which also studies the chronically instrumented swine model, but in Project 1 themodel is one of regional cardiac denervation. Indeed, several of the aims are shared by Projects 1 and 2,using two different models. It will be critical to compare the cellular/molecular alterations in Projects 1 and 2to derive an understanding of the differences between the second and potentially, third window of protection.Project 2 interacts with Project 3 in terms of molecular signaling and mechanisms of apoptosis, and withProject 4 particularly related to H11 kinase and its role in the protection afforded by chronic, repetitivestunning. Project 2 also utilizes all of the Cores.
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