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. Project 1 involves the study of the mechanisms of cardiac protection inthe second window of ischemic protection (SWOP) in chronically instrumented conscious swine. One uniqueaspect of this Project is the use of the large mammalian model, which resembles pathophysiology in humansmore closely than rodents, lacks preformed coronary collateral vessels, and the heart is sufficiently large toprovide measurements of regional function, blood flow, biochemistry, molecular biology and pathology fromthe same animals in both the ischemic zone and a contralateral, remote, non-ischemic zone. The project isbased, in part, on the novel observation that either regional cardiac denervation or adrenergic receptorblockade abrogates the second window of protection. There are three major hypotheses: A)SWOP iscritically dependent on the sympathetic nervous system; B)Regional cardiac denervation alters SWOP in theremote, non-ischemic zone; C)SWOP results in enhanced long chain fatty acid (LCFA) oxidation duringischemia, potentially due to AMP kinase elevation, an effect which is abolished following SWOP in consciouspigs with regional cardiac denervation. Project 1 is tied closely to the other projects and cores, as well as tothe major themes of the Program Project, which are: 1)Mechanisms of myocardial ischemia and reperfusion;2)Molecular signaling; 3)Myocardial protection and cell survival vs. cell death; 4)lntegrative cardiovascularresearch. This project is also linked closely to Project 2, which also studies the chronically instrumentedswine model, but in Project 2 the model is one of repetitive stunning (myocardial hibernation). Indeed,several of the aims are shared by Projects 1 and 2, since the two projects will address several of the samequestions in the two different models. Project 1 interacts with Project 3 in terms of molecular signaling andmechanisms of apoptosis, and with Project 4 particularly related to H11 kinase, which will be administered topigs with regional cardiac denervation, to determine if H11 kinase can restore protection after cardiacdenervation. Project 1 also utilizes all of the Cores.
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