Ischemia/reperfusion (I/R) injury contributes significantly to morbidity and mortality in patients with ischemic heart disease. Paradoxically, reperfusion of oxygen-deprived tissue, the mainstay of therapy for ischemia, causes further myocardial injury, limiting current therapeutic modalities. NF-kappaB is a transcription factor in many cell types that controls the mechanism of cellular responses to stress, such as I/R injury. The goals of this proposal are to examine at a molecular level NF-kappaB-dependent mechanisms of oxidative stress responses in human endothelial cells and human cardiomyocytes, and to apply these findings to in vivo models of I/R injury and, ultimately, clinical conditions where I/R injury is encountered. To accomplish this goal we have 3 specific aims: (1) Characterize NF-kappaB-dependent cell signal transduction pathways activated by oxidant stress (in the context of this proposal, we define oxidative stress as alterations in cellular redox states resulting from exposure of cells to hypoxia or reactive oxygen intermediates; these stresses form the pathogenic basis of I/R injury consisting of inflammation, apoptosis, necrosis and myocardial infarction), (2) Define the role of NF-kappaB in cardiomyocyte oxidative stress responses, and (3) Determine the cytoprotective role of NF-kappaB in ischemic preconditioning (in response to oxidative stress, NF-kappaB also mediates the expression of cytoprotective proteins; ischemic preconditioning is a unique phenomenon in which this protective response occurs). Although we focus on the role of NF-kappaB in myocardial I/R injury, we anticipate that results generated from experiments described in this proposal will be applicable to many clinical settings in which I/R injury is the principal pathogenetic event, such as stroke peripheral vascular disease, hemorrhagic shock and early transplant graft dysfunction. Currently the only therapy potentially available for I/R injury is immunosuppression with anti-neutrophil adherence monoclonal antibodies. However, neutrophil adherence function is also required for host responses to septic challenges, and this form of therapy for I/R injury leaves the patient vulnerable to infectious complications. Our intention is to focus on the role of NF-kappaB in I/R injury to more precisely define therapeutic targets that are specific to myocardial I/R injury. With identification of a specific molecular pathway that mediates I/R injury, we may then be able to block this deleterious response in the host yet still preserve other host stress responses that are beneficial.
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