The long-term goal of this proposal is to define the biochemical and cellular mechanisms that underlie myocardial ischemia and reperfusion injury with a specific focus on the ale of reactive oxygen species and inflammatory cells. The Primary hypothesis of this proposal is that myoglobin, through its ability to promote oxidative reactions and serve as a potential source of hematin and reactive low molecular weight forms of iron, functions to enhance myocardial injury resulting from ischemia and reperfusion. To test this hypothesis the biochemical mechanisms by which products of activated neutrophils react with myoglobin and promote the generation of oxidative derivatives of myoglobin and release of reactive low molecular forms of iron will be determined. Subsequent studies will evaluate the ability of myoglobin to mediate oxidative injury of specific sarcolemma, sarcoplasmic reticulum, and mitochondrial enzyme systems involved in ion transport. The ability of ferriperoxy derivatives of myoglobin, especially the recently characterized """"""""myoglobin oxidase"""""""" product, to initiate peroxidation of free arachidonic acid and modulate the function of ion transport enzymes will he determined. Finally, using in vitro and in vivo studies, we will investigate the ability of heme oxygenase, the rate limiting enzyme in heme degradation, to modulate myoglobin dependent oxidation reactions and myocardial ischemia reperfusion injury. The relationship between the biochemical and morphologic alterations in cardiac function and structure will be investigated. Results of these studies will address the question as to whether or not myoglobin plays an important role in myocardial ischemia and reperfusion injury and to define the cellular and biochemical mechanisms involved. Furthermore, insight into the potential for the development of novel pharmacologic approaches for modulating injury associated with myocardial ischemia and reperfusion will be generated. Due to the widespread application of new medical interventions in the treatment of coronary artery occlusion and myocardial ischemia, it is likely that the results of these studies will have direct clinical application.
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