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 role 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 rest 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 to initiate peroxidation of free arachidonic acid will also be determined and the primary peroxidation products biochemically characterized and their biologic activity toward inflammatory cells evaluated. Finally, using an in vivo model of myocardial ischemia and reperfusion injury, the generation of oxidized forms of myoglobin and reactive low molecular weight forms of iron will be evaluated and correlated with biochemical evidence of oxidant-mediated injury and morphologic changes of myocardial tissue. Particular attention will be focused on determining the temporal relationship between the oxidation of myoglobin and biochemical and morphologic changes. 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 nad 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 recent development 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 in the near future.
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