LONG CHAIN ACYL COA INTERACTIONS IN THE HEART

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Abnormalities of lipid metabolism have been implicated as a causative factor for the cellular damage that occurs during myocardial ischemia. Long chain acyl CoA derivatives have been shown to accumulate in heart tissue during ischemia and may interact adversely with intracellular membranes, producing functional changes. This proposal is designed to obtain new information on the interaction of long chain acyl CoA with membranes from cardiac tissue and to determine how such interactions might influence intracellular lipid metabolism. The long term objective of this proposal is to determine if the data obtained on acyl CoA-membrane interactions are consistent with the hypothesis that long chain acyl CoA molecules actually do cause membrane damage in cardiac tissue during ischemia. The specific aims are: 1.) To examine the interaction of acyl CoA with phospholipid bilayers in vitro. Unilamellar phospholipid vesicles will be used as a model system and the effects of surface charge, chemical composition and physical state of the vesicles will be determined. 2.) To study directly the interaction of acyl CoA with intracellular membranes from cardiac tissue. Sarcoplasmic reticulum and inner mitochondrial membrane will be used and an assay system developed to determine the kinetics of the interaction, specificity, and effects of surface modification of the membranes. In addition, the possibility that acyl CoA alters the activity of selected enzymes associated with the isolated organelles will be tested. 3.) To establish the presence of a soluble protein in rat or rabbit heart that binds acyl CoA, to purify the protein, and to characterize the nature of the binding. 4.) The effect of the soluble acyl CoA binding protein on the interaction of acyl CoA with unilamellar vesicles and isolated membranes will be determined and the possibility that the binding protein may facilitate transport or metabolism of acyl CoA will be tested.