Degradation of membrane phospholipids play a crucial role in the pathophysiology of myocardial reperfusion injury. Inositol phosphates and diglycerides, novel second messengers, released from the phospholipids may be instrumental for reperfusion injury, the former causing Ca2+ release and the latter activating protein C kinase thereby initiating a cascade of reactions. Arachidonic acid released from phospholipids can also cause cellular injury in many ways. The proposed research will continue to explore the mechanisms of phospholipid breakdown in the ischemic-reperfused heart. The relative contribution of various pathways of phospholipid breakdown will be examined using specific inhibitors of rate controlling steps in each pathway, simultaneously estimating corresponding enzymes and metabolites and studying myocardial preservation during ischemia and reperfusion. In addition, the role of various mediators (transducing and regulatory proteins) for phospholipid degradation, fatty acid binding protein, lipocortin, endothelin as well as alpha and beta adrenergic receptors will be studied by blocking the actions of these mediators by specific blockers, simultaneously examining the effects on phospholipid breakdown and myocardial preservation. Breakdown of phospholipids will be monitored by estimating various phospholipids and their degradation products. To monitor minor changes in breakdown, the membrane phospholipids will be radiolabeled with various isotopes followed by subsequent analysis of incorporated radioactivities from the metabolites. A study will be conducted to examine whether free radicals, important mediators of reperfusion injury, are generated from the phospholipid degradation. The goals of this investigation are to establish the mechanism of phospholipid breakdown and to apply the knowledge gained to appropriate interventions to protect an ischemic heart from reperfusion injury. This will eventually be applicable to patient care for reduction of myocardial injury during ischemia and reperfusion.
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