Recent studies have demonstrated that the development of membrane permeability defects are closely related to the development of irreversible cell injury. Although the biochemical basis of these defects is unknown, recent work suggests that the degradation of membrane phospholipids may contribute to cellular injury during myocardial ischemia. The central hypothesis to be tested in this proposal is that the degradation of membrane phospholipids is responsible for the development of a sarcolemmal Ca++ permeability defect and associated irreversible cell injury during myocardial ischemia. Furthermore, it is postulated that the ultimate depletion of the membrane phospholipids is dependent on the relative activities of the phospholipases and the lysolipid reacylase activities. Since the reacylation of fatty acids into membrane phospholipids first requires the ATP dependent activation to their corresponding fatty acyl CoA derivatives, the inhibition of long chain acyl CoA synthetase, secondary to ATP depletion, may contribute to the net loss of the phospholipid molecule during ischemia. Accordingly, the specific aims of this grant are four-fold: 1) to examine the correlation between the degradation of membrane phospholipids (as assessed by the accumulation of free arachidonate) with the development of sarcolemmal membrane permeability defects, loss of myocardial contractile function, and the development of irreversible cell injury in several models of myocardial ischemia; 2) to examine the relationship of arachidonate accumulation with the production of prostaglandins in ischemic myocardium; 3) to examine the biochemical mechanism of phospholipid degradation and its relationship to oxygen deprivation and high energy phosphate depletion; and 4) to examine the relationship between phospholipid degradation, calcium accumulation, and high energy phosphate depletion during myocardial ischemia. The results of these studies will delineate the role of phospholipid degradation in the development of irreversible cell injury and myocardial dysfunction. If the degradation of phospholipids is contributing to the development of irreversible cell injury during myocardial ischemia, the development and application of specific phospholipase inhibitors might have protective effects on ischemic myocardium in man.
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