The objective of this proposal is to characterize the changes in sarcolemmal/sarcoplasmic membrane phospholipids and in tissue phospholipase activities upon ischemia, and to correlate these events with the onset of ischemia-promoted cell injury in guinea pig heart. Activation of phospholipases and enhanced membrane phospholipid breakdown are believed to represent one of the early biochemical derangements associated with the onset of injury to ischemic tissue. Preliminary experiments using guinea pig hearts indicate that the soluble form of phospholipase C undergoes a three-fold activation upon ischemia. Phospholipid analysis of ischemic hearts revealed a selective degradation of phosphatidylinositol, phosphatidylserine and lysophosphatidylcholine. These observations suggest that activation of phospholipase C and lysophospholipase may contribute to events that lead to ischemia-promoted tissued injury. Studies will include the investigation of the temporal relationship between ischemia-promoted phospholipase activation (A1, A2, C and lysophospholipase), phospholipid degradation, and cell injury. Chlorpromazine which has been shown to inhibit phospolipase activities or interfere with calcium dependent cellular processes, will be examined as an inhibitor of ischemia-promoted activation of phospholipases and onset of cell injury. Studies will include investigation into the mechanism of activation of phospholipase C (i.e. by sulfhydryl-disulfide interconversion, proteolysis, or by phosphorylation-dephosphorylation), as well as the examination of the substrate specificity and the potential regulatory role of phosphatidylinositol-4,5-trisphosphate and calcium on phospholipase C.
| Schwertz, D W; Halverson, J B; Palmer, J W et al. (1987) Characterization of phospholipase C-mediated phosphatidylinositol degradation in rat heart ventricle. Arch Biochem Biophys 253:388-98 |
| Schwertz, D W; Halverson, J; Isaacson, T et al. (1987) Alterations in phospholipid metabolism in the globally ischemic rat heart: emphasis on phosphoinositide specific phospholipase C activity. J Mol Cell Cardiol 19:685-97 |
