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- W2138550759 abstract "Ischemic heart disease is the leading cause of congestive heart failure and death in the Western world. Early reperfusion after coronary occlusion improves cardiac function and reduces infarct size, but it is invariably accompanied by an overload of intracellular Ca2+ that mediates cellular damage and contractile dysfunction. Since cytosolic Ca2+ overload is a critical mediator of myocardial damage following cardiac ischemia-reperfusion, it has been proposed that normalization of sarcoplasmic reticulum Ca2+ cycling through inhibition or ablation of the Ca2+ ATPase inhibitor phospholamban (PLN), which shows promise as a treatment for heart failure, could be beneficial in ischemic heart disease. However, globally ischemic PLN deficient hearts exhibit increased ischemic injury, with impaired contractile, ATP, and phosphocreatine recoveries, compared to wild type hearts. The increased susceptibility of PLN deficient hearts to ischemic injury has the potential to limit therapeutic approaches aimed at inhibiting PLN in human heart failure; thus, it becomes a scientific priority to delineate the responsible mechanisms underlying this deficiency and develop approaches to alleviate this shortcoming. Since protein kinase C (PKC) family members are widely recognized as mediators of both post-ischemic injury and ischemic preconditioning, we assessed PKC levels in PLN deficient hearts. Compared to genetically normal hearts, PLN deficient hearts exhibited diminished translocation of PKCε, a known cardioprotective PKC isoform, without alterations in translocation of PKCδ nor PKCα. To determine if loss of translocation of cardioprotective PKCε was a cause of increased ischemic injury in PLN deficient hearts, PLN deficient mice were mated with mice expressing a myocardial specific PKCε translocation activator peptide, ΨεRACK. In ΨεRACK/PLN deficient hearts, PKCε translocation was not only restored but also increased by 20%, relative to WT levels. Furthermore, ΨεRACK/PLN deficient hearts exhibited a significant acceleration (significant at 6 minutes) of post-ischemic contraction and relaxation rates, associated with 98% reduced creatine phosphokinase release, compared with PLN deficient hearts. Importantly, post-ischemic functional recovery in ΨεRACK/PLN deficient hearts reached pre-ischemic hyperdynamic values, indicating super-rescue by the combination of PLN ablation and ΨεRACK expression. These findings suggest that diminished PKCε translocation in PLN deficient hearts is associated with attenuated contractile recovery upon ischemia-reperfusion and that restoration of PKCε translocation confers full cardioprotection, suggesting a synergistic beneficial effect of PLN ablation and PKCε translocation in ischemic heart disease." @default.
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- W2138550759 date "2003-10-01" @default.
- W2138550759 modified "2023-09-26" @default.
- W2138550759 title "Perpetual preconditioning by PKCε reverses susceptibility of phospholamban deficient hearts to ischemic injury" @default.
- W2138550759 doi "https://doi.org/10.1016/s1071-9164(03)00269-0" @default.
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