Perpetual preconditioning by PKCε reverses susceptibility of phospholamban deficient hearts to ischemic injury

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 Ca that mediates cellular damage and contractile dysfunction. Since cytosolic Ca overload is a critical mediator of myocardial damage following cardiac ischemia-reperfusion, it has been proposed that normalization of sarcoplasmic reticulum Ca cycling through inhibition or ablation of the Ca 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 PKCe, a known cardioprotective PKC isoform, without alterations in translocation of PKCe nor PKCe. To determine if loss of translocation of cardioprotective PKCe was a cause of increased ischemic injury in PLN deficient hearts, PLN deficient mice were mated with mice expressing a myocardial specific PKCe translocation activator peptide, ΨeRACK. In ΨeRACK/PLN deficient hearts, PKCe translocationwas not only restored but also increased by 20%, relative toWT levels. Furthermore, ΨeRACK/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 inΨeRACK/PLN deficient hearts reached pre-ischemic hyperdynamic values, indicating super-rescue by the combination of PLN ablation andΨeRACK expression. These findings suggest that diminished PKCe translocation in PLN deficient hearts is associated with attenuated contractile recovery upon ischemia-reperfusion and that restoration of PKCe translocation confers full cardioprotection, suggesting a synergistic beneficial effect of PLN ablation and PKCe translocation in ischemic heart disease. The Discordance between Localized Induction of Membrane Type-MMPS and Tissue Inhibitors with Ischemia andReperfusion: A Potential Therapeutic Target Anne M. Deschamps, William M. Yarbrough, Rebecca A. Allen, Kathryn B. Dowdy, Julie E. McLean, Joseph T. Mingoia, Jeffrey A. Sample, Rupak Mukherjee, Francis G. Spinale1—Division of Cardiothoracic Surgery Research, Medical University of South Carolina, Charleston, SC