Increased particulate partitioning of PKCε reverses susceptibility of phospholamban knockout hearts to ischemic injury

Kimberly N. Gregory, Harvey Hahn, Kobra Haghighi, Yehia Marreez, Amy Odley, Gerald W. Dorn, Evangelia G. Kranias

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cytosolic Ca2+ overload is a critical mediator of myocardial damage following cardiac ischemia-reperfusion. It has therefore been proposed that normalization of sarcoplasmic reticulum Ca2+ cycling through inhibition or ablation of the Ca2+ ATP-ase inhibitor phospholamban (PLN), which shows promise as a treatment for heart failure, could be beneficial in ischemic heart disease. However, a recent study has shown that globally ischemic PLN-deficient hearts exhibit increased ischemic injury, with impaired contractile, ATP, and phosphocreatine recoveries, compared to wild-type hearts. 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 particulate partitioning of PKCε, a known cardioprotective PKC isoform, without alterations in the levels of membrane-associated PKCδ nor PKCα. To determine if decreased particulate partitioning 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, pseudo-epsilon receptor for activated kinase C (ψεRACK). In ψεRACK/PLN knockout (KO) hearts, PKCε translocation to membranous cellular structures was augmented and this was associated with a significant acceleration of post-ischemic contraction and relaxation rates, as well as reduction of creatine phosphokinase release, compared to PLN-deficient hearts. Importantly, post-ischemic functional recovery reached pre-ischemic hyperdynamic values in ψεRACK/PLN KO hearts, indicating super-rescue by the combination of PLN ablation and ψεRACK expression. These findings suggest that diminished PKCε particulate partitioning in PLN-deficient hearts is associated with attenuated contractile recovery upon ischemia-reperfusion and that increased translocation of PKCε to membranous cellular structures confers full cardioprotection.

Original languageEnglish
Pages (from-to)313-318
Number of pages6
JournalJournal of Molecular and Cellular Cardiology
Volume36
Issue number2
DOIs
StatePublished - Feb 2004

Keywords

  • Ca cycling
  • Ischemia
  • Phospholamban
  • Protein kinase C epsilon
  • Reperfusion

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