Sustained in vivo cardiac protection by a rationally designed peptide that causes ε protein kinase C translocation

Brief periods of cardiac ischemia trigger protection from subsequent prolonged ischemia (preconditioning). ε Protein kinase C (εPKC) has been suggested to mediate preconditioning. Here, we describe an εPKC-selective agonist octapeptide, ψε receptor for activated C-kinase (ψ®ACK), derived from an εPKC sequence homologous to its anchoring protein, εRACK. Introduction of ψεRACK into isolated cardiomyocytes, or its postnatal expression as a transgene in mouse hearts, increased εPKC translocation and caused cardio-protection from ischemia without any deleterious effects. Our data demonstrate that εPKC activation is required for protection from ischemic insult and suggest that small molecules that mimic this εPKC agonist octapeptide provide a powerful therapeutic approach to protect hearts at risk for ischemia.