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