Conflicting roles for protein kinase C (PKC) isozymes in cardiac disease have been reported. Here, ␦PKC-selective activator and inhibitor peptides were designed rationally, based on molecular modeling and structural homology analyses. Together with previously identified activator and inhibitor peptides of PKC, ␦PKC peptides were used to identify cardiac functions of these isozymes. In isolated cardiomyocytes, perfused hearts, and transgenic mice, ␦PKC and PKC had opposing actions on protection from ischemiainduced damage. Specifically, activation of PKC caused cardioprotection whereas activation of ␦PKC increased damage induced by ischemia in vitro and in vivo. In contrast, ␦PKC and PKC caused identical nonpathological cardiac hypertrophy; activation of either isozyme caused nonpathological hypertrophy of the heart. These results demonstrate that two related PKC isozymes have both parallel and opposing effects in the heart, indicating the danger in the use of therapeutics with nonselective isozyme inhibitors and activators. Moreover, reduction in cardiac damage caused by ischemia by perfusion of selective regulator peptides of PKC through the coronary arteries constitutes a major step toward developing a therapeutic agent for acute cardiac ischemia.

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