Sustained in vivo Cardiac Protection by a Rationally Designed Peptide That Causes ε Protein Kinase C Translocation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 22; pp. 12798 - 12803
• Main Authors: Dorn, Gerald W., Souroujon, Miriam C., Liron, Tamar, Chen, Che-Hong, Gray, Mary O., Zhou, Hui Zhong, Csukai, Michael, Wu, Guangyu, Lorenz, John N., Mochly-Rosen, Daria
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 26-10-1999; National Academy of Sciences
• Subjects: Agonists; Amino Acid Sequence; Amino acids; Animals; Biological Transport; Cardiotonic Agents - chemical synthesis; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cardiovascular disease; Cell Death - drug effects; Enzymes; Heart; In Vitro Techniques; Insults; Ischemia; Isoenzymes - metabolism; Male; Mice; Mice, Transgenic; Molecular biology; Molecular Sequence Data; Myocardial Ischemia - prevention & control; Myocardium; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Particulate matter; Peptides; Preconditioning; Protein Kinase C - metabolism; Protein Kinase C-epsilon; Proteins; Rats; Rats, Wistar; Receptors for Activated C Kinase; Receptors, Cell Surface - therapeutic use; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.22.12798

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