Protein Kinase C Isozymes in Heart

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DESCRIPTION (provided by applicant): Protein kinase C (PKC) isozymes play a key role in ischemic heart disease and in hypertrophic heart failure. Conflicting data for the role of individual PKC isozymes in modulating these functions have been reported, mainly because these studies relied on non-selective pharmacological tools. Our research focuses on identifying PKC isozyme-selective inhibitors and activators and we applied them to determine the role of individual isozymes in normal and diseased heart. We showed that epsilonPKC activation or deltaPKC inhibition provides cardioprotection from ischemia in vitro, ex vivo and recently in vivo. We find that the peptides can be effectively delivered into the heart to produce these effects and that cardioprotection by a deltaPKC inhibitor delivered only during reperfusion can be achieved when using as little as 250ng of peptide per kg. Here, we plan to examine the mechanism by which inhibition of deltaPKC protects from reperfusion injury. Several PKC isozymes (notably, beta, delta, and epsilonPKCs) have been suggested to modulate cardiac hypertrophy and transition to heart failure. We recently found that our isozyme-specific peptide regulators of PKC remain effective when delivered in vivo daily, for 10 days. Therefore, for the first time, we can determine whether these PKC-regulating peptides can prevent or reduce these pathological cardiac changes in two animal models. Together, these studies will identify the PKC isozymes and the molecular pathways that should be targeted for the development of new therapeutics for human cardiac ischemia and heart failure.