Hypertrophy, Heart Failure and PKC

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Protein kinase C (PKC) isozymes play a key role in insult-induced cardiac remodeling and the progression to heart failure (HF). Conflicting data on the role of individual PKC isozymes in modulating these functions have been reported, in part due to the use of PKC isozyme non-selective pharmacological tools. Our research identified PKC isozyme-selective inhibitors and activators, which we apply to determine the role of individual isozymes in normal and diseased heart. We identified peptide inhibitors and activators for each isozyme and found that the peptides can be effectively delivered into the heart, in vivo. Using these PKC regulating peptides, we previously showed opposing roles for specific PKC isozymes in various functions; we showed that ePKC activation or delta PKC inhibition provides cardioprotection from ischemia in vitro, ex vivo and recently in vivo. We also found that our isozyme-specific peptide regulators of PKC remain effective when continuously delivered in vivo, for 10 days. Therefore, for the first time, we can determine whether these PKC-regulating peptides can prevent, enhance or reduce cardiac remodeling and transition to heart failure, a study that requires regulation of PKC in a sustained fashion. Due to the limitations of animal models for cardiac remodeling and HF, we plan to use 3 different models, and use the peptides as selective pharmacological tools to determine the role of each PKC isozyme in the development of HF. The first model involves pressure overload using transverse aortic constriction in mice. The second uses pressure overload in hypertensive Dahl rats, which develop reliable cardiac remodeling and heart failure after initiation of a high salt diet. The third model follows post myocardial infarction-induced cardiac remodeling and HF in mice. Peptide regulators of individual isozymes (activators or inhibitors) will be delivered in a sustained fashion at different times during the course of the disease to determine the role of each PKC isozyme in the development of adaptive and maladaptive remodeling and the transition to heart failure. Together, these studies will identify the PKC isozyme(s) that should be targeted for the development of new therapeutics for human heart failure, especially if PKC-based pharmacotherapy is considered