Protein kinase C (PKC) isozymes comprise a family of related cytosolic kinases that translocate to the cell particulate fraction on stimulation. There are at least nine different PKC isozymes, six of which are found in the heart. PKC involvement in regulation of cardiac contractility, hypertrophy, organization of myofibrils and gene expression has been indicated by numerous studies. However, since isozyme-specific inhibitors are currently unavailable, the role of individual PKC isozymes in mediating each of these cardiac functions has not yet been determined. Activation of PKC isozymes in cardiac myocytes caused translocation of individual PKC isozymes to distinct subcellular sites. Some of the sequences in different PKC isozymes that are required for this specific translocation have already been identified, and others will be identified as described in the following proposal. Using peptides, homologous to these sequences, the translocation of specific PKC isozymes will be inhibited. We have previous demonstrated that inhibition of translocation of PKC also inhibits PKC mediated functions. Therefore, using these isozyme-specific translocation inhibitory peptides, it will be possible to determine the role of individual PKC isozymes in cardiac contractility, hypertrophy and organization of myofibrils. PKC is implicated in pathological conditions in the heart including hypertrophy and dysrhythmia. Our work will elucidate the role of various PKC isozymes using a new family of isozyme-specific inhibitors that is being developed. These data will lead to generation of therapeutic agents that interfere only with the activity of individual malfunctioning isozymes and not with the normal activity of other PKC isozymes.
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