The protein kinase C (PKC) family of Ca2+ and/or lipid-activated serine-threonine kinases function downstream of most membrane-associated signal transduction pathways, where in the heart they are critically involved in cellular protection, hypertrophy, and regulation of contractility. PKCalpha is the predominant PKC isofomri expressed in the mammalian heart where we and others have shown it to be associated with human heart failure, cardiac ischemia, and other disease stimuli. Previous analysis of PKCalpha KO mice and transgenic overexpressors has shown that this kinase serves as a fundamental regulator of cardiac contractility and Ca2+* handling in myocytes, which affects how the heart responded to insults. Specifically, toss of PKCalpha from the heart or its inhibition with a dominant negative mutant protected from heart failure. Moreover, use of drugs with that inhibit PKCalpha also preserved cardiac contractility in vivo and restored ventricular function in mouse and rat models of heart failure. These studies have suggested the hypothesis that inhibition of PKCalpha, such as with the drug ruboxistaurin, can be translated into humans as a novel therapy for heart failure. However, before this is possible we need to better understand the mechanism of action of PKCalpha, as well as conduct translational studies in a pig model of Ml-induced heart failure. Thus, specific Aim #1 will investigate the mechanisms in cells and transgenic mice whereby PKCalpha regulates cardiac contractility and propensity to heart failure after injury, while Specific Aim #2 will involve an elaborate translational approach in a pig Ml model of heart failure using ruboxistaurin treatment, as well as gene therapy with AAV6-dnPKCalpha. If our studies are successful, we believe that ruboxistaurin (or other PKCa inhibitors) would represent an attractive agent to apply to the heart failure clinical setting post-MI, especially given its apparent safety in late phase human clinical trials.
The relevance of this application is rooted in the fundamental issue of how PKCalpha signaling regulates cardiac contractility and protection from insults that would otherwise cause heart failure. Such an initiative is of major medical importance considering the centrality that PKC isoforms play in regulating heart disease in rodent models. The proposed translation of these observations to a large mammal, such as the pig, should provide the necessary proof that this novel target should be evaluated in humans with heart failure, especially since safe investigational drugs are available.
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