Given the relatively poor prognosis associated with end-stage heart failure, investigators and clinicians have long searched for therapies that alleviate or reverse the progressive loss of pump function that typifies a failing heart. The predominant strategy employed over the past two decades has been based on pharmacologic manipulation of cardiac contractility, aimed at agonizing or antagonizing beta-adrenergic receptor activity or the downstream accumulation of cAMP. Here we have identified a novel signaling pathway that utilizes PKCa as a feedback regulator to dampen cardiac contractility, presumably in response to periods of enhanced inotropic drive. Indeed, loss of PKCalpha through gene targeting revealed a hypercontractile phenotype, while PKCalpha overexpression in transgenic mice or acutely in isolated adult rat myocytes showed reduced contractility, supporting our first hypothesis that PKCalpha functions within a negative contractility feedback pathway in the heart. Augmentation in cardiac function observed in the absence of PKCalpha rescued a model of pressure overload-induced heart failure, supporting our second hypothesis that selective enhancement of cardiac contractility can benefit a failing heart. To examine these two hypotheses we will: 1) define the biochemical mechanism whereby PKCalpha regulates cardiac contractility, 2) investigate the ability of inducible gain- or loss-of-function for PKCalpha to alter the progression towards heart failure in two distinct mouse models of disease, 3) examine the ability of acute pharmacologic inhibition of PKCa to potentially benefit a large animal model of heart failure. Collectively, the proposed course of investigation will span a biochemical and mechanistic evaluation of a PKCalpha function in vitro through a physiologic assessment of PKCalpha in animal models of heart failure suggesting disease ramifications in humans. Thus, this component will address the central theme of the SCCOR proposal pertaining to signaling pathways and cardiac contractile responsiveness, through investigation of single gene-function correlations.
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