| Heart failure is the leading cause of death in the western world and continues to represent an enormous clinical challenge despite significant improvements using pharmacological therapies. Recent evidence suggests that enhancing cardiac contractility is of potential benefit for the treatment of heart failure. The loss of contractility that accompanies heart failure is associated with increased PKCalpha protein content and activity. While cardiac overexpression of PKCalpha blunted contractility, deletion of PKCalpha in the mouse resulted in augmented contractility and attenuated disease in mouse heart failure models. We hypothesize that acute inhibition of PKCalpha antagonizes heart failure by increasing contractility. The role of PKCalpha in regulating cardiac contractility and the benefits of inhibiting PKCalpha on cardiac performance and in antagonizing heart failure will be examined in this dissertation by using both pharmacological and genetic inhibition of PKCalpha in animal models of heart failure. PKCalpha was determined to be the most abundant conventional PKC isoform in the adult human heart, providing possible relevance to human pathophysiology. In addition, short-term pharmacological inhibition of PKCalpha augmented contractility in wildtype (WT) and in two different mouse models of heart failure, but not in PKCalpha deficient mice. Moreover, short- or long-term treatment with a PKCalpha/beta inhibitor in a mouse model of heart failure significantly augmented cardiac contractility and restored normal pump function. Adenoviral-mediated gene therapy with a dominant-negative (DN) PKCalpha cDNA rescued heart failure in a chronic rat model of post-infarction cardiomyopathy. To examine if specific and inducible inhibition of PKCalpha in the heart alters functional performance and heart failure propensity, without the confounding possibility of developmental compensation by other PKC isoforms, we generated transgenic mice containing an inducible tetracycline-regulated DN-PKCalpha cDNA controlled by a cardiac-specific promoter. Expression of DN-PKCalpha in the adult heart augmented contractility and initially maintained ventricular performance following myocardial infarction in mice. Similarly, PKCalpha-/- mice were protected from infarction-induced heart failure. Thus, PKCalpha has an immediate effect on cardiac contractility and its inhibition may serve as a novel therapeutic strategy for acutely enhancing cardiac contractility in the setting of severe functional deterioration, or even as a longer-term treatment for certain stages of heart failure. |
