Cardiotrophic effects of protein kinase C epsilon - Analysis by in vivo modulation of PKC epsilon translocation

Protein kinase C (PKC) is a key mediator of many diverse physiological and pathological responses. Although little is known about the specific in vivo roles of the various cardiac PKC isozymes, activation-induced translocatio n of PKC is believed to be the primary determinant of isozyme-specific func tions. Recently, we have identified a catalytically inactive peptide transl ocation inhibitor (epsilon V1) and translocation activator (psi epsilon RAC K [receptors for activated C kinase]) specifically targeting PKC epsilon. U sing cardiomyocyte-specific transgenic expression of these peptides, we com bined loss- and gain-of-function approaches to elucidate the in vivo conseq uences of myocardial PKC epsilon signaling. As expected for a PKC epsilon R ACK binding peptide, confocal microscopy showed that epsilon V1 decorated c ross-striated elements and intercalated disks of cardiac myocytes. Inhibiti on of cardiomyocyte PKC epsilon by epsilon V1 at lower expression levels up regulated alpha-skeletal actin gene expression, increased cardiomyocyte cel l size, and modestly impaired left ventricular fractional shortening. At hi gh expression levels, epsilon V1 caused a lethal dilated cardiomyopathy, In contrast, enhancement of PKC epsilon translocation with psi epsilon RACK r esulted in selectively increased beta myosin heavy chain gene expression an d normally functioning concentric ventricular remodeling with decreased car diomyocyte size. These results identify for the first time a role for PKC e psilon signaling in normal postnatal maturational myocardial development an d suggest the potential for PKC epsilon activators to stimulate "physiologi cal" cardiomyocyte growth.