PKCε activation induces dichotomous cardiac phenotypes and modulates PKCε-RACK interactions and RACK expression

Receptors for activated C kinase (RACKs) have been shown to facilitate activation of protein kinase C (PKC). However, it is unknown whether PKC activation modulates RACK protein expression and PKC-RACK interactions. This issue was studied in two PKC epsilon transgenic lines exhibiting dichotomous cardiac phenotypes: one exhibits increased resistance to myocardial ischemia (cardioprotected phenotype) induced by a modest increase in PKC epsilon activity (228 +/- 23% of control), whereas the other exhibits cardiac hypertrophy and failure (hypertrophied phenotype) induced by a marked increase in PKCe activity (452 +/- 28% of control). Our data demonstrate that activation of PKC modulates the expression of RACK isotypes and PKC-RACK interactions in a PKC epsilon activity- and dosage-dependent fashion. We found that, in mice displaying the cardioprotected phenotype, activation of PKC epsilon enhanced RACK2 expression (178 +/- 13% of control) and particulate PKC epsilon -RACK2 protein-protein interactions (178 +/- 18% of control). In contrast, in mice displaying the hypertrophied phenotype, there was not only an increase in RACK2 expression (330 +/- 33% of control) and particulate PKC epsilon -RACK2 interactions (154 +/- 14% of control) but also in RACK1 protein expression (174 +/- 10% of control). Most notably, PKC epsilon -RACK1 interactions were identified in this line. With the use of transgenic mice expressing a dominant negative PKC epsilon, we found that the changes in RACK expression as well as the attending cardiac phenotypes were dependent on PKC epsilon activity. Our observations demonstrate that RACK expression is dynamically regulated by PKC epsilon and suggest that differential patterns of PKC epsilon -RACK interactions may be important determinants of PKC epsilon -dependent cardiac phenotypes.