PKC epsilon activation induces dichotomous cardiac phenotypes and modulates PKC epsilon-RACK interactions and RACK expression

Receptors for activated C kinase (RACKs) have been shown to facilitate acti vation of protein kinase C (PKC). However, it is unknown whether PKC activa tion modulates RACK protein expression and PKC-RACK interactions. This issu e was studied in two PKC epsilon transgenic lines exhibiting dichotomous ca rdiac phenotypes: one exhibits increased resistance to myocardial ischemia (cardioprotected phenotype) induced by a modest increase in PKC epsilon act ivity (228 +/- 23% of control), whereas the other exhibits cardiac hypertro phy and failure (hypertrophied phenotype) induced by a marked increase in P KCe 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 e nhanced RACK2 expression (178 +/- 13% of control) and particulate PKC epsil on -RACK2 protein-protein interactions (178 +/- 18% of control). In contras t, in mice displaying the hypertrophied phenotype, there was not only an in crease in RACK2 expression (330 +/- 33% of control) and particulate PKC eps ilon -RACK2 interactions (154 +/- 14% of control) but also in RACK1 protein expression (174 +/- 10% of control). Most notably, PKC epsilon -RACK1 inte ractions were identified in this line. With the use of transgenic mice expr essing a dominant negative PKC epsilon, we found that the changes in RACK e xpression as well as the attending cardiac phenotypes were dependent on PKC epsilon activity. Our observations demonstrate that RACK expression is dyn amically regulated by PKC epsilon and suggest that differential patterns of PKC epsilon -RACK interactions may be important determinants of PKC epsilo n -dependent cardiac phenotypes.