Enhanced PKCβII translocation and PKCβII-RACK1 interactions in PKCε-induced heart failure: a role for RACK1

Abstract

Recent investigations have established a role for the βII-isoform of protein kinase C (PKCβII) in the induction of cardiac hypertrophy and failure. Although receptors for activated C kinase (RACKs) have been shown to direct PKC signal transduction, the mechanism through which RACK1, a selective PKCβII RACK, participates in PKCβII-mediated cardiac hypertrophy and failure remains undefined. We have previously reported that PKCε activation modulates the expression of RACKs, and that altered ε-isoform of PKC (PKCε)-RACK interactions may facilitate the genesis of cardiac phenotypes in mice. Here, we present evidence that high levels of PKCε activity are commensurate with impaired left ventricular function (dP/d t = 6,074 ± 248 mmHg/s in control vs. 3,784 ± 269 mmHg/s in transgenic) and significant myocardial hypertrophy. More importantly, we demonstrate that high levels of PKCε activation induce a significant colocalization of PKCβII with RACK1 (154 ± 7% of control) and a marked redistribution of PKCβII to the particulate fraction (17 ± 2% of total PKCβII in control mice vs. 49 ± 5% of total PKCβII in hypertrophied mice), without compensatory changes of the other eight PKC isoforms present in the mouse heart. This enhanced PKCβII activation is coupled with increased RACK1 expression and PKCβII-RACK1 interactions, demonstrating PKCε-induced PKCβII signaling via a RACK1-dependent mechanism. Taken together with our previous findings regarding enhanced RACK1 expression and PKCε-RACK1 interactions in the setting of cardiac hypertrophy and failure, these results suggest that RACK1 serves as a nexus for at least two isoforms of PKC, the ε-isoform and the βII-isoform, thus coordinating PKC-mediated hypertrophic signaling.