Enhanced PKC beta II translocation and PKC beta II-RACK1 interactions in PKC epsilon-induced heart failure: a role for RACK1

Recent investigations have established a role for the beta II-isoform of pr otein kinase C (PKC beta II) in the induction of cardiac hypertrophy and fa ilure. Although receptors for activated C kinase (RACKs) have been shown to direct PKC signal transduction, the mechanism through which RACK1, a selec tive PKC beta II RACK, participates in PKC beta II-mediated cardiac hypertr ophy and failure remains undefined. We have previously reported that PKC ep silon activation modulates the expression of RACKs, and that altered epsilo n -isoform of PKC (PKC epsilon)-RACK interactions may facilitate the genesi s of cardiac phenotypes in mice. Here, we present evidence that high levels of PKC epsilon activity are commensurate with impaired left ventricular fu nction (dP/dt = 6,074 +/- 248 mmHg/s in control vs. 3,784 +/- 269 mmHg/s in transgenic) and significant myocardial hypertrophy. More importantly, we d emonstrate that high levels of PKC epsilon activation induce a significant colocalization of PKC beta II with RACK1 (154 +/- 7% of control) and a mark ed redistribution of PKC beta II to the particulate fraction (17 +/- 2% of total PKC beta II in control mice vs. 49 +/- 5% of total PKC beta II in hyp ertrophied mice), without compensatory changes of the other eight PKC isofo rms present in the mouse heart. This enhanced PKC beta II activation is cou pled with increased RACK1 expression and PKC beta II-RACK1 interactions, de monstrating PKC epsilon -induced PKC beta II signaling via a RACK1-dependen t mechanism. Taken together with our previous findings regarding enhanced R ACK1 expression and PKC epsilon -RACK1 interactions in the setting of cardi ac hypertrophy and failure, these results suggest that RACK1 serves as a ne xus for at least two isoforms of PKC, the epsilon -isoform and the beta II- isoform, thus coordinating PKC-mediated hypertrophic signaling.