Recent investigations have established a role for the beta II-
isoform of
protein kinase C (
PKC beta II) 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
PKC beta II RACK, participates in
PKC beta II-mediated
cardiac hypertrophy and failure remains undefined. We have previously reported that
PKC epsilon activation modulates the expression of RACKs, and that altered epsilon-
isoform of PKC (
PKC epsilon)-RACK interactions may facilitate the genesis of cardiac phenotypes in mice. Here, we present evidence that high levels of
PKC epsilon activity are commensurate with impaired left ventricular function (dP/dt = 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
PKC epsilon activation induce a significant colocalization of
PKC beta II with RACK1 (154 +/- 7% of control) and a marked 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 hypertrophied mice), without compensatory changes of the other eight PKC
isoforms present in the mouse heart. This enhanced
PKC beta II activation is coupled with increased RACK1 expression and
PKC beta II-RACK1 interactions, demonstrating
PKC epsilon-induced
PKC beta II signaling via a RACK1-dependent mechanism. Taken together with our previous findings regarding enhanced RACK1 expression and PKC epsilon-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 epsilon-
isoform and the beta II-
isoform, thus coordinating PKC-mediated hypertrophic signaling.