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

Pass, Jason M., Yuting Zheng, William B. Wead, Jun Zhang, Richard C. X. Li, Roberto Bolli, and Peipei Ping. PKCe activity induces dichotomous cardiac phenotypes and modulates PKCe-RACK interactions and RACK expression. Am J Physiol Heart Circ Physiol 280: H946–H955, 2001.—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 PKCe transgenic lines exhibiting dichotomous cardiac phenotypes: one exhibits increased resistance to myocardial ischemia (cardioprotected phenotype) induced by a modest increase in PKCe activity (228 6 23% of control), whereas the other exhibits cardiac hypertrophy and failure (hypertrophied phenotype) induced by a marked increase in PKCe activity (452 6 28% of control). Our data demonstrate that activation of PKC modulates the expression of RACK isotypes and PKC-RACK interactions in a PKCe activityand dosage-dependent fashion. We found that, in mice displaying the cardioprotected phenotype, activation of PKCe enhanced RACK2 expression (178 6 13% of control) and particulate PKCe-RACK2 proteinprotein interactions (178 6 18% of control). In contrast, in mice displaying the hypertrophied phenotype, there was not only an increase in RACK2 expression (330 6 33% of control) and particulate PKCe-RACK2 interactions (154 6 14% of control) but also in RACK1 protein expression (174 6 10% of control). Most notably, PKCe-RACK1 interactions were identified in this line. With the use of transgenic mice expressing a dominant negative PKCe, we found that the changes in RACK expression as well as the attending cardiac phenotypes were dependent on PKCe activity. Our observations demonstrate that RACK expression is dynamically regulated by PKCe and suggest that differential patterns of PKCeRACK interactions may be important determinants of PKCedependent cardiac phenotypes.