Differential Activation of Mitogen-Activated Protein Kinase Cascades and Apoptosis by Protein Kinase C e and d in Neonatal Rat Ventricular Myocytes
نویسندگان
چکیده
Protein kinase C (PKC) e and PKCd translocation in neonatal rat ventricular myocytes (NRVMs) is accompanied by subsequent activation of the ERK, JNK, and p38 cascades; however, it is not known if either or both novel PKCs are necessary for their downstream activation. Use of PKC inhibitors to answer this question is complicated by a lack of isoenzyme specificity, and the fact that many PKC inhibitors stimulate JNK and p38 activity. Therefore, replication-defective adenoviruses (Advs) encoding constitutively active (ca) mutants of PKCe and PKCd were used to test if either or both of these PKCs are sufficient to activate ERKs, JNKs, and/or p38 in NRVMs. Adv-caPKCe infection (1 to 25 multiplicities of viral infection (MOI); 4 to 48 hours) increased total PKCe levels in a timeand dose-dependent manner, with maximal expression observed 8 hours after Adv infection. Adv-caPKCe induced a timeand dose-dependent increase in phosphorylated p42 and p44 ERKs, as compared with a control Adv encoding b-galactosidase (Adv-nebgal). Maximal ERK phosphorylation occurred 8 hours after Adv infection. In contrast, JNK was only minimally activated, and p38 was relatively unaffected. Adv-caPKCd infection (1 to 25 MOI, 4 to 48 hours) increased total PKCd levels in a similar fashion. Adv-caPKCd (5 MOI) induced a 29-fold increase in phosphorylated p54 JNK, and a 15-fold increase in phosphorylated p38 24 hours after Adv infection. In contrast, p42 and p44 ERK were only minimally activated. Whereas neither Adv induced NRVM hypertrophy, Adv-caPKCd, but not Adv-caPKCe, induced NRVM apoptosis. We conclude that the novel PKCs differentially regulate MAPK cascades and apoptosis in an isoenzyme-specific and time-dependent manner. (Circ Res. 2001;89:●●●-●●●.)
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