Circulation Research. 2001
Published online before print September 27, 2001, doi: 10.1161/hh2201.099434
Published online before print September 27, 2001, doi: 10.1161/hh2201.099434
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Submitted on April 30, 2001
Revised on August 17, 2001
Accepted on September 19, 2001
Differential Activation of Mitogen-Activated Protein Kinase Cascades and Apoptosis by Protein Kinase C 
and 
in Neonatal Rat Ventricular Myocytes
From the Cardiovascular Institute, Loyola University Chicago, Maywood, Ill.
* To whom correspondence should be addressed. E-mail: mheidka{at}lumc.edu.
Protein kinase C (PKC) and PKC translocation in neonatal rat ventricular myocytes (NRVMs) is accompanied by subsequent activation of the ERK, JNK, and p38MAPK 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 p38MAPK activity. Therefore, replication-defective adenoviruses (Advs) encoding constitutively active (ca) mutants of PKC and PKC were used to test if either or both of these PKCs are sufficient to activate ERKs, JNKs, and/or p38MAPK in NRVMs. Adv-caPKC infection (1 to 25 multiplicities of viral infection (MOI); 4 to 48 hours) increased total PKC levels in a time- and dose-dependent manner, with maximal expression observed 8 hours after Adv infection. Adv-caPKC induced a time- and dose-dependent increase in phosphorylated p42 and p44 ERKs, as compared with a control Adv encoding ß-galactosidase (Adv-neßgal). Maximal ERK phosphorylation occurred 8 hours after Adv infection. In contrast, JNK was only minimally activated, and p38MAPK was relatively unaffected. Adv-caPKC infection (1 to 25 MOI, 4 to 48 hours) increased total PKC levels in a similar fashion. Adv-caPKC (5 MOI) induced a 29-fold increase in phosphorylated p54 JNK, and a 15-fold increase in phosphorylated p38MAPK 24 hours after Adv infection. In contrast, p42 and p44 ERK were only minimally activated. Whereas neither Adv induced NRVM hypertrophy, Adv-caPKC, but not Adv-caPKC, induced NRVM apoptosis. We conclude that the novel PKCs differentially regulate MAPK cascades and apoptosis in an isoenzyme-specific and time-dependent manner.
Key words: signal transduction • cardiomyocyte • hypertrophy • adenovirus
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