Circulation Research. 2001;89:882-890
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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© 2001 American Heart Association, Inc.
Cellular Biology |
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.
Correspondences to Maria C. Heidkamp, PhD, Loyola University Medical Center, 2160 South First Ave, Maywood, IL 60153. E-mail mheidka{at}lumc.edu
Abstract—— 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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