Effect of protein kinase C on cyclic 3',5'-adenosine monophosphate- dependent phosphodiesterase in hypertrophic cardiomyopathic hamster hearts

H. C. Lee, J. J. Cai, H. Yu

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15 Scopus citations

Abstract

'Cross-talk,' or interaction between different signal transduction pathways, is known to exist in noncardiac cells, but it has not been demonstrated previously in mammalian hearts. We found that hypertrophic cardiomyopathic Syrian hamster (BIO 14.6, 6 months old) hearts were deficient in cyclic 3',5'-adenosine monophosphate (cAMP) [11.9 ± 0.4 vs. 15.4 ± 0.4 pmol/mg protein in age-matched control hamsters (BIO RB), n = 6, P = .0005] but not in cyclic 3',5'-guanosine monophosphate (1.23 ± 0.10 vs. 1.34 ± 0.18 pmol/mg protein in BIO RB, n = 6, P = N.S.). The reduction in cAMP was at least partly accounted for by an increase in the cytosolic phosphodiesterase (PDE) activity in BIO 14.6 hearts (1709 ± 119 vs. 1341 ± 113 pmol/min/mg protein in age-matched BIO RBs, n = 12, P = .006), suggesting that there is an increase in cAMP turnover in BIO 14.6 hearts. Protein kinase C (PKC) activities were also significantly elevated in BIO 14.6 hearts (77.9 ± 2.1 vs. 54.6 ± 3.3 pmol/min/mg protein in BIO RBs, n = 6, P < .001). Activation of PKC by phorbol 12-myristate 13-acetate (PMA, 10 μM) produced significant potentiation in PDE activities in BIO 14.6 but not in BIO RB hearts, and the PMA-induced increase in PDE activity could be blocked by the PKC-specific pseudosubstrate inhibitor peptide PKC(19-31). Removal of PKC by incubation with PKC-specific antibodies and then with protein A-agarose eliminated the ability of PMA to stimulate PDE in BIO 14.6 hearts, suggesting that activation of PKC produced potentiation of PDE activity in hypertrophic BIO 14.6 hearts and may lead to acceleration in degradation of cAMP. Activation of PKC by PMA resulted in a 2-fold increase in the V(max) value without changing the K(M) value of PDE in BIO 14.6 hearts, and such effects were not present in BIO RB hearts. These results indicate that there is 'cross-talk' between PKC and the cAMP regulatory pathways in BIO 14.6 hearts but not in BIO RB hearts. Such 'cross-talk' may cause acceleration in cAMP degradation, resulting in cAMP deficiency and its associated abnormalities in excitation-contraction coupling in BIO 14.6 hearts.

Original languageEnglish (US)
Pages (from-to)1171-1176
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume270
Issue number3
StatePublished - 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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