Cyclic AMP-dependent phosphodiesterase isozyme-specific potentiation by protein kinase C in hypertrophic cardiomyopathic hamster hearts

Hongwei Yu, John J. Cai, Hon Chi Lee

Research output: Contribution to journalArticle

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Abstract

We recently reported that protein kinase C (PKC) potentiates cAMP- dependent phosphodiesterase (PDE) activity in Syrian hamster hearts with hypertrophic cardiomyopathy (HCM) but not in control hamster heads. In this study, we examined the mechanism of this PKC/PDE interaction by identifying the PDE isozyme that is the target of PKC modulation. Using Mono-Q high performance liquid chromatography, both control and HCM hamster cardiac PDE could be partially purified into the calcium/calmodulin-dependent (I), the cGMP-stimulated (II), and the low K(M) (III) isozyme fractions. The elution profiles of PDE isozyme fractions were similar to those in isolated hamster cardiac myocytes. The percentages of PDE isozymes activities (I/II/III) were 68.8:22.4:8.8% and 51.1:38.4:10.5% for HCM and control heads, respectively (n = 4), suggesting a change in the quantitative expression of isozymes activities in HCM hearts with a significant increase in the calcium/calmodulin-dependent PDE isozyme activities (p < 0.05 compared with control). The addition of exogenous PKC (100 munits of rat brain) produced a 60% stimulation in the calcium/calmodulin-dependent PDE isozyme fraction but not in other PDE isozymes of HCM and in none of the isozymes in control heads. This PKC-mediated potentiation of the calcium/calmodulin-dependent PDE activity was completely blocked by the PKC-specific peptide inhibitor PKC(19-31). Analysis of enzymatic kinetics showed that PKC enhanced the calcium/calmodulin-dependent PDE isozyme activity in HCM by increasing its V(max) (from 350 pmol/mg/min at baseline to 758 pmol/min/mg with PKC) without changing its K(M) (0.69 μM at baseline versus 0.89 μM with PKC). These results suggest that there are both quantitative and qualitative abnormalities in the expression of the calcium/calmodulin-dependent PDE isozyme in HCM hearts and that the PKC modulation of PDE activity in the HCM heart is isozyme specific.

Original languageEnglish (US)
Pages (from-to)549-555
Number of pages7
JournalMolecular Pharmacology
Volume50
Issue number3
StatePublished - Sep 1996
Externally publishedYes

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Phosphoric Diester Hydrolases
Cricetinae
Cyclic AMP
Protein Kinase C
Isoenzymes
Hypertrophic Cardiomyopathy
Type 1 Cyclic Nucleotide Phosphodiesterases
Head
Mesocricetus
Calmodulin
Cardiac Myocytes
High Pressure Liquid Chromatography
Calcium

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cyclic AMP-dependent phosphodiesterase isozyme-specific potentiation by protein kinase C in hypertrophic cardiomyopathic hamster hearts. / Yu, Hongwei; Cai, John J.; Lee, Hon Chi.

In: Molecular Pharmacology, Vol. 50, No. 3, 09.1996, p. 549-555.

Research output: Contribution to journalArticle

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abstract = "We recently reported that protein kinase C (PKC) potentiates cAMP- dependent phosphodiesterase (PDE) activity in Syrian hamster hearts with hypertrophic cardiomyopathy (HCM) but not in control hamster heads. In this study, we examined the mechanism of this PKC/PDE interaction by identifying the PDE isozyme that is the target of PKC modulation. Using Mono-Q high performance liquid chromatography, both control and HCM hamster cardiac PDE could be partially purified into the calcium/calmodulin-dependent (I), the cGMP-stimulated (II), and the low K(M) (III) isozyme fractions. The elution profiles of PDE isozyme fractions were similar to those in isolated hamster cardiac myocytes. The percentages of PDE isozymes activities (I/II/III) were 68.8:22.4:8.8{\%} and 51.1:38.4:10.5{\%} for HCM and control heads, respectively (n = 4), suggesting a change in the quantitative expression of isozymes activities in HCM hearts with a significant increase in the calcium/calmodulin-dependent PDE isozyme activities (p < 0.05 compared with control). The addition of exogenous PKC (100 munits of rat brain) produced a 60{\%} stimulation in the calcium/calmodulin-dependent PDE isozyme fraction but not in other PDE isozymes of HCM and in none of the isozymes in control heads. This PKC-mediated potentiation of the calcium/calmodulin-dependent PDE activity was completely blocked by the PKC-specific peptide inhibitor PKC(19-31). Analysis of enzymatic kinetics showed that PKC enhanced the calcium/calmodulin-dependent PDE isozyme activity in HCM by increasing its V(max) (from 350 pmol/mg/min at baseline to 758 pmol/min/mg with PKC) without changing its K(M) (0.69 μM at baseline versus 0.89 μM with PKC). These results suggest that there are both quantitative and qualitative abnormalities in the expression of the calcium/calmodulin-dependent PDE isozyme in HCM hearts and that the PKC modulation of PDE activity in the HCM heart is isozyme specific.",
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