Key result
Myocardial stretch induces PKC-epsilon activation via calcineurin, leading to the formation of a calcineurin-PKC-epsilon complex at the perinuclear membrane in rat cardiomyocytes.
Calcineurin is required for stretch-induced PKC-epsilon activation, and the two form a complex at the perinuclear membrane, suggesting a coordinated role in the development of ventricular hypertrophy and heart failure.
No immediate clinical implications; leaves open calcineurin-PKC-epsilon targeting in human hypertrophy.
OBJECTIVES: Myocardial stretch activates a number of interconnected pathways including the protein kinase C (PKC) pathway that in turn activates mitogen activated protein kinases (MAPK), leading to gene expression stimulation and ventricular hypertrophy. A role of calcineurin has also been shown during hypertrophy. The goal of our study was to look for a possible interconnection between PKC and calcineurin in myocardial stretch. METHODS: Neonatal rat cardiomyocytes were cultured for 5 days and a 15% stretch was applied. Expression of MAPK and PKC-epsilon was evaluated by Western blot analysis. The specific role of PKC-epsilon was evaluated by transfection of cardiomyocytes with a specific inhibitor peptide. Calcineurin and PKC-epsilon complex formation and co-localization were evaluated by co-immunoprecipitation and by immunolocalization. RESULTS: The PKC isoform involved in stretch-induced ERK and JNK activations was PKC-epsilon. We show here that calcineurin is also found to be involved in the stretch response and that calcineurin and PKC-epsilon co-operate at 2 levels during stretch. First, stretch-induced translocation of PKC-epsilon from the cytosolic to the membrane fraction was inhibited by calcineurin inhibitors, indicating that calcineurin was necessary for PKC-epsilon activation induced by stretch. A second level of interaction was the formation of a calcineurin-PKC-epsilon complex, which increased during stretch. Immunofluorescent studies indicated that, after stretch, calcineurin and PKC-epsilon were co-localized at the level of the perinuclear membrane. These results may have a major relevance in vivo since we also found similar PKC-epsilon-calcineurin complexes in the phase of thoracic aortic stenosis in rats during which heart failure develops. CONCLUSION: Calcineurin appears to be necessary for stretch-induced PKC-epsilon activation after which the phosphatase and the kinase are co-localized in a complex at the level of the perinuclear membrane where they may finely regulate the phosphorylation of their target proteins.
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Vincent et al. (2006) studied Myocardial stretch and ventricular hypertrophy. Myocardial stretch vs. Unstretched cells was evaluated on Expression of MAPK and PKC-epsilon, and calcineurin-PKC-epsilon complex formation. Myocardial stretch induces PKC-epsilon activation via calcineurin, leading to the formation of a calcineurin-PKC-epsilon complex at the perinuclear membrane in rat cardiomyocytes.
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