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Rescue of cardiac failing and remodelling by inhibition of protein phosphatase 1γ is associated with suppression of the alternative splicing factor‐mediated splicing of Ca2+/calmodulin‐dependent protein kinase δ

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Our previous studies showed that protein phosphatase 1γ (PP1γ) exacerbates cardiomyocyte apoptosis through promotion of Ca2+/calmodulin‐dependent protein kinase δ (CaMKIIδ) splicing. Here we determine the role of PP1γ in abdominal aorta constriction‐induced hypertrophy and remodelling in rat hearts. Systolic blood pressure and echocardiographic measurements were used to evaluate the model of cardiac hypertrophy. Sirius red staining and invasive haemodynamic/cardiac index measurements were used to evaluate the effects of PP1γ or inhibitor 1 of PP1 transfection. Western blot, reverse transcription polymerase chain reaction and co‐immunoprecipitation were applied to investigate the molecular mechanisms. Transfection of PP1γ increased the value of the heart mass index, left ventricular mass index and cardiac fibrosis, and simultaneously decreased the value of maximal left ventricular pressure increase and decline rate, ejection fraction, fractional shortening, and left ventricular end‐diastolic pressure, as well as left ventricular systolic pressure. Transfection of inhibitor 1 of PP1, however, showed opposite effects on the aforementioned indexes. Overexpression of PP1γ potentiated CaMKIIδC production and decreased CaMKIIδB production in the hypertrophic heart. In contrast, inhibition of PP1γ re‐balanced the CaMKIIδ splicing. Furthermore, CaMKII activity was found to be augmented or attenuated by PP1γ overexpression or inhibition, respectively. Further mechanistic studies showed that abdominal aorta constriction stress specifically increased the association of alternative splicing factor with PP1γ, but not with PP1β. Overexpression of PP1γ, but not inhibitor 1 of PP1, further potentiated this association. These results suggest that PP1γ alters the cardiac hypertrophy and remodelling likely through promotion of the alternative splicing factor‐mediated splicing of CaMKIIδ.
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Keywords: Ca2+/calmodulin‐dependent protein kinase δ; alternative splicing factor; cardiac hypertrophy; inhibitor 1 of protein phosphatase 1; protein phosphatase 1γ

Document Type: Research Article

Publication date: December 1, 2014

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