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

Our previous studies showed that protein phosphatase 1 gamma (PP1 gamma) exacerbates cardiomyocyte apoptosis through promotion of Ca2+/calmodulin-dependent protein kinase delta (CaMKII delta) splicing. Here we determine the role of PP1 gamma 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 PP1 gamma 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 PP1 gamma 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 PP1 gamma potentiated CaMKII delta C production and decreased CaMKII delta B production in the hypertrophic heart. In contrast, inhibition of PP1 gamma re-balanced the CaMKII delta splicing. Furthermore, CaMKII activity was found to be augmented or attenuated by PP1 gamma overexpression or inhibition, respectively. Further mechanistic studies showed that abdominal aorta constriction stress specifically increased the association of alternative splicing factor with PP1 gamma, but not with PP1 beta. Overexpression of PP1 gamma, but not inhibitor 1 of PP1, further potentiated this association. These results suggest that PP1 gamma alters the cardiac hypertrophy and remodelling likely through promotion of the alternative splicing factor-mediated splicing of CaMKII delta.