Sex-specific regulation of the cardiac transcriptome by the protein phosphatase 2A regulatory subunit B55α

Abstract

1.Protein phosphatase 2A (PP2A) regulatory subunit B55 has been implicated in the transcriptional regulation of cardiac growth and fibrosis by suppressing HDAC5/MEF2 signalling in cardiomyocytes. We created and characterised two mouse models with global or cardiomyocyte-specific disruption of the gene encoding B55 (Ppp2r2a) to conduct the first detailed exploration of B55 in the heart. Global homozygous B55 knockout mice died in utero, while heterozygous mice had thinner left ventricular walls at 12 months, an effect more pronounced in males. At 10-12 weeks of age, cardiomyocyte-specific B55 knockout mice displayed normal cardiac morphology with increased left ventricular collagen deposition, identifying B55 as a negative regulator of cardiac fibrosis. Gene expression analyses revealed extensive remodelling of the cardiac transcriptome in male but not female mice, identifying a sexually dimorphic role for B55 in cardiac transcriptional regulation. These findings provide a basis for future work investigating B55 in cardiac stress settings.