Sex-specific regulation of the cardiac transcriptome by the protein phosphatase 2A regulatory subunit B55a

Protein phosphatase 2A (PP2A) enzymes containing the regulatory subunit isoform B55a (PP2A-B55a) suppress HDAC5/MEF2 signalling in cardiac myocytes, implicating B55a in the transcriptional regulation of cardiac growth and fibrosis. The role of B55a in the heart has not been investigated. In this study, we generated and characterised two loss-of-function mouse models, with global or cardiomyocyte-specific disruption of the gene encoding B55a (Ppp2r2a). Mice with global homozygous knockout of B55a died in utero, but cardiac morphology was unremarkable compared with wildtype littermates. Mice with global heterozygous knockout of B55a had thinner left ventricular walls compared with wildtype mice at 12 months of age, an effect that was more pronounced in males. Mice with cardiomyocyte-specific deletion of B55a displayed normal cardiac morphology at 10-12 weeks of age, demonstrating that cardiomyocyte B55a is not required for postnatal heart growth. Despite no obvious morphological differences, gene expression analyses revealed extensive remodelling of the cardiac transcriptome in male, but not female, mice. In males, B55a knockout increased the expression of genes associated with extracellular matrix composition, and downregulated genes associated with mitochondrial energy production. This study reveals a sexually dimorphic role for B55a in postnatal cardiac transcriptional regulation and provides a foundation for future work investigating the role of B55a in cardiac stress settings. Overall design: Samples are left ventricle tissue from cardiomyocyte-specific Ppp2r2a knockout (cKO) mice (genotype: aMHC-CreTg/0-Ppp2r2aL/L) or floxed control (Ctrl) mice (genotype: aMHC-Cre0/0-Ppp2r2aL/L), on a mixed background (floxed Ppp2r2a mice: C57BL6/N, aMHC-Cre mice: FVB).