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

ABSTRACT: Protein phosphatase 2A (PP2A) enzymes containing the regulatory subunit isoform B55α (PP2A-B55α) suppress HDAC5/MEF2 signalling in cardiac myocytes, implicating B55α in the transcriptional regulation of cardiac growth and fibrosis. The role of B55α 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 B55α (Ppp2r2a). Mice with global homozygous knockout of B55α died in utero, but cardiac morphology was unremarkable compared with wildtype littermates. Mice with global heterozygous knockout of B55α 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 B55α displayed normal cardiac morphology at 10-12 weeks of age, demonstrating that cardiomyocyte B55α 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, B55α 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 B55α in postnatal cardiac transcriptional regulation and provides a foundation for future work investigating the role of B55α in cardiac stress settings.

ORGANISM(S): Mus musculus

PROVIDER: GSE266131 | GEO | 2024/05/05

REPOSITORIES: GEO

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Project description:Aims: We investigate sex differences and the role of oestrogen receptor beta (ERbeta) in a mouse model of pressure overload-induced myocardial hypertrophy. Methods and results: We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER knockout (ERbeta-/-) C57Bl6 mice. All mice were characterised by echocardiography and haemodynamic measurements and were sacrificed nine weeks after surgery. Left ventricular (LV) samples were analysed by microarray profiling, real-time RT-PCR and histology. After nine weeks, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. These sex differences were abolished in ERbeta-/- mice. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that male WT hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than female hearts. ERbeta-/- mice exhibited a different transcriptome. Induction of pro-apoptotic genes after TAC occurred in ERbeta-/- mice of both sexes with a stronger expression in ERbeta-/- males. Histological analysis revealed, that cardiac fibrosis was more pronounced in male WT TAC than in female mice. This was abolished in ERbeta-/- mice. Apoptosis was significantly induced in both sexes of ERbeta-/- TAC mice, but it was most prominent in males. Conclusion: Female sex offers protection against ventricular chamber dilation in the TAC model. Both the female sex and ER attenuate the development of fibrosis and apoptosis; thus slowing the progression to heart failure. The influence of sex (male/female) and estrogen receptor beta expression (ERbeta knockout/wildtype) on cardiac hypertrophy (transverse aortic constriction/sham operated) was investigated. The left ventricular transcriptome of four individual mice for each combination of the three factors (sex, genotype, surgery) was detected with Affymetrix RAE 430 2.0 GeneChip arrays.

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

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