094 Characterisation of Novel Knockout Mouse Models to Investigate the Role of B55α in the Heart

Abstract

Protein phosphatase 2A (PP2A) is a critical regulator of cardiac function. PP2A catalytic activity is targeted to specific protein substrates by regulatory B subunits, of which ≥13 are expressed in the mammalian heart. Of these, B55α has been identified in vitro as a potential regulator of cardiomyocyte hypertrophy and heart failure pathogenesis. However, the role of B55α in cardiac physiology and pathology remains unknown. To investigate the function of cardiac B55α in vivo. Male and female mice with global or cardiomyocyte-specific disruption of Ppp2r2a were characterised at 3 months of age. Left ventricular dimensions and function were assessed by echocardiography, and heart tissue collected for gravimetric, histological and molecular analyses. Global heterozygote mice displayed a ∼65% (female; p=0.002) or ∼40% (male; p=0.02) reduction in ventricular B55α expression (n=6-7/group). No overt cardiac pathology was observed in heterozygote mice (normal systolic function, no fibrosis or induction of the cardiac stress markers Nppa or Nppb, p>0.05). Global knockout embryos were smaller than wildtype littermates (∼10% reduction in crown-to-rump length) and died between embryonic day 13.5 and birth. Preliminary analyses of female cardiomyocyte-specific knockout mice revealed a ∼90% decrease in ventricular B55α expression (p=0.10, n=3/group), in the absence of overt hypertrophy, systolic dysfunction, fibrosis, atrial enlargement or lung congestion (p>0.05; n=4-6/group). B55α is essential for embryogenesis, but does not appear to be required for postnatal cardiac development. Ongoing analyses are investigating the impact of B55α deficiency in settings of cardiac stress/injury.