Abstract
AimsB56α is a protein phosphatase 2A (PP2A) regulatory subunit that is highly expressed in the heart. We previously reported that cardiomyocyte B56α localizes to myofilaments under resting conditions and translocates to the cytosol in response to acute β-adrenergic receptor (β-AR) stimulation. Given the importance of reversible protein phosphorylation in modulating cardiac function during sympathetic stimulation, we hypothesized that loss of B56α in mice with targeted disruption of the gene encoding B56α (Ppp2r5a) would impact on cardiac responses to β-AR stimulation in vivo.Methods and resultsCardiac phenotype of mice heterozygous (HET) or homozygous (HOM) for the disrupted Ppp2r5a allele and wild type (WT) littermates was characterized under basal conditions and following acute β-AR stimulation with dobutamine (DOB; 0.75 mg/kg i.p.) or sustained β-AR stimulation by 2-week infusion of isoproterenol (ISO; 30 mg/kg/day s.c.). Left ventricular (LV) wall thicknesses, chamber dimensions and function were assessed by echocardiography, and heart tissue collected for gravimetric, histological, and biochemical analyses. Western blot analysis revealed partial and complete loss of B56α protein in hearts from HET and HOM mice, respectively, and no changes in the expression of other PP2A regulatory, catalytic or scaffolding subunits. PP2A catalytic activity was reduced in hearts of both HET and HOM mice. There were no differences in the basal cardiac phenotype between genotypes. Acute DOB stimulation induced the expected inotropic response in WT and HET mice, which was attenuated in HOM mice. In contrast, DOB-induced increases in heart rate were unaffected by B56α deficiency. In WT mice, ISO infusion increased LV wall thicknesses, cardiomyocyte area and ventricular mass, without LV dilation, systolic dysfunction, collagen deposition or foetal gene expression. The hypertrophic response to ISO was blunted in mice deficient for B56α.ConclusionThese findings identify B56α as a potential regulator of cardiac structure and function during β-AR stimulation.
Highlights
Phosphorylation is a post-translational modification that plays a fundamental role in modulating cardiac structural and functional responses to neurohormonal stimuli
To explore if the loss of B56α protein was associated with altered expression of other components of the heterotrimeric phosphatase 2A (PP2A) holoenzyme, we explored the protein levels of PP2A catalytic (PP2AC) and scaffolding (PP2AA) subunits, and three other PP2A regulatory B subunit isoforms (B56d, B56g and B55α), in hearts from WT, HET and HOM mice (Figure 2)
These observations build on our previous work that revealed translocation of B56α between subcellular compartments upon b-AR stimulation in cardiomyocytes[17, 18] and suggest that B56α plays an important role in regulating cardiac responses to such stimulation in vivo
Summary
Phosphorylation is a post-translational modification that plays a fundamental role in modulating cardiac structural and functional responses to neurohormonal stimuli. The type 1 and type 2A protein phosphatases (PP1 and PP2A, respectively) provide the majority of serine/threonine phosphatase activity in the myocardium, and play critical roles in the regulation of cardiac function.[9, 12, 13] PP2A is a heterotrimeric enzyme consisting of a catalytic C subunit (PP2AC, encoded by PPP2CA and PPP2CB), a scaffolding A subunit (PP2AA, encoded by PPP2R1A and PPP2R1B) and a regulatory B subunit (encoded by at least 15 different genes, including members of the PPP2R2, PPP2R3, PPP2R5 and STRN families, with multiple splice variants). The diversity of PP2A cellular functions derives from the fact that numerous biochemically distinct complexes may be assembled from different combinations of A, B and C subunits, with the regulatory B subunits providing the essential determinants for subcellular targeting, substrate specificity and fine-tuning of phosphatase activity.[14, 15]
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