Abstract 20080: Deletion Of B56α, a Regulatory Subunit of Protein Phosphatase 2A, is Associated With Improved Cardiac Performance

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Abstract

Protein Phosphatase 2A (PP2A) is a major intracellular phosphatase that regulates myocardial excitation-contraction coupling. We have demonstrated that patients suffering from heart failure exhibit reduced protein levels of PP2A subunits (A, B and C). It is suggested that B56α is crucial for substrate specificity and targeting of the PP2A-AC heterodimer. Hence, we tested whether the decrease of B56α in human heart failure exerts detrimental or protective effects on cardiac function. B56α knockout (KO, excision of exon 7) mice showed no differences in heart weights along with unchanged expression of genes regulating hypertrophy, fibrosis and cell-cell interaction compared to wild type mice (WT). The loss of B56α was associated with a decreased protein level of PP2A-C (by 34±5%, n=8, P<0.05) and higher protein levels of B56β and B56γ. The diminished protein level of PP2A-Cwas in line with a lower PP2A activity in KO compared to WT (0.36±0.01 vs. 0.50±0.03nmol/min/mg, respectively, n=11-15, P<0.05). PP1 remained unchanged between both groups. Functional consequences of B56α deletion were assessed by in vivo hemodynamic measurements showing increased left-ventricular pressure (Pmax: by 11.1±0.3%, n=8, P<0.05) and relaxation (dP/dtmin: by 21.6±0.4%, n=8, P<0.05) compared to WT under basal conditions. In isolated work-performing hearts relaxation was increased in KO compared to WT (-3608.3±683.6 vs. -1833.7±42.7mmHg/s, respectively, n=5-6, P<0.05) under basal conditions (30 mmHg). Interestingly, the increase of relaxation at higher afterload conditions (60 mmHg) was lower in KO (by 40.2±2.8%, n=6, n.s.) compared to WT (by 75.1±2.4%, n=5, P<0.05). Improved relaxation of KO hearts can be explained by enhanced phosphorylation states of phospholamban at Thr17 and troponin inhibitor at Ser23/24 (by 94.7±2.1% and 38.2±9.3%, respectively, n=7-8, P<0.05).

In conclusion, deletion of B56α was followed by lower PP2A activity leading to higher phosphorylation levels of Ca2+ regulatory and myofilament proteins paralleled by an improved relaxation. Hence, the reduction of B56α in human heart failure may contribute to maintain cardiac function.

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