Application of purified PP2A catalytic subunit significantly increased the Ca2+-sensitivity of the contractile apparatus in isolated skinned myocytes of non-failing hearts (ΔpCa50 = 0.05), but had no effect in failing myocardium.
Effect estimate: ΔpCa50 0.05
Absolute Event Rate: 5.48% vs 5.43%
p-value: p=<0.01
Protein phosphatase (PP) type 2A is a multifunctional serine/threonine phosphatase that is involved in cardiac excitation-contraction coupling. The PP2A core enzyme is a dimer, consisting of a catalytic C and a scaffolding A subunit, which is targeted to several cardiac proteins by a regulatory B subunit. At present, it is controversial whether PP2A and its subunits play a critical role in end-stage human heart failure. Here we report that the application of purified PP2AC significantly increased the Ca2+-sensitivity (ΔpCa50=0.05±0.01) of the contractile apparatus in isolated skinned myocytes of non-failing (NF) hearts. A higher phosphorylation of troponin I (cTnI) was found at protein kinase A sites (Ser23/24) in NF compared to failing myocardium. The basal Ca2+-responsiveness of myofilaments was enhanced in myocytes of ischemic (ICM, ΔpCa50=0.10±0.03) and dilated (DCM, ΔpCa50=0.06±0.04) cardiomyopathy compared to NF. However, in contrast to NF myocytes the treatment with PP2AC did not shift force-pCa relationships in failing myocytes. The higher basal Ca2+-sensitivity in failing myocytes coincided with a reduced protein expression of PP2AC in left ventricular tissue from patients suffering from ICM and DCM (by 50 and 56% compared to NF, respectively). However, PP2A activity was unchanged in failing hearts despite an increase of both total PP and PP1 activity. The expression of PP2AB56α was also decreased by 51 and 62% in ICM and DCM compared to NF, respectively. The phosphorylation of cTnI at Ser23/24 was reduced by 66 and 49% in ICM and DCM compared to NF hearts, respectively. Our results demonstrate that PP2A increases myofilament Ca2+-sensitivity in NF human hearts, most likely via cTnI dephosphorylation. This effect is not present in failing hearts, probably due to the lower baseline cTnI phosphorylation in failing compared to non-failing hearts.
Wijnker et al. (Thu,) conducted a other in End-stage heart failure (ischemic or dilated cardiomyopathy) (n=27). Purified PP2A catalytic subunit (PP2Ac) vs. Baseline (before PP2A treatment) was evaluated on Ca2+-sensitivity (pCa50) in non-failing myocytes (ΔpCa50 0.05, p=<0.01). Application of purified PP2A catalytic subunit significantly increased the Ca2+-sensitivity of the contractile apparatus in isolated skinned myocytes of non-failing hearts (ΔpCa50 = 0.05), but had no effect in failing myocardium.