Protein phosphatase 2A affects myofilament contractility in non-failing but not in failing human myocardium

作者：Wijnker Paul J M^*; Boknik Peter; Gergs Ulrich; Mueller Frank U; Neumann Joachim; dos Remedios Cris; Schmitz Wilhelm; Sindermann Juergen R; Stienen Ger J M; van der Velden Jolanda; Kirchhefer Uwe

来源：Journal of Muscle Research and Cell Motility, 2011, 32(3): 221-233.

DOI：10.1007/s10974-011-9261-x

• Protein phosphatase 2A
• Myofilament function
• Protein phosphorylation
• Cardiomyocyte
• Troponin I

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 PP2A(C) significantly increased the Ca(2+)-sensitivity (Delta pCa(50) = 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 Ca(2+)-responsiveness of myofilaments was enhanced in myocytes of ischemic (ICM, Delta pCa(50) = 0.10 +/- 0.03) and dilated (DCM, Delta pCa(50) = 0.06 +/- 0.04) cardiomyopathy compared to NF. However, in contrast to NF myocytes the treatment with PP2A(C) did not shift force-pCa relationships in failing myocytes. The higher basal Ca(2+)-sensitivity in failing myocytes coincided with a reduced protein expression of PP2A(C) 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 PP2A(B56 alpha) 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 Ca(2+)-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.

• 出版日期2011-11