Thomas H Fischer1,2,3, Jörg Eiringhaus1,3, Nataliya Dybkova1,3, Alireza Saadatmand4, Steffen Pabel3,5, Silvio Weber6, Yansong Wang7, Maja Köhn7,8, Theodor Tirilomis9, Senka Ljubojevic10, André Renner11, Jan Gummert11, Lars S Maier5, Gerd Hasenfuß1,3, Ali El-Armouche6, Samuel Sossalla1,3,5. 1. Klinik für Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Germany. 2. Medizinische Klinik II, Kardiologie, Angiologie, Pneumologie, Klinikum Coburg, Germany. 3. Deutsches Zentrum für Herz-Kreislauf Forschung (DZHK), Standort Göttingen, Germany. 4. Abt. Molekulare Kardiologie und Epigenetik, Universitätsklinikum Heidelberg, Germany. 5. Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Germany. 6. Institut für Pharmakologie, Technische Universität Dresden, Germany. 7. European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany. 8. Centre for Biological Signalling Studies (BIOSS) and Faculty of Biology, University of Freiburg, Germany. 9. Klinik für Thorax-, Herz-, Gefäßchirurgie, Georg-August-Universität Göttingen, Germany. 10. Abteilung für Kardiologie, Medizinische Universität Graz, Austria. 11. Abteilung für Herz- und Transplantationschirurgie, Herz- und Diabeteszentrum, Bad Oeynhausen, Germany.
Abstract
BACKGROUND: Disruption of Ca2+ homeostasis is a key pathomechanism in heart failure. CaMKII-dependent hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum (SR) increases the arrhythmogenic SR Ca2+ leak and depletes SR Ca2+ stores. The contribution of conversely acting serine/threonine phosphatases [protein phosphatase 1 (PP1) and 2A (PP2A)] is largely unknown. METHODS AND RESULTS: Human myocardium from three groups of patients was investigated: (i) healthy controls (non-failing, NF, n = 8), (ii) compensated hypertrophy (Hy, n = 16), and (iii) end-stage heart failure (HF, n = 52). Expression of PP1 was unchanged in Hy but greater in HF compared to NF while its endogenous inhibitor-1 (I-1) was markedly lower expressed in both compared to NF, suggesting increased total PP1 activity. In contrast, PP2A expression was lower in Hy and HF compared to NF. Ca2+ homeostasis was severely disturbed in HF compared to Hy signified by a higher SR Ca2+ leak, lower systolic Ca2+ transients as well as a decreased SR Ca2+ load. Inhibition of PP1/PP2A by okadaic acid increased SR Ca2+ load and systolic Ca2+ transients but severely aggravated diastolic SR Ca2+ leak and cellular arrhythmias in Hy. Conversely, selective activation of PP1 by a PP1-disrupting peptide (PDP3) in HF potently reduced SR Ca2+ leak as well as cellular arrhythmias and, importantly, did not compromise systolic Ca2+ release and SR Ca2+ load. CONCLUSION: This study is the first to functionally investigate the role of PP1/PP2A for Ca2+ homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca2+ cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca2+ leak. It may thus represent a promising future antiarrhythmic therapeutic approach.
BACKGROUND: Disruption of Ca2+ homeostasis is a key pathomechanism in heart failure. CaMKII-dependent hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum (SR) increases the arrhythmogenic SR Ca2+ leak and depletes SR Ca2+ stores. The contribution of conversely acting serine/threonine phosphatases [protein phosphatase 1 (PP1) and 2A (PP2A)] is largely unknown. METHODS AND RESULTS:Human myocardium from three groups of patients was investigated: (i) healthy controls (non-failing, NF, n = 8), (ii) compensated hypertrophy (Hy, n = 16), and (iii) end-stage heart failure (HF, n = 52). Expression of PP1 was unchanged in Hy but greater in HF compared to NF while its endogenous inhibitor-1 (I-1) was markedly lower expressed in both compared to NF, suggesting increased total PP1 activity. In contrast, PP2A expression was lower in Hy and HF compared to NF. Ca2+ homeostasis was severely disturbed in HF compared to Hy signified by a higher SR Ca2+ leak, lower systolic Ca2+ transients as well as a decreased SR Ca2+ load. Inhibition of PP1/PP2A by okadaic acid increased SR Ca2+ load and systolic Ca2+ transients but severely aggravated diastolic SR Ca2+ leak and cellular arrhythmias in Hy. Conversely, selective activation of PP1 by a PP1-disrupting peptide (PDP3) in HF potently reduced SR Ca2+ leak as well as cellular arrhythmias and, importantly, did not compromise systolic Ca2+ release and SR Ca2+ load. CONCLUSION: This study is the first to functionally investigate the role of PP1/PP2A for Ca2+ homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca2+ cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca2+ leak. It may thus represent a promising future antiarrhythmic therapeutic approach.
Authors: Jörg Eiringhaus; Christoph M Wünsche; Petros Tirilomis; Jonas Herting; Nadja Bork; Viacheslav O Nikolaev; Gerd Hasenfuss; Samuel Sossalla; Thomas H Fischer Journal: ESC Heart Fail Date: 2020-07-25
Authors: Kathryn G Helmstadter; Senka Ljubojevic-Holzer; Brent M Wood; Khanha D Taheri; Simon Sedej; Jeffrey R Erickson; Julie Bossuyt; Donald M Bers Journal: Basic Res Cardiol Date: 2021-02-15 Impact factor: 17.165