PP1 activation as novel antiarrhythmic approach in human heart failure

2017 | journal article; research paper

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​PP1 activation as novel antiarrhythmic approach in human heart failure​
Eiringhaus, J. ; Fischer, T. H. ; Kohn, M.; Wang, Y.; Maier, L. S. ; Hasenfuss, G.   & Sossalla, S. T. ​ (2017) 
European Heart Journal38(suppl_1) art. P5841​.​ DOI: https://doi.org/10.1093/eurheartj/ehx493.P5841 

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Authors
Eiringhaus, J. ; Fischer, T. H. ; Kohn, M.; Wang, Y.; Maier, L. S. ; Hasenfuss, G. ; Sossalla, S. T. 
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.
Issue Date
2017
Journal
European Heart Journal 
Project
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur 
Working Group
RG Hasenfuß (Transition zur Herzinsuffizienz) 
RG L. Maier (Experimentelle Kardiologie) 
RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung) 
RG T. Fischer 
ISSN
0195-668X
Language
English

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