Fischer, Thomas H. and Eiringhaus, Joerg and Dybkova, Nataliya and Saadatmand, Alireza and Pabel, Steffen and Weber, Silvio and Wang, Yansong and Koehn, Maja and Tirilomis, Theodor and Ljubojevic, Senka and Renner, Andre and Gummert, Jan and Maier, Lars S. and Hasenfuss, Gerd and El-Armouche, Ali and Sossalla, Samuel (2018) Activation of protein phosphatase 1 by a selective phosphatase disrupting peptide reduces sarcoplasmic reticulum Ca2+ leak in human heart failure. EUROPEAN JOURNAL OF HEART FAILURE, 20 (12). pp. 1673-1685. ISSN 1388-9842, 1879-0844
Full text not available from this repository. (Request a copy)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 approawch.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KINASE-II; CALCIUM-RELEASE; PHOSPHORYLATION; CONTRACTILITY; INHIBITOR-1; EXPRESSION; LEVEL; PP1; Heart failure; Ca2+ cycling; Arrhythmia; Diastolic Ca2+ leak; Protein phosphatases |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2019 08:44 |
| Last Modified: | 04 Oct 2019 08:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13412 |
Actions (login required)
 |
View Item |
