Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation.

Autor: Meyer-Roxlau S; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany., Lämmle S; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany., Opitz A; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany., Künzel S; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany., Joos JP; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany., Neef S; Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany., Sekeres K; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany., Sossalla S; Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany., Schöndube F; Department of Thoracic and Cardiovascular Surgery, University Medical Centre Goettingen, Göttingen, Germany., Alexiou K; Department of Heart Surgery, Dresden University of Technology, Dresden, Germany., Maier LS; Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany., Dobrev D; Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany., Guan K; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany., Weber S; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany. Silvio.Weber@tu-dresden.de., El-Armouche A; Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany. Ali.El-Armouche@tu-dresden.de.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2017 Jul; Vol. 112 (4), pp. 43. Date of Electronic Publication: 2017 Jun 09.
DOI: 10.1007/s00395-017-0635-0
Abstrakt: Protein phosphatase 1 (PP1) is a key regulator of important cardiac signaling pathways. Dysregulation of PP1 has been heavily implicated in cardiac dysfunctions. Accordingly, pharmacological targeting of PP1 activity is considered for therapeutic intervention in human cardiomyopathies. Recent evidence from animal models implicated previously unrecognized, isoform-specific activities of PP1 in the healthy and diseased heart. Therefore, this study examined the expression of the distinct PP1 isoforms PP1α, β, and γ in human heart failure (HF) and atrial fibrillation (AF) and addressed the consequences of β-adrenoceptor blocker (beta-blocker) therapy for HF patients with reduced ejection fraction on PP1 isoform expression. Using western blot analysis, we found greater abundance of PP1 isoforms α and γ but unaltered PP1β levels in left ventricular myocardial tissues from HF patients as compared to non-failing controls. However, expression of all three PP1 isoforms was higher in atrial appendages from patients with AF compared to patients with sinus rhythm. Moreover, we found that in human failing ventricles, beta-blocker therapy was associated with lower PP1α abundance and activity, as indicated by higher phosphorylation of the PP1α-specific substrate eIF2α. Greater eIF2α phosphorylation is a known repressor of protein translation, and accordingly, we found lower levels of the endoplasmic reticulum (ER) stress marker Grp78 in the very same samples. We propose that isoform-specific targeting of PP1α activity may be a novel and innovative therapeutic strategy for the treatment of human cardiac diseases by reducing ER stress conditions.
Databáze: MEDLINE
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