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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Stefanie Meyer-Roxlau - , TUD Dresden University of Technology (Author)
  • Simon Lämmle - , TUD Dresden University of Technology (Author)
  • Annett Opitz - , TUD Dresden University of Technology (Author)
  • Stephan Künzel - , Department of Dermatology (Author)
  • Julius P. Joos - , TUD Dresden University of Technology (Author)
  • Stefan Neef - , University of Regensburg (Author)
  • Karolina Sekeres - , TUD Dresden University of Technology (Author)
  • Samuel T. Sosalla - , University of Regensburg (Author)
  • Friedrich Schöndube - , University of Göttingen (Author)
  • Konstantin Alexiou - , TUD Dresden University of Technology (Author)
  • Lars S. Maier - , University of Regensburg (Author)
  • Dobromir Dobrev - , University of Duisburg-Essen (Author)
  • Kaomei Guan - , Institute of Pharmacology and Toxicology (Author)
  • Silvio Weber - , TUD Dresden University of Technology (Author)
  • Ali El-Armouche - , Institute of Pharmacology and Toxicology (Author)

Abstract

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.

Details

Original languageEnglish
Article number43
JournalBasic Research in Cardiology
Volume112
Issue number4
Publication statusPublished - 1 Jul 2017
Peer-reviewedYes

External IDs

Scopus 85020662724
PubMed 28597249
ORCID /0000-0003-2514-9429/work/148606765

Keywords

Sustainable Development Goals

Keywords

  • Atrial fibrillation, Beta-blocker, Endoplasmic reticulum stress response, Human heart failure, Protein phosphatase 1 (PP1) isoforms