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SHR Neuro Krebs Kardio Lipid

Wallner, M; Kolesnik, E; Ablasser, K; Khafaga, M; Wakula, P; Ljubojevic, S; Thon-Gutschi, EM; Sourij, H; Kapl, M; Edmunds, NJ; Kuzmiski, JB; Griffith, DA; Knez, I; Pieske, B; von Lewinski, D.
Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium.
J Mol Cell Cardiol. 2015; 89(Pt B):365-375
Web of Science PubMed FullText FullText_MUG


Autor/innen der Med Uni Graz:
Ablasser Klemens
Holzer Senka
Kapl Martin
Khafaga Mounir
Knez Igor
Kolesnik Ewald
Pieske Burkert Mathias
Sourij Harald
Thon-Gutschi Eva-Maria
von Lewinski Dirk
Wakula-Heinzel Paulina
Wallner Markus

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Glucagon-like peptide-1 receptor (GLP-1R) agonists are a rapidly growing class of drugs developed for treating type-2 diabetes mellitus. Patients with diabetes carry an up to 5-fold greater mortality risk compared to non-diabetic patients, mainly as a result of cardiovascular diseases. Although beneficial cardiovascular effects have been reported, exact mechanisms of GLP-1R-agonist action in the heart, especially in human myocardium, are poorly understood. The effects of GLP-1R-agonists (exenatide, GLP-1(7-36)NH2, PF-06446009, PF-06446667) on cardiac contractility were tested in non-failing atrial and ventricular trabeculae from 72 patients. The GLP-1(7-36)NH2 metabolite, GLP-1(9-36)NH2, was also examined. In electrically stimulated trabeculae, the effects of compounds on isometric force were measured in the absence and presence of pharmacological inhibitors of signal transduction pathways. The role of β-arrestin signaling was examined using a β-arrestin partial agonist, PF-06446667. Expression levels were tested by immunoblots. Translocation of GLP-1R downstream molecular targets, Epac2, GLUT-1 and GLUT-4, were assessed by fluorescence microscopy. All tested GLP-1R-agonists significantly increased developed force in human atrial trabeculae, whereas GLP-1(9-36)NH2 had no effect. Exendin(9-39)NH2, a GLP-1R-antagonist, and H-89 blunted the inotropic effect of exenatide. In addition, exenatide increased PKA-dependent phosphorylation of phospholamban (PLB), GLUT-1 and Epac2 translocation, but not GLUT-4 translocation. Exenatide failed to enhance contractility in ventricular myocardium. Quantitative real-time PCR (qRT-PCR) revealed a significant higher GLP-1R expression in the atrium compared to ventricle. Exenatide increased contractility in a dose-dependent manner via GLP-1R/cAMP/PKA pathway and induced GLUT-1 and Epac2 translocation in human atrial myocardium, but had no effect in ventricular myocardium. Therapeutic use of GLP-1R-agonists may therefore impart beneficial effects on myocardial function and remodelling. Copyright © 2015 Elsevier Ltd. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Calcium-Binding Proteins - metabolism
Cardiotonic Agents - pharmacology
Cyclic AMP-Dependent Protein Kinases - metabolism
Glucagon-Like Peptide-1 Receptor - agonists
Glucagon-Like Peptide-1 Receptor - metabolism
Glucose Transporter Type 1 - metabolism
Glucose Transporter Type 4 - metabolism
Guanine Nucleotide Exchange Factors - metabolism
Heart Atria - drug effects
Heart Atria - metabolism
Heart Ventricles - drug effects
Heart Ventricles - metabolism
Humans -
Myocardial Contraction - drug effects
Myocardium - metabolism
Peptides - pharmacology
Phosphorylation - drug effects
Protein Transport - drug effects
Signal Transduction - drug effects
Venoms - pharmacology

Find related publications in this database (Keywords)
Myocardial contraction
Signal transduction
Inotropic agents
Diabetes mellitus
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