Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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
Doi: 10.1016/j.yjmcc.2015.09.018
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- von Lewinski Dirk
- Wallner Markus
- Co-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
- Wakula-Heinzel Paulina
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- Abstract:
- 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.
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- Calcium-Binding Proteins - metabolism
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- Cyclic AMP-Dependent Protein Kinases - metabolism
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- Glucagon-Like Peptide-1 Receptor - metabolism
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- Find related publications in this database (Keywords)
- Myocardial contraction
- Signal transduction
- GLP-1
- Inotropic agents
- Diabetes mellitus