title: Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium.
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.
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Wallner
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Ewald
authors.initials: E
authors.lastname: Kolesnik
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Klemens
authors.initials: K
authors.lastname: Ablasser
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Department of Pharmacology, School of Medicine, University of California Davis, Genome Building, 451 Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Mounir
authors.initials: M
authors.lastname: Khafaga
authors.affiliation: Department of Cardiology, Charité-Universitaetsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Paulina
authors.initials: P
authors.lastname: Wakula
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Senka
authors.initials: S
authors.lastname: Ljubojevic
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Thon-Gutschi
authors.affiliation: Division of Endocrinology and Metabolism, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Division of Cardiac Surgery, Department of Surgery, Medical University of Graz, Auenbruggerplatz 29, 8036 Graz, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Sourij
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Kapl
authors.affiliation: Safety Pharmacology, Worldwide Research and Development, Pfizer Inc., Groton, CT 06340, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Edmunds
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139, United States.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Kuzmiski
authors.affiliation: Worldwide Medicinal Chemistry, Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.affiliation: Division of Endocrinology and Metabolism, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Division of Cardiac Surgery, Department of Surgery, Medical University of Graz, Auenbruggerplatz 29, 8036 Graz, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Knez
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Department of Cardiology, Charité-Universitaetsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Electronic address: dirk.von-lewinski@medunigraz.at.
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
mesh_terms: D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D020662:Guanine Nucleotide Exchange Factors; D010455:Peptides; D014688:Venoms; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000099211:Phospholamban; C442864:RAPGEF4 protein, human
keywords: Diabetes mellitus; GLP-1; Inotropic agents; Myocardial contraction; Signal transduction