title: Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor.
abstract: Several studies have demonstrated the expression of odorant receptors (OR) in various human tissues and their involvement in different physiological and pathophysiological processes. However, the functional role of ORs in the human heart is still unclear. Here, we firstly report the functional characterization of an OR in the human heart. Initial next-generation sequencing analysis revealed the OR expression pattern in the adult and fetal human heart and identified the fatty acid-sensing OR51E1 as the most highly expressed OR in both cardiac development stages. An extensive characterization of the OR51E1 ligand profile by luciferase reporter gene activation assay identified 2-ethylhexanoic acid as a receptor antagonist and various structurally related fatty acids as novel OR51E1 ligands, some of which were detected at receptor-activating concentrations in plasma and epicardial adipose tissue. Functional investigation of the endogenous receptor was carried out by Ca2+imaging of human stem cell-derived cardiomyocytes. Application of OR51E1 ligands induced negative chronotropic effects that depended on activation of the OR. OR51E1 activation also provoked a negative inotropic action in cardiac trabeculae and slice preparations of human explanted ventricles. These findings indicate that OR51E1 may play a role as metabolic regulator of cardiac function.
authors.affiliation: Department of Cell Physiology, Ruhr-University Bochum, 44801, Bochum, Germany. Nikolina.Jovancevic@rub.de.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Jovancevic
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, 80336, Munich, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dendorfer
authors.affiliation: Institute for Neurophysiology, University of Cologne, 50931, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Matzkies
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University of Tuebingen, 72076, Tuebingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kovarova
authors.affiliation: Department of Cell Physiology, Ruhr-University Bochum, 44801, Bochum, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Heckmann
authors.affiliation: Department of Cell Physiology, Ruhr-University Bochum, 44801, Bochum, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Osterloh
authors.affiliation: Department of Cell Physiology, Ruhr-University Bochum, 44801, Bochum, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Department of Cell Physiology, Ruhr-University Bochum, 44801, Bochum, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Weber
authors.affiliation: Institute for Neurophysiology, University of Cologne, 50931, Cologne, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Nguemo
authors.affiliation: Institute for Neurophysiology, University of Cologne, 50931, Cologne, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Semmler
authors.affiliation: Institute for Neurophysiology, University of Cologne, 50931, Cologne, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Erich and Hanna Klessmann Institute, Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr-University Bochum, 32545, Bad Oeynhausen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Milting
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University of Tuebingen, 72076, Tuebingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schleicher
authors.affiliation: Department of Cell Physiology, Ruhr-University Bochum, 44801, Bochum, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Gelis
authors.affiliation: Department of Cell Physiology, Ruhr-University Bochum, 44801, Bochum, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Hatt
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D009363:Neoplasm Proteins; C510734:OR51E1 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: Calcium transients; Medium-chain fatty acids; Negative chronotropic effect; Negative inotropic effect; Olfactory receptor