Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor

Nikolina Jovancevic,H Hatt,F Nguemo,L Gelis,J Semmler,H Milting,J Hescheler,A Dendorfer,E Schleicher,M Matzkies,M Osterloh,M Kovarova,L Weber,J C Heckmann,M Boehm

doi:10.1007/s00395-017-0600-y

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.

Highlights

Transmembrane signal transduction by membrane receptor proteins enables a cell to convert an extracellular signal into cellular responses
Olfactory receptor OR51E1 is expressed in the human heart and in stem cell-derived cardiomyocytes
A broad spectrum of odorant receptors (OR) was detected at the RNA level, whereas the odorant receptor OR51E1 was identified as the highest expressed OR by transcriptome analysis [28]

Summary

Introduction

Transmembrane signal transduction by membrane receptor proteins enables a cell to convert an extracellular signal into cellular responses. GPCRs play a prominent role in sensing extracellular signals, which cover a broad spectrum from physical to chemical stimuli, e.g., transmitters, hormones or ligands for taste and smell The significance of these receptors is reflected by the fact that more than 60% of all commercially available drugs target a GPCR (more than half of all GPCRs are orphan receptors), including pharmaceuticals for cardiovascular diseases such as hypertension, arrhythmias and heart failure [20, 76]. Many groups have reported mammalian OR expression at the transcript and/or protein level in various healthy as well as pathophysiologically altered tissues such as prostate cancer [19, 25, 31, 34, 70, 101, 105, 109, 111, 115]

Objectives

Results

Conclusion