title: Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling.
abstract: In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETA only in sympathetic neurons (SN-KO) showed less adverse structural remodeling and cardiac dysfunction in response to pathological pressure overload induced by transverse aortic constriction (TAC). In contrast, mice lacking ETA only in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [(124)I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETA amplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, antiadrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with β blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi.
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, D-69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany;
authors.forename: Lorenz H
authors.initials: LH
authors.lastname: Lehmann
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, D-69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany;
authors.forename: Julia S
authors.initials: JS
authors.lastname: Rostosky
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany; Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany;
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Buss
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, D-69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany;
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kreusser
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, D-69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany;
authors.forename: Jutta
authors.initials: J
authors.lastname: Krebs
authors.affiliation: Department of Nuclear Medicine, University Hospital, D-69120 Heidelberg, Germany;
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: Division of Cardiology, University Hospital Zürich, CH-8091 Zürich, Switzerland;
authors.forename: Frank
authors.initials: F
authors.lastname: Enseleit
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany; Institute of Experimental and Clinical Pharmacology and Toxicology, Heidelberg University, Medical Faculty Mannheim, D-68169 Mannheim, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Spiger
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany; Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany;
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Hardt
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany; Institute of Experimental and Clinical Pharmacology and Toxicology, Heidelberg University, Medical Faculty Mannheim, D-68169 Mannheim, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Department of Cardiology, Theresienkrankenhaus, 68165 Mannheim, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Haass
authors.affiliation: Division of Cardiology, University Hospital Zürich, CH-8091 Zürich, Switzerland;
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London WC2A 3LJ, United Kingdom;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: Institute of Applied Physiology, University of Ulm, D-89081 Ulm, Germany; Institute of Anatomy and Cell Biology, University of Heidelberg, D-69120 Heidelberg, Germany;
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parlato
authors.affiliation: Department of Molecular Pathology, German Cancer Research Center, D-69120 Heidelberg, Germany;
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Department of Nuclear Medicine, University Hospital, D-69120 Heidelberg, Germany;
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050; and International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany; Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany;
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, D-69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany; johannes.backs@med.uni-heidelberg.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006655:Histone Deacetylases / Q000378:metabolism; D066298:In Vitro Techniques; D064326:MEF2 Transcription Factors / Q000378:metabolism; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D011941:Receptors, Adrenergic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D065130:Endothelin A Receptor Antagonists; D064326:MEF2 Transcription Factors; D044022:Receptor, Endothelin A; D011941:Receptors, Adrenergic; D006655:Histone Deacetylases
keywords: HDACs; epigenetic regulation; norepinephrine reuptake; sympathetic nervous system; β adrenergic signaling