title: H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway.
abstract: Nitroxyl (HNO) is a redox sibling of nitric oxide (NO) that targets distinct signalling pathways with pharmacological endpoints of high significance in the treatment of heart failure. Beneficial HNO effects depend, in part, on its ability to release calcitonin gene-related peptide (CGRP) through an unidentified mechanism. Here we propose that HNO is generated as a result of the reaction of the two gasotransmitters NO and H2S. We show that H2S and NO production colocalizes with transient receptor potential channel A1 (TRPA1), and that HNO activates the sensory chemoreceptor channel TRPA1 via formation of amino-terminal disulphide bonds, which results in sustained calcium influx. As a consequence, CGRP is released, which induces local and systemic vasodilation. H2S-evoked vasodilatatory effects largely depend on NO production and activation of HNO-TRPA1-CGRP pathway. We propose that this neuroendocrine HNO-TRPA1-CGRP signalling pathway constitutes an essential element for the control of vascular tone throughout the cardiovascular system.
authors.affiliation: 1] Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen, Germany [2] Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany [3] Department of Anesthesiology and Intensive Care, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Eberhardt
authors.affiliation: 1] Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany [2] Department of Physiology, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
authors.forename: Maria
authors.initials: M
authors.lastname: Dux
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Namer
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Miljkovic
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
authors.forename: Nada
authors.initials: N
authors.lastname: Cordasic
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Will
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.
authors.forename: Tatjana I
authors.initials: TI
authors.lastname: Kichko
authors.affiliation: Department of Anesthesiology and Intensive Care, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Jeanne
authors.initials: J
authors.lastname: de la Roche
authors.affiliation: 1] Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany [2] Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB1 2PD, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, C1428EHA, Buenos Aires, Argentina.
authors.forename: Sebastián A
authors.initials: SA
authors.lastname: Suárez
authors.affiliation: Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, C1428EHA, Buenos Aires, Argentina.
authors.forename: Damian
authors.initials: D
authors.lastname: Bikiel
authors.affiliation: Institute of Pathology, University of Ulm, Albert-Einstein-Allee 23, 89070 Ulm, Germany.
authors.forename: Karola
authors.initials: K
authors.lastname: Dorsch
authors.affiliation: Department of Anesthesiology and Intensive Care, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
authors.affiliation: 1] Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany [2] Department of Anatomy, Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independentei 91-95, 050095 Bucharest, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Babes
authors.affiliation: 1] Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany [2].
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.affiliation: Institute of Pathology, University of Ulm, Albert-Einstein-Allee 23, 89070 Ulm, Germany.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Jacobi
authors.affiliation: 1] Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, C1428EHA, Buenos Aires, Argentina [2] Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, C1428EHA, Buenos Aires, Argentina.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Martí
authors.affiliation: Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, C1428EHA, Buenos Aires, Argentina.
authors.forename: Fabio
authors.initials: F
authors.lastname: Doctorovich
authors.affiliation: Clinical Chemistry & Pharmacology, Department of Laboratory Medicine, Lund University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Högestätt
authors.affiliation: Clinical Chemistry & Pharmacology, Department of Laboratory Medicine, Lund University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Zygmunt
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Ivanovic-Burmazovic
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Messlinger
authors.affiliation: 1] Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany [2].
authors.forename: Peter
authors.initials: P
authors.lastname: Reeh
authors.affiliation: 1] Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen, Germany [2].
authors.forename: Milos R
authors.initials: MR
authors.lastname: Filipovic
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism
chemical_list: D009589:Nitrogen Oxides; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D009569:Nitric Oxide; C039900:nitroxyl; D015740:Calcitonin Gene-Related Peptide; D006862:Hydrogen Sulfide