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Nat Commun. 2014 Jul 15;5:4381. doi: 10.1038/ncomms5381.

H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway.

Author information

1
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.
2
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.
3
Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.
4
Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen, Germany.
5
Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
6
Department of Anesthesiology and Intensive Care, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
7
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.
8
Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, C1428EHA, Buenos Aires, Argentina.
9
Institute of Pathology, University of Ulm, Albert-Einstein-Allee 23, 89070 Ulm, Germany.
10
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.
11
1] Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany [2].
12
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.
13
Clinical Chemistry & Pharmacology, Department of Laboratory Medicine, Lund University Hospital, SE-221 85 Lund, Sweden.
14
1] Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen, Germany [2].

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.

PMID:
25023795
PMCID:
PMC4104458
DOI:
10.1038/ncomms5381
[Indexed for MEDLINE]
Free PMC Article

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