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

Mirjam Eberhardt, Maria Dux, Barbara Namer, Jan Miljkovic, Nada Cordasic, Christine Will, Tatjana I. Kichko, Jeanne de la Roche, Michael Fischer, Sebastián A. Suárez, Damian Bikiel, Karola Dorsch, Andreas Leffler, Alexandru Babes, Angelika Lampert, Jochen K. Lennerz, Johannes Jacobi, Marcelo A. Martí, Fabio Doctorovich, Edward D. Högestätt, Peter M. Zygmunt, Ivana Ivanovic-Burmazovic, Karl Messlinger, Peter Reeh and Milos R. Filipovic ()
Additional contact information
Mirjam Eberhardt: Friedrich-Alexander University Erlangen-Nuremberg
Maria Dux: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Barbara Namer: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Jan Miljkovic: Friedrich-Alexander University Erlangen-Nuremberg
Nada Cordasic: University of Erlangen-Nuremberg
Christine Will: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Tatjana I. Kichko: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Jeanne de la Roche: Hannover Medical School
Michael Fischer: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Sebastián A. Suárez: Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria
Damian Bikiel: Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria
Karola Dorsch: Institute of Pathology, University of Ulm
Andreas Leffler: Hannover Medical School
Alexandru Babes: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Angelika Lampert: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Jochen K. Lennerz: Institute of Pathology, University of Ulm
Johannes Jacobi: University of Erlangen-Nuremberg
Marcelo A. Martí: Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria
Fabio Doctorovich: Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria
Edward D. Högestätt: Clinical Chemistry & Pharmacology, Lund University Hospital
Peter M. Zygmunt: Clinical Chemistry & Pharmacology, Lund University Hospital
Ivana Ivanovic-Burmazovic: Friedrich-Alexander University Erlangen-Nuremberg
Karl Messlinger: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Peter Reeh: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg
Milos R. Filipovic: Friedrich-Alexander University Erlangen-Nuremberg

Nature Communications, 2014, vol. 5, issue 1, 1-17

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5381

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