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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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 Högestätt
  • Ivana Ivanovic-Burmazovic
  • Karl Messlinger
  • Peter Reeh
  • Milos R Filipovic
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology
  • Medicinal Chemistry
Original languageEnglish
Article number4381
JournalNature Communications
Volume5
Issue numberJul 15
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes

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