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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Brain Stem / drug effects
  • Brain Stem / metabolism
  • Calcitonin Gene-Related Peptide / genetics
  • Calcitonin Gene-Related Peptide / metabolism*
  • Humans
  • Hydrogen Sulfide / metabolism*
  • Immunohistochemistry
  • In Vitro Techniques
  • Mice
  • Mice, Knockout
  • Nitric Oxide / pharmacology*
  • Nitrogen Oxides / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels / genetics
  • Transient Receptor Potential Channels / metabolism*
  • Trigeminal Ganglion / drug effects
  • Trigeminal Ganglion / metabolism

Substances

  • Nitrogen Oxides
  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • Nitric Oxide
  • nitroxyl
  • Calcitonin Gene-Related Peptide
  • Hydrogen Sulfide