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.

Nitric oxide, afferent sensory nerves, and antioxidative enzymes in the mechanism of protection mediated by tricarbonyldichlororuthenium(II) dimer and sodium hydrosulfide against aspirin-induced gastric damage

“…We studied whether the protection by H 2 S against aspirin ulcerogenesis could be mediated by the NO-TRPV1-CGRP signaling pathway. Recently, the H 2 Sevoked vasodilatory effects were attributed to NO production and activation of the HNO-transient receptor potential cation channel A1 (TRPA1)-CGRP pathway, indicating that these mediators can contribute to the enhancement in the gastric microcirculation observed in the present study [35]. When an H 2 S donor was administered in combination with the TRPV1 antagonist capsazepine, the NaHS-induced protection was reversed.…”

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

“…Effect of sulfide 1, 2 and 5 μM versus 0.5 μM the 'SSNO -mix' was determined using the Dunnett multiple comparison; λλ P < 0.01. must account for the relaxation observed. These may include Sn and SSNO - [12,13,50]. Using EPR spectroscopy we confirmed the release of NO from the reaction mixture, but SSNO -is not known to release HNO.…”

“…Similarly, H2S can be stored in the form of sulfane sulfur and transported and released in response to a physiological stimulus [3]. A number of publications reported on the molecular interaction between H2S and NO or NO-donors [4][5][6][7][8][9][10][11][12][13][14], and H2S and NO were found to cooperatively regulate vascular tone by activating a neuroendocrine signaling pathway in which formation of nitroxyl (HNO) appears to play an important role [13]. Products of this H2S/NO interaction appear to have pronounced biological effects; however the nature of the reaction intermediates is currently unclear and many inconsistencies remain; for example, H2S donors were found to either potentiate or attenuate relaxation effect of NO donors in isolated aortic rings in vitro [15,16], or result in complete loss of vasodepressor activity in anesthetized rats [16].…”

Photosensitization in Porphyrias and Photodynamic Therapy Involves TRPA1 and TRPV1

“…The experiments measuring release of CGRP were performed as previously described (Averbeck and Reeh, 2001;Kichko et al, 2015). Briefly, hindpaw skin flaps of adult mice were carefully excised and washed for 30 min in carbogen-saturated synthetic interstitial fluid with or without PpIX (5 M).…”

“…Activation of TRPA1 by electrophilic compounds involves certain critical cysteine residues located in the cytoplasmic N-terminal domain of the protein (Macpherson et al, 2007). The role of these residues in the activation of hTRPA1 by UV A light was investigated in two mutants: hTRPA1-3C, in which cysteines were substituted by serines in positions 621, 641, and 665; and hTRPA1-2C, in which the cysteines C633 and C651 involved in disulfide bonds with the cysteines of the hTRPA1-3C mutant were replaced by serine (Eberhardt et al, 2012(Eberhardt et al, , 2014. Cells transfected with either mutant displayed substantially diminished responses to UV A light: the response of the hTRPA1-3C mutant to 390 nm (90 s) was reduced by ϳ70% (Fig.…”