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.
Highlights
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
Knowing that the primary targets for HNO are thiols[1,2] and the reason for its cardioprotective effect is calcitonin gene-related peptide (CGRP) release[3,4], we hypothesized that HNO acts as an endogenous agonist of transient receptor potential channel A1 (TRPA1), a potential target for H2S that is expressed in sensory nerve fibres and activated by numerous endogenous metabolites and environmental irritants[20,21,22] through covalent modification of particular cysteine residues[23,24], leading to paraand/or endocrine CGRP release and to local or general vasodilation, respectively
The effects of HNO on Chinese hamster ovary cells stably expressing mTRPA1 were examined by whole-cell voltage clamp
Summary
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. 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. HNO exerts systemic cardiovascular effects by releasing calcitonin gene-related peptide (CGRP) that combines general vasodilation with positive inotropic and lusitropic actions[3,4]. 19) that is expressed in sensory nerve fibres and activated by numerous endogenous metabolites and environmental irritants[20,21,22] through covalent modification of particular cysteine residues[23,24], leading to paraand/or endocrine CGRP release and to local or general vasodilation, respectively Knowing that the primary targets for HNO are thiols[1,2] and the reason for its cardioprotective effect is CGRP release[3,4], we hypothesized that HNO acts as an endogenous agonist of transient receptor potential channel A1 (TRPA1), a potential target for H2S (ref. 19) that is expressed in sensory nerve fibres and activated by numerous endogenous metabolites and environmental irritants[20,21,22] through covalent modification of particular cysteine residues[23,24], leading to paraand/or endocrine CGRP release and to local or general vasodilation, respectively
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