Hydrogen Sulfide Signaling in Cardiovascular and Neurological Systems

Hydrogen sulfide (H₂S) is recognised as the third endogenous gasotransmitter alongside nitric oxide and carbon monoxide, playing multifaceted roles in vascular and neural physiology. Endogenously generated by enzymes such as cystathionine β‐synthase, cystathionine γ‐lyase and 3‐mercaptopyruvate sulfurtransferase, H₂S modulates vascular tone through activation of potassium channels, interacts with nitric oxide pathways to fine-tune vasodilatation and contributes to endothelial homeostasis by counteracting oxidative stress and inflammation. In the nervous system, H₂S influences synaptic transmission, promotes long-term potentiation and affords neuroprotection via redox regulation and mitochondrial support. The dynamic interconversion of H₂S into polysulfides underpins signal transduction processes, linking cellular bioenergetics to redox status. Perturbations in H₂S signalling are implicated in hypertension, atherosclerosis, neurodegenerative disorders and metabolic syndromes, while exogenous donors or modulators of H₂S metabolism present emerging therapeutic opportunities for cardiovascular and neurological diseases.

Research from Nature Portfolio

Recent studies have elucidated the enzymatic basis and physiological impact of protein persulfidation. Key work has demonstrated that cysteinyl-tRNA synthetases catalyse cysteine polysulfidation, yielding hydropersulfides that regulate mitochondrial biogenesis and bioenergetics in cardiac and neuronal cells, thus linking H₂S-derived persulfides to cellular energy homeostasis and redox signalling. Parallel investigations have revealed that H₂S reacts with nitric oxide to generate nitroxyl, which activates the TRPA1 channel on sensory nerve endings. This activation triggers release of calcitonin gene-related peptide, evoking potent vasodilatation and establishing a neuroendocrine axis by which gasotransmitter crosstalk governs vascular tone throughout the cardiovascular system.

Hydrogen Sulfide Signaling in Cardiovascular and Neurological Systems publication trend

The graph below shows the total number of articles in hydrogen sulfide signaling in cardiovascular and neurological systems across all publications each year (not limited to Nature Index journals).

Technical terms

Gasotransmitter: A small gaseous signalling molecule, such as hydrogen sulfide, nitric oxide or carbon monoxide, that diffuses across membranes to modulate physiological processes.

Persulfidation (polysulfidation): A post-translational modification in which a sulphur atom is added to a cysteine thiol, forming hydropersulfides (CysSSH) or longer polysulphide chains, thereby altering protein activity.

Cysteinyl-tRNA synthetase (CARS): An enzyme that charges tRNA with cysteine and catalyses the formation of cysteine-derived persulfides for redox signalling and mitochondrial regulation.

Transient receptor potential ankyrin 1 (TRPA1): A sensory neuron cation channel activated by electrophilic or redox stimuli, mediating calcium influx and neurogenic vasodilatation.

Calcitonin gene-related peptide (CGRP): A neuropeptide released from sensory nerves that induces potent vasodilatation and contributes to vascular homeostasis.

Endothelial dysfunction: A pathological state characterised by impaired vasodilation, inflammation and oxidative stress in the vascular endothelium, driving cardiovascular disease.

Carbon nanozyme: A nanomaterial with enzyme-like catalytic properties capable of mediating specific biochemical reactions, such as the oxidation of hydrogen sulfide to polysulfides and thiosulfate.

References

1. Oxidation of Hydrogen Sulfide to Polysulfide and Thiosulfate by a Carbon Nanozyme: Therapeutic Implications with an Emphasis on Down Syndrome. Advanced Materials (2023).
2. Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. Nature Communications (2017).
3. H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO–TRPA1–CGRP signalling pathway. Nature Communications (2014).
4. Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Frontiers in Pharmacology (2020).
5. Relative Contributions of Cystathionine β-Synthase and γ-Cystathionase to H2S Biogenesis via Alternative Trans-sulfuration Reactions*. Journal of Biological Chemistry (2009).
6. Identification of H2S3 and H2S produced by 3-mercaptopyruvate sulfurtransferase in the brain. Scientific Reports (2015).