Hydrogen sulfide (H2S) is considered to be the third gasotransmitter after carbon monoxide (CO) and nitric oxide (NO). It plays an important role in the regulation of vascular homeostasis. Vascular remodeling have has proved to be related to the impaired H2S generation. This study aimed to summarize and discuss current data about the function of H2S in vascular physiology and pathophysiology as well as the underlying mechanisms. Endogenous hydrogen sulfide (H2S) as a third gasotransmitter is primarily generated by the enzymatic pathways and regulated by several metabolic pathways. H2S as a physiologic vascular regulator, inhibits proliferation, regulates its apoptosis and autophagy of vascular cells and controls the vascular tone. Accumulating evidence shows that the downregulation of H2S pathway is involved in the pathogenesis of a variety of vascular diseases, such as hypertension, atherosclerosis and pulmonary hypertension. Alternatively, H2S supplementation may greatly help to prevent the progression of the vascular diseases by regulating vascular tone, inhibiting vascular inflammation, protecting against oxidative stress and proliferation, and modulating vascular cell apoptosis, which has been verified in animal and cell experiments and even in the clinical investigation. Besides, H2S system and angiotensin-converting enzyme (ACE) inhibitors play a vital role in alleviating ischemic heart disease and left ventricular dysfunction. Notably, sulfhydryl-containing ACEI inhibitor zofenopril is superior to other ACE inhibitors due to its capability of H2S releasing, in addition to ACE inhibition. The design and application of novel H2S donors have significant clinical implications in the treatment of vascular-related diseases. However, further research regarding the role of H2S in vascular physiology and pathophysiology is required.

At appropriate concentrations, hydrogen sulfide, a well-known gasotransmitter, plays important roles in both physiology and pathophysiology. Increasing evidence suggests that modifying thiol groups of specific cysteines in target proteins via sulfhydration or persulfidation is one of the important mechanisms responsible for the biological functions of hydrogen sulfide. A variety of key proteins of different cellular pathways in mammals have been reported to be sulfhydrated by hydrogen sulfide to participate and regulate the processes of cell survival/death, cell differentiation, cell proliferation/hypertrophy, cellular metabolism, mitochondrial bioenergetics/biogenesis, endoplasmic reticulum stress, vasorelaxtion, inflammation, oxidative stress, etc. Moreover, S-sulfhydration also exerts many biological functions through the cross-talk with other post-translational modifications including phosphorylation, S-nitrosylation and tyrosine nitration. This review summarizes recent studies of hydrogen sulfide-induced sulfhydration as a posttranslational modification, an important biological function of hydrogen sulfide, and sulfhydrated proteins are introduced. Additionally, we discuss the main methods of detecting sulfhydration of proteins.

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and β subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.

Significance: Previously, sulfur dioxide (SO ₂ ) was recognized as an air pollutant. However, it is found to be endogenously produced in mammalian tissues. As a new gasotransmitter, SO ₂ is involved in regulating the structure and function of blood vessels, heart, lung, gastrointestinal tract, nervous system, etc. Recent Advances: Increasing evidence showed that endogenous SO ₂ regulates cardiovascular physiological processes, such as blood pressure control, vasodilation, maintenance of the normal vascular structure, and cardiac negative inotropy. Under pathological conditions including hypertension, atherosclerosis, vascular calcification, aging endothelial dysfunction, myocardial injury, myocardial hypertrophy, diabetic myocardial fibrosis, sepsis-induced cardiac dysfunction, pulmonary hypertension, acute lung injury, colitis, epilepsy-related brain injury, depression and anxiety, and addictive drug reward memory consolidation, endogenous SO ₂ protects against the pathological changes via different molecular mechanisms and the disturbed SO ₂ /aspartate aminotransferase pathway is likely involved in the mechanisms for the earlier mentioned pathologic processes. Critical Issues: A comprehensive understanding of the biological effects of endogenous SO ₂ is extremely important for the development of novel SO ₂ therapy. In this review, we summarized the biological effects, mechanism of action, SO ₂ detection methods, and its related prodrugs. Future Directions: Further studies should be conducted to understand the effects of endogenous SO ₂ in various physiological and pathophysiological processes and clarify its underlying mechanisms. More efficient and accurate SO ₂ detection methods, as well as specific and effective SO ₂ -releasing systems should be designed for the treatment and prevention of clinical related diseases. The translation from SO ₂ basic medical research to its clinical application is also worthy of further study. Antioxid. Redox Signal . 36, 256–274.

Endogenous hydrogen sulfide (H₂S) and sulfur dioxide (SO₂) are regarded as important regulators to control endothelial cell function and protect endothelial cell against various injuries. In our present study, we aimed to investigate the effect of endogenous H₂S on the SO₂ generation in the endothelial cells and explore its significance in the endothelial inflammation in vitro and in vivo. The human umbilical vein endothelial cell (HUVEC) line (EA.hy926), primary HUVECs, primary rat pulmonary artery endothelial cells (RPAECs), and purified aspartate aminotransferase (AAT) protein from pig heart were used for in vitro experiments. A rat model of monocrotaline (MCT)-induced pulmonary vascular inflammation was used for in vivo experiments. We found that endogenous H₂S deficiency caused by cystathionine-γ-lyase (CSE) knockdown increased endogenous SO₂ level in endothelial cells and enhanced the enzymatic activity of AAT, a major SO₂ synthesis enzyme, without affecting the expressions of AAT1 and AAT2. While H₂S donor could reverse the CSE knockdown-induced increase in the endogenous SO₂ level and AAT activity. Moreover, H₂S donor directly inhibited the activity of purified AAT protein, which was reversed by a thiol reductant DTT. Mechanistically, H₂S donor sulfhydrated the purified AAT1/2 protein and rescued the decrease in the sulfhydration of AAT1/2 protein in the CSE knockdown endothelial cells. Furthermore, an AAT inhibitor l-aspartate-β-hydroxamate (HDX), which blocked the upregulation of endogenous SO₂/AAT generation induced by CSE knockdown, aggravated CSE knockdown-activated nuclear factor-κB pathway in the endothelial cells and its downstream inflammatory factors including ICAM-1, TNF-α, and IL-6. In in vivo experiment, H₂S donor restored the deficiency of endogenous H₂S production induced by MCT, and reversed the upregulation of endogenous SO₂/AAT pathway via sulfhydrating AAT1 and AAT2. In accordance with the results of the in vitro experiment, HDX exacerbated the pulmonary vascular inflammation induced by the broken endogenous H₂S production in MCT-treated rat. In conclusion, for the first time, the present study showed that H₂S inhibited endogenous SO₂ generation by inactivating AAT via the sulfhydration of AAT1/2; and the increased endogenous SO₂ generation might play a compensatory role when H₂S/CSE pathway was downregulated, thereby exerting protective effects in endothelial inflammatory responses in vitro and in vivo.

The metabolic pathway of sulfur-containing amino acids in organisms begins with methionine, which is metabolized to produce important sulfur-containing biomolecules such as adenosylmethionine, adenosylhomocysteine, homocysteine, cystine, and hydrogen sulfide (H₂S). These sulfur-containing biomolecules play a wide range of physiological roles in the body, including anti-inflammation, antioxidant stress, DNA methylation, protein synthesis, etc., which are essential for maintaining cellular function and overall health. In contrast, dysregulation of the metabolic pathway of sulfur-containing amino acids leads to abnormal levels of sulfur-containing biomolecules, which produce a range of pathological consequences in multiple systems of the body, such as neurodegenerative diseases, cardiovascular diseases, and cancer. This review traces the milestones in the development of these sulfur-containing biomolecules from their initial discovery to their clinical applications and describes in detail the structure, physiochemical properties, metabolism, sulfide signaling pathway, physiopathological functions, and assays of sulfur-containing biomolecules. In addition, the paper also explores the regulatory role and mechanism of sulfur-containing biomolecules on cardiovascular diseases, liver diseases, neurological diseases, metabolic diseases and tumors. The focus is placed on donors of sulfur-containing biological macromolecule metabolites, small-molecule drug screening targeting H₂S-producing enzymes, and the latest advancements in preclinical and clinical research related to hydrogen sulfide, including clinical trials and FDA-approved drugs. Additionally, an overview of future research directions in this field is provided. The aim is to enhance the understanding of the complex physiological and pathological roles of sulfur-containing biomolecules and to offer insights into developing effective therapeutic strategies for diseases associated with dysregulated sulfur-containing amino acid metabolism.