Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
editorial
. 2020 Feb 16;177(4):715–719. doi: 10.1111/bph.14929

From primordial gas to the medicine cabinet

Andreas Papapetropoulos 1,✉, John L Wallace 2, Rui Wang 3
PMCID: PMC7024704  PMID: 31726475

LINKED ARTICLES

This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9532 (H2S) is a signalling gasotransmitter which plays important roles in regulating the functions of cardiovascular and respiratory systems, metabolism and liver function, kidney and reproduction function, neuronal activity and cognitive function, antioxidant and anti‐inflammatory responses and mitochondrial bioenergetics, among others (Wallace & Wang, 2015; Wang, 2002). The biological and physiological effects of H2S are produced through an array of interactions with its numerous molecular targets. Well‐known examples of these targets include the activation of KATP channels to hyperpolarize membrane potential (Zhao, Zhang, Lu, & Wang, 2001), activation of eNOS to produce more NO (Altaany, Ju, Yang, & Wang, 2014), inhibition of PDEs to increase cGMP levels (Bucci et al., 2012) and induction of S‐sulfhydration to alter the functions of the targeted proteins. This special issue of BJP has examined some of the existing and newly discovered mechanisms that underlie the cellular effects of H2S.

Although protein S‐sulfhydration has been established for 10 years (Mustafa et al., 2009), Kimura has provided an updated review on this mechanism with a focus on the comparison between hydrogen sulfide and polysulfides (2020). This comparison is important and relevant since endogenous H2S is produced via the enzymatic actions of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=279 (CSE), https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=279 (CBS) and https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=279#1443 (MST) and H2S can also be further oxidized to polysulfides by MST. Both H2S and polysulfides have the potential to induce S‐sulfhydration but the enabling conditions for them are not identical.

Mitidieri et al. (2020) reported the effects of L‐serine on vascular tone, especially its correlation with the functionality of the reverse trans‐sulfuration pathway in vascular endothelium. This is a novel mechanism considering that conversion of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4782 to https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=726 and H2S occurs in the presence of CBS. The condensation of L‐serine with https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6765 leads to de novo sphingolipid biosynthesis. https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=778#2524 (S1P) is a major sphingolipid and it can activate https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1249 to increase https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509 production. Mitidieri et al. linked the reverse trans‐sulfuration pathway to S1P/NO axis through L‐serine. They report that the addition of exogenous L‐serine to the organ bath caused relaxation of mouse aorta rings in an endothelium‐dependent manner, similar to the effects of L‐cysteine. This vasorelaxant effect of L‐serine was suppressed after application of an S1P receptor antagonist. Whether stimulation of CBS increases endogenous L‐serine levels and whether an increase in endogenous L‐serine levels results in vasorelaxation remain unknown.

Demonstrating the role of H2S as a gasotransmitter requires proof that the physiological effects of endogenous H2S can be mimicked by exogenous H2S donors (Wang, 2002). H2S donors may be ideal agents for the treatment of human diseases related to deficiency of endogenous H2S, but only if they can be delivered at appropriate concentrations/rates to the desired sites of action. The most widely used H2S donors for animal and in vitro studies are https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6278 and Na2S. These simple sulfur salts provide fast but short‐lived H2S release, generally with rapid uptake by the targeted cells. Of course, for many studies, a more controlled and generally slower release of H2S is desired. This was first achieved with the compound of GYY4137 (Li et al., 2008). Over the last decade, numerous other slow‐releasing H2S donors have been developed and characterized, including sulfur‐hybrid molecules (Szabo & Papapetropoulos, 2017; Wallace & Wang, 2015) and H2S prodrugs (Polhemus et al., 2015). Beyond the rate of release, the targeted delivery of H2S has also become a hot area for the design of novel H2S donors. The mitochondrion‐targeted H2S donor, AP39, is a case‐in‐point (Szczesny et al., 2014).

The distribution and access of various H2S donors to mammalian cells, which are encompassed by a lipid bilayer, constitutes an important consideration when evaluating the rapidity and efficacy of H2S release. In this issue, Durham et al. (2020) described the cellular uptake mechanism for ammonium tetrathiotungstate (ATTT) and ammonium tetrathiomolybdate (ATTM), two representatives of the thiometallate slow‐releasing sulfide donors. Sulfide release by ATTT and ATTM is a thiol‐dependent process. Interestingly, pretreatment of intact human red blood cells with the inhibitor for anion exchange‐1 (AE‐1) decreased ATTT‐induced formation of intracellular sulfhaemoglobin, an indicator of the elevation of intracellular H2S level. The role of AE‐1 in mediating cellular uptake of thiometallates was also confirmed by direct measurement of the intracellular and extracellular concentrations of thiometallates in the presence and absence of AE‐1 inhibitor. On the other hand, the cellular uptake of NaHS, again reflected by the formation of intracellular sulfhaemoglobin, was not affected by AE‐1 inhibition. These observations support the notion that the trans‐membrane movement of H2S is not limited by the plasma membrane and that thiometallates require the presence of AE‐1 to gain access to the intracellular milieu. AE‐1 is a plasma membrane anion transporter, present in various types of mammalian cells, including cardiomyocytes, endothelial cells and intercalated cells of the kidney. The requirement of AE‐1 for the cellular uptake of selective H2S donors may offer an option for target‐selective delivery of exogenous H2S.

Manipulation of H2S levels to achieve positive therapeutic effects has been used in various disease models, such as lipid metabolism‐associated liver disease. Loiselle, Yang, and Wu (2020) reviewed the critical importance of H2S in hepatic lipid metabolism, which has significant implications for liver disease establishment and progression. The authors suggest that increasing endogenous H2S production is a valuable strategy for prevention and treatment of liver disease. The insulin‐sensitizing drug, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4779, and lipid‐lowering statins both increased endogenous H2S levels in rodents, contributing to the amelioration of fatty liver, steatosis and non‐alcoholic fatty liver disease (NAFLD). Other examples for impacting liver lipid metabolism and H2S production include garlic oil and sulforaphane (contained in broccoli sprouts), which decreased lipid accumulation and liver damage in animal models of both NAFLD and alcohol‐induced fatty liver. These treatment strategies remain to be tested in humans. As the authors pointed out, “understanding of the molecular mechanisms through which the H2S metabolic pathway regulates hepatic lipid levels, as well as the functioning of other organs, will be key for the development of effective therapeutic options” (Loiselle et al., 2020).

Advances in fundamental research on the biomedical effects of H2S over the past two decades and the development of a range of novel H2S donors, have not been matched with consequential clinical applications. Clinical trials with the aim of H2S supplementation for different human diseases have been limited (Wallace & Wang, 2015). However, a phase 2B, double‐blind clinical trial of the gastrointestinal safety of a H2S‐releasing drug reported in this issue of BJP (Wallace et al., 2020) is promising and encouraging. In this 2‐week, double‐blind clinical trial, 244 healthy volunteers received https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9534 or https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5230 and had their upper gastrointestinal (GI) ulceration examined endoscopically. Naproxen is one of the most widely used non‐steroidal anti‐inflammatory drugs (NSAIDs) for reducing pain, fever and inflammation. However, the adverse effects of naproxen and other NSAIDs, particularly GI ulceration and bleeding, have been the reasons for serious concerns about the safety of this class of drugs. The key mechanism underlying the ability of NSAIDs to cause gastro‐duodenal ulceration is inhibition of https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1375 https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1376 (Vane, 1971). ATB‐346 is an anti‐inflammatory and analgesic H2S‐releasing derivative of naproxen. Administration of ATB‐346 to healthy subjects resulted in a significant elevation of plasma H2S. ATB‐346 and naproxen were equally effective in inhibiting COX activity (>94%). However, the incidence of at least one ulcer in the upper GI tract was 14‐times greater in the subjects receiving naproxen than in the subjects receiving ATB‐346 (P < .001).

This Themed Issue features two reports on H2S and biomineralization. Castelblanco and colleagues analysed the existing literature on the distinct roles of H2S in physiological (bone and teeth) versus pathological calcification. In the context of physiological calcification, H2S promotes the differentiation of mesenchymal stem cells into osteoblasts, odontoblasts and chondrocytes at the growth plate and enhances the expression of calcifying genes, while inhibiting mesenchymal‐induced osteoclast precursor differentiation. In contrast, during pathological calcification that occurs in the blood vessels, the cartilage, or the kidney, H2S exerts a protective role by decreasing oxidative stress, inhibiting inflammatory cytokine production, and inhibiting trans‐differentiation of non‐calcifying cells to a pro‐calcifying phenotype.

Calcification of cardiovascular tissues (typically, large and medium size arteries and valves) is a chronic disease, associated with increased risk of cardiovascular morbidity and mortality (Yutzey et al., 2014). It occurs more frequently in patients with diabetes and chronic kidney disease and in the elderly. As detailed in the review by Castelblanco, Nasi, Pasch, So, and Busso (2020), H2S donors reduce vascular smooth muscle calcification. Sikura et al. (2020) extended these observations to heart valves and unravelled the molecular mechanisms that H2S employs to protect valve calcification. The authors isolated valvular interstitial cells (VIC) from human aortic valves and tested the ability of a series of H2S donors to modify VIC mineralization/osteoblastic trans‐differentiation. They found that several H2S donors (NaHS, Na2S, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9808, AP67 and AP72) all inhibited calcium content of VIC grown in calcification medium. They proposed that the anti‐calcifying effect of exogenous H2S resulted from reduced phosphate uptake that limited runt‐related transcription factor 2 (RUNX2) nuclear translocation and activation. This in turn limited alkaline phosphatase expression, reduced osteocalcin secretion and limited calcium deposition in the extracellular matrix. The inhibitory effect of H2S on Pi uptake was postulated, but not proven, to be due to sulfhydration of the phosphate transporter Pit. H2S also increased the expression of Ankyrin G1 (ANK1) and ectonucleotide pyrophosphatase/PDE family member 2 (ENPP2), leading to generation of pyrophosphate that inhibits hydroxyapatite formation. This latter pathway is targeted by endogenously generated H2S through CSE and CBS. Silencing CSE and CBS simultaneously reduced ANK1 and ENPP2 expression exacerbating calcification. Interestingly, aortic valves with calcification expressed more CSE but produced less H2S. Although not directly tested in the study, it is possible that CSE in calcified tissue is hyperphosphorylated on S377, leading to reduced activity. A similar finding has been recently reported for CSE in atheromas (Bibli et al., 2019). Based on their findings, the authors proposed that H2S donors might be useful in the treatment of valve calcification. Interestingly, sodium thiosulfate, a degradation product of H2S that has the ability to be converted to H2S, has been successfully used in patients with calciphylaxis (vascular calcification; Nigwekar et al., 2015).

Unlike the plethora of information available for the roles of H2S in smooth muscle function (Wang, 2012), only limited information about its production and biological activities in skeletal muscle is available. Malignant hyperthermia (MH) is a rare condition in which affected individuals exhibit uncontrolled release of calcium in striated muscle after exposure to general anaesthetics, depolarizing muscle agents (https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4004) or during extreme physical activity in hot environments (Hopkins, 2011). The authors had previously shown enhanced CBS expression and H2S levels in skeletal muscle of patients susceptible to MH that contributed to hypercontractility (Vellecco et al., 2016). They have now unravelled the molecular alterations through which H2S leads to the hypercontractility characteristic of MH (Vellecco et al., 2020). They demonstrated that the Kv 7.4 channel in human biopsies from MH‐susceptible individuals is persulfidated and that the Kv7 activator retigabine exhibits an anomalous pharmacological profile, triggering depolarization rather than hyperpolarization. Moreover, in biopsies from non‐susceptible individuals, prior exposure to H2S led to a contractile response after stimulation with retigabine. These findings not only provide clues for the molecular mechanism underlaying MH but also suggest that H2S levels and Kv7.4 persulfidation could help identify individuals likely to manifest MH using a less invasive needle biopsy, compared to the currently used in vitro contracture test.

Based on the fact that H2S exerts a variety of protective effects in the cardiovascular system and that H2S levels are depleted in cardiovascular disease (Wang et al., 2015), H2S donors have been proposed as putative therapeutic modalities (Szabo & Papapetropoulos, 2017). Although most of the commonly used H2S donors are synthetic, a few naturally occurring H2S‐releasing molecules have been described. Among them, the garlic constituents diallyl disulfide and diallyl trisulfide are the best characterized (Szabo & Papapetropoulos, 2017). In this issue, Martelli and collaborators have studied the vasodilatory and anti‐hypertensive properties of erucin, an H2S‐releasing molecule found in edible cruciferous plants. They report that incubation of vascular smooth muscle cells with erucin raises intracellular H2S levels and hyperpolarizes their membrane. Moreover, erucin triggered vasorelaxation in an endothelium‐independent manner. In line with the known synergistic actions of H2S and NO (Bucci et al., 2012; Coletta et al., 2012), the effects of erucin were potentiated by NO release from the endothelium. The authors also demonstrated that erucin increased coronary blood flow of preconstricted coronary arteries and reduced systolic blood pressure in hypertensive rats. Based on the above‐mentioned results, erucin can now be added to the list of H2S donors with favourable vascular actions.

Previous studies have demonstrated the ability of H2S to ameliorate the vascular and cardiac complications of diabetes (Wang et al., 2015). In this issue, Sun et al. (2020) unravelled the role of MuRF1, an https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1023, in the protective effects of H2S in diabetic cardiomyopathy. After demonstrating that H2S levels and CSE expression were reduced in myocardial tissue from db/db mice, the authors used NaHS to “replenish” H2S. Interestingly, treatment with an exogenous source of H2S up‐regulated endogenous production of H2S. This response has been seen in several different experimental settings (Li et al., 2016; Wu et al., 2017) and is contrary to the general principle of agonist‐induced down‐regulation of receptors and effectors. NaHS administration restored cardiac function and rescued sarcomere degradation in the hearts of db/db mice. The improvement seen following NaHS treatment was associated with reduced muscle RING finger‐1 (MuRF1) expression and enhanced sulfhydration of MuRF1 on Cys44 that inhibited its function, leading to reduced ubiquitination and prevention of degradation of myosin heavy chain 6 and myosin light chain 2.

H2S also plays a range of important roles on the external surfaces of organisms, including the skin and in the GI tract. Indeed, some of the earliest applications of H2S as a therapeutic include the still very popular use of thermal sulfur baths. Coavoy‐Sanchez, Costa, and Muscara (2020) have comprehensively reviewed the current and potential future use of H2S donors for treating conditions such as psoriasis, atopic dermatitis, wounds, urticaria, rosacea, acne, diabetic ulcers and melanoma. Based on laboratory studies, there appears to be great promise of utilizing H2S donors for many of these conditions. As mentioned above, release of H2S within the GI tract has been shown to accelerate the healing of ulcers (Wallace, Dicay, McKnight, & Martin, 2007), as well as preventing the formation of ulcers in response to use of NSAIDs such as naproxen (Wallace et al., 2020). One of the most remarkable elements of the biology of H2S is the capacity for it to drive generation of ATP, particularly in the GI epithelial cells (Goubern, Andriamihaja, Nübel, Blachier, & Bouillaud, 2007). It has long been known that NSAIDs can uncouple oxidative phosphorylation in the GI tract and that this contributes to ulcer formation. Administration of H2S donors has been shown to prevent these effects (Goubern et al., 2007; Wallace et al., 2007). Moreover, H2S released from microbiota within the intestine contribute significantly to maintenance of the integrity of the intestinal lining, including promoting healing and resolution of inflammation (Motta et al., 2015).

Continuing on the theme of healing, Modis et al. (this issue) examined newly identified regulatory roles for the enzyme 3‐MST, particularly in angiogenesis and in metabolic switching by endothelial cells. The suggested “a wider role of 3‐MST activity” in the metabolome of endothelial cells, beyond sulfur metabolism. They further suggested that pharmacological inhibitors of 3‐MST may be exploited as anti‐angiogenic therapeutics.

For many years, there has been strong interest in the possible use of H2S donors to prevent various forms of cancer. De Cicco et al. (2020) performed a series of elegant experiments focused on modulation of myeloid suppressor cells (MDSC) in vivo. The growth of tumours in melanoma‐bearing mice could be significantly reduced by treating the mice with H2S donors (e.g. diallyl trisulfide). These effects appeared to be related to a reduction of the immune suppressive effects of MDSCs, leading to a restoration of T cell proliferation.

This issue of BJP highlights the substantial breadth of research related to H2S. Like NO and carbon monoxide, H2S plays very important roles in a wide range of physiological and pathophysiological processes. Moreover, significant progress has been made in recent years towards targeting H2S in drug design, with translation to human applications on the horizon.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

REFERENCES

  1. Altaany, Z. , Ju, Y. , Yang, G. , & Wang, R. (2014). The coordination of S‐sulfhydration, S‐nitrosylation, and phosphorylation of endothelial nitric oxide synthase by hydrogen sulfide. Science Signaling, 7(342), ra87 10.1126/scisignal.2005478 [DOI] [PubMed] [Google Scholar]
  2. Bibli, S. I. , Hu, J. , Sigala, F. , Wittig, I. , Heidler, J. , Zukunft, S. , … Fleming, I. (2019). Cystathionine γ lyase sulfhydrates the RNA binding protein human antigen R to preserve endothelial cell function and delay atherogenesis. Circulation, 139, 101–114. 10.1161/circulationaha.118.034757 [DOI] [PubMed] [Google Scholar]
  3. Bucci, M. , Papapetropoulos, A. , Vellecco, V. , Zhou, Z. , Zaid, A. , Giannogonas, P. , … Cirino, G. (2012). cGMP‐dependent protein kinase contributes to hydrogen sulfide‐stimulated vasorelaxation. PLoS ONE, 7, e53319 10.1371/journal.pone.0053319 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Castelblanco, M. , Nasi, S. , Pasch, A. , So, A. , & Busso, N. (2020). The role of the gasotransmitter hydrogen sulfide in pathological calcification. British Journal of Pharmacology, 177(4), 778–792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coavoy‐Sanchez, S. A. , Costa, S. K. P. , & Muscara, M. N. (2020). Hydrogen sulfide and dermatological diseases. British Journal of Pharmacology, 177(4), 857–865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coletta, C. , Papapetropoulos, A. , Erdelyi, K. , Olah, G. , Módis, K. , Panopoulos, P. , … Szabo, C. (2012). Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium‐dependent vasorelaxation. Proceedings of the National Academy of Sciences of the United States of America, 109, 9161–9166. 10.1073/pnas.1202916109 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. De Cicco, P. , Ercolano, G. , Rubino, V. , Terrazzano, G. , Ruggiero, G. , Cirino, G. , & Ianaro, A. (2020). Modulation of myeloid derived suppressor cells (MDSCs) functions: A new strategy towards hydrogen sulfide anti‐cancer effects. British Journal of Pharmacology, 177(4), 884–897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Durham, T. , Zander, D. , Stomeo, N. , Minnion, M. , Hogarth, G. , Feelisch, M. , … Dyson, A. (2020). Chemistry, pharmacology and cellular uptake mechanisms of thiometallate sulfide donors. British Journal of Pharmacology, 177(4), 745–756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goubern, M. , Andriamihaja, M. , Nübel, T. , Blachier, F. , & Bouillaud, F. (2007). Sulfide, the first inorganic substrate for human cells. The FASEB Journal, 21, 1699–1706. 10.1096/fj.06-7407com [DOI] [PubMed] [Google Scholar]
  10. Govar, A. A. , Toro, G. , Szaniszlo, P. , Pavlidou, A. , Bibli, S. , Thanki, K. , … Módis, K. (2020). 3‐mercaptopyruvate sulfurtransferase supports endothelial cell angiogenesis and bioenergetics. British Journal of Pharmacology, 177(4), 866–883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hopkins, P. M. (2011). Malignant hyperthermia: Pharmacology of triggering. British Journal of Anaesthesia, 107, 48–56. 10.1093/bja/aer132 [DOI] [PubMed] [Google Scholar]
  12. Kimura, H. (2020). Signaling by hydrogen sulfide and polysulfides via protein S‐sulfuration. British Journal of Pharmacology, 177(4), 720–733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Li, L. , Whiteman, M. , Guan, Y. Y. , Neo, K. L. , Cheng, Y. , Lee, S. W. , … Moore, P. K. (2008). Characterization of a novel, water‐soluble hydrogen sulfide‐releasing molecule (GYY4137): New insights into the biology of hydrogen sulfide. Circulation, 117, 2351–2360. 10.1161/CIRCULATIONAHA.107.753467 [DOI] [PubMed] [Google Scholar]
  14. Li, N. , Wang, M. J. , Jin, S. , Bai, Y. D. , Hou, C. L. , Ma, F. F. , … Zhu, Y. C. (2016). The H2S donor NaHS changes the expression pattern of H2S‐producing enzymes after myocardial infarction. Oxidative Medicine and Cellular Longevity, 2016, 6492469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Loiselle, J. J. , Yang, G. , & Wu, L. (2020). Hydrogen sulfide and hepatic lipid metabolism—A critical pairing for liver health. British Journal of Pharmacology, 177(4), 757–768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Martelli, A. , Piragine, E. , Citi, V. , Testai, L. , Pagnotta, E. , Ugolini, L. , … Calderone, V. (2020). Erucin exhibits vasorelaxing effects and antihypertensive activity by H2S‐releasing properties. British Journal of Pharmacology, 177(4), 824–835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mitidieri, E. , Gurgone, D. , Caiazzo, E. , Tramontano, T. , Cicala, C. , Sorrentino, R. , & d'Emmanuele di Villa Bianca R. (2020). L‐cysteine/cystathionine‐β‐synthase‐induced relaxation in mouse aorta involves Lserine/sphingosine‐1‐phosphate/nitric oxide axis. British Journal of Pharmacology, 177(4), 734–744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Motta, J. P. , Flannigan, K. L. , Agbor, T. A. , Beatty, J. K. , Blackler, R. W. , Workentine, M. L. , … Wallace, J. L. (2015). Hydrogen sulfide protects from colitis and restores intestinal microbiota and mucus production. Inflammatory Bowel Diseases, 21, 1006–1017. 10.1097/MIB.0000000000000345 [DOI] [PubMed] [Google Scholar]
  19. Mustafa, A. K. , Gadalla, M. M. , Sen, N. , Kim, S. , Mu, W. , Gazi, S. K. , … Snyder, S. H. (2009. Nov 10). H2S signals through protein S‐sulfhydration. Science Signaling, 2(96), ra72 10.1126/scisignal.2000464 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nigwekar, S. U. , Kroshinsky, D. , Nazarian, R. M. , Goverman, J. , Malhotra, R. , Jackson, V. A. , … Thadhani, R. I. (2015). Calciphylaxis: Risk factors, diagnosis, and treatment. American Journal of Kidney Diseases, 66, 133–146. 10.1053/j.ajkd.2015.01.034 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Polhemus, D. J. , Li, Z. , Pattillo, C. B. , Gojon, G. Sr. , Gojon, G. Jr. , & Giordano, T. (2015). A novelhydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients. Cardiovascular Therapeutics, 33, 216–226. 10.1111/1755-5922.12128 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sikura, K. É. , Potor, L. , Szerafin, T. , Oros, M. , Nagy, P. , Méhes, G. , … Balla, J. (2020). Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease. British Journal of Pharmacology, 177(4), 793–809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sun, X. , Zhao, D. , Lu, F. , Peng, S. , Yu, M. , Liu, N. , … Zhang, W. (2020). Hydrogen sulfide regulates muscle RING finger‐1 protein S‐sulfhydration at Cys44 to prevent cardiac structural damage in diabetic cardiomyopathy. British Journal of Pharmacology, 177(4), 836–856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Szabo, C. , & Papapetropoulos, A. (2017). International union of basic and clinical pharmacology. CII: Pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors. Pharmacological Reviews, 69, 497–564. 10.1124/pr.117.014050 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Szczesny, B. , Módis, K. , Yanagi, K. , Coletta, C. , Le Trionnaire, S. , Perry, A. , … Szabo, C. (2014). AP39, a novel mitochondria‐targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro. Nitric Oxide, 41, 120–130. 10.1016/j.niox.2014.04.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vane, J. R. (1971). Inhibition of prostaglandin synthesis as the mechanism of action for aspirin‐like drugs. Nature: New Biology, 231, 232–235. 10.1038/newbio231232a0 [DOI] [PubMed] [Google Scholar]
  27. Vellecco, V. , Mancini, A. , Ianaro, A. , Calderone, V. , Attanasio, C. , Cantalupo, A. , … Bucci, M. (2016). Cystathionine β‐synthase‐derived hydrogen sulfide is involved in human malignant hyperthermia. Clinical Science (London, England), 130, 35–44. 10.1042/CS20150521 [DOI] [PubMed] [Google Scholar]
  28. Vellecco, V. , Martelli, A. , Bibli, I. S. , Vallifuoco, M. , Manzo, O. L. , Panza, E. , … Cirino, G. (2020). Anomalous Kv 7 channel activity in human malignant hyperthermia syndrome unmasks a key role for H2S and persulfidation in skeletal muscle. British Journal of Pharmacology, 177(4), 810–823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wallace, J. L. , Dicay, M. , McKnight, W. , & Martin, G. R. (2007). Hydrogen sulfide enhances ulcer healing in rats. The FASEB Journal, 21, 4070–4076. 10.1096/fj.07-8669com [DOI] [PubMed] [Google Scholar]
  30. Wallace, J. L. , Nagy, P. , Feener, T. D. , Allain, T. , Ditrói, T. , Vaughan, D. J. , … Buret, A. G. (2020). A proof‐of‐concept, phase 2 clinical trial of the gastrointestinal safety of a hydrogen sulfide‐releasing anti‐inflammatory drug. British Journal of Pharmacology, 177(4), 769–777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wallace, J. L. , & Wang, R. (2015). Hydrogen sulfide‐based therapeutics: Exploiting a unique but ubiquitous gasotransmitter. Nature Reviews. Drug Discovery, 14, 329–345. 10.1038/nrd4433 [DOI] [PubMed] [Google Scholar]
  32. Wang, R. (2002). Two's company, three's a crowd—Can H2S be the third endogenous gaseous transmitter? The FASEB Journal, 16, 1792–1798. 10.1096/fj.02-0211hyp [DOI] [PubMed] [Google Scholar]
  33. Wang, R. (2012). Physiological implications of hydrogen sulfide: A whiff exploration that blossomed. Physiological Reviews, 92, 791–896. 10.1152/physrev.00017.2011 [DOI] [PubMed] [Google Scholar]
  34. Wang, R. , Szabo, C. , Ichinose, F. , Ahmed, A. , Whiteman, M. , & Papapetropoulos, A. (2015). The role of H2S bioavailability in endothelial dysfunction. Trends in Pharmacological Sciences, 36, 568–578. 10.1016/j.tips.2015.05.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wu, W. , Hou, C. L. , Mu, X. P. , Sun, C. , Zhu, Y. C. , Wang, M. J. , & Lv, Q. Z. (2017). H2S donor NaHS changes the production of endogenous H2S and NO in D‐galactose‐induced accelerated ageing. Oxidative Medicine and Cellular Longevity, 2017, 5707830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yutzey, K. E. , Demer, L. L. , Body, S. C. , Huggins, G. S. , Towler, D. A. , Giachelli, C. M. , & Aikawa, E. (2014). Calcific aortic valve disease: A consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 2387–2393. 10.1161/ATVBAHA.114.302523 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zhao, W. , Zhang, J. , Lu, Y. , & Wang, R. (2001). The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. The EMBO Journal, 20, 6008–6016. 10.1093/emboj/20.21.6008 [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES