Hydrogen sulfide and translational medicine

Hydrogen sulfide (H₂S) along with carbon monoxide and nitric oxide is an important signaling molecule that has undergone large numbers of fundamental investigations. H₂S is involved in various physiological activities associated with the regulation of homeostasis, vascular contractility, pro- and anti-inflammatory activities, as well as pro- and anti-apoptotic activities etc. However, the actions of H₂S are influenced by its concentration, reaction time, and cell/disease types. Therefore, H₂S is a signaling molecule without definite effect. The use of existing H₂S donors is limited because of the instant release and short lifetime of H₂S. Thus, translational medicine involving the sustained and controlled release of H₂S is of great value for both scientific and clinical uses. H₂S donation can be manipulated by different ways, including where H₂S is given, how H₂S is donated, or the specific structures of H₂S-releasing drugs and H₂S donor molecules. This review briefly summarizes recent progress in research on the physiological and pathological functions of H₂S and H₂S-releasing drugs, and suggests hope for future investigations.     

Hydrogen sulfide and renal ischemia

Hydrogen sulfide (H(2)S), an endogenously produced gasotransmitter, which is soluble in both water and lipids, is now known for its protective effects against various disease models and cellular injuries. A wide range of studies have been published on the protective effects of H(2)S against ischemia-reperfusion injuries, with findings focusing mainly on the heart and liver. It was not until recently that the effect of H(2)S on kidneys gained the attention and interest of researchers, and studies have begun to unveil the role of H(2)S under physiological conditions, as well as during pathological renal diseases. This article will provide a summary of current research findings on the relationship between H(2)S and the kidneys, based on existing literature, with prime emphasis on renal ischemia-reperfusion injuries. In this article, a brief discussion will be dedicated to providing insight of the currently known signaling mechanisms underlying the protective effects of H(2)S in the kidneys.     

Hydrogen sulfide and the metabolic syndrome

The metabolic syndrome is a group of abnormalities including obesity, high blood pressure, hyperinsulinemia, high blood glucose levels and hyperlipidemia that together greatly increase the risk of developing cardiovascular disease and Type 2 diabetes. Hydrogen sulfide (H(2)S) is a vasodilatory gasotransmitter mediator in the cardiovascular system, proposed as an endothelium-derived relaxing factor. A lack of H(2)S and its synthesizing enzyme, cystathionine γ-lyase, in the vasculature causes hypertension, whereas an increase in the pancreas reduces insulin secretion. Thus, research is making inroads to determine whether H(2)S is involved in the pathogenesis of the metabolic syndrome. Several laboratories are synthesizing and testing clinically used drugs that release H(2)S. Some of these compounds are being tested for effectiveness in the metabolic syndrome.     

Hydrogen sulfide and the metabolic syndrome

The metabolic syndrome is a group of abnormalities including obesity, high blood pressure, hyperinsulinemia, high blood glucose levels and hyperlipidemia that together greatly increase the risk of developing cardiovascular disease and Type 2 diabetes. Hydrogen sulfide (H₂S) is a vasodilatory gasotransmitter mediator in the cardiovascular system, proposed as an endothelium-derived relaxing factor. A lack of H₂S and its synthesizing enzyme, cystathionine γ-lyase, in the vasculature causes hypertension, whereas an increase in the pancreas reduces insulin secretion. Thus, research is making inroads to determine whether H₂S is involved in the pathogenesis of the metabolic syndrome. Several laboratories are synthesizing and testing clinically used drugs that release H₂S. Some of these compounds are being tested for effectiveness in the metabolic syndrome.     

Hydrogen sulfide in the endocrine and reproductive systems

Hydrogen sulfide (H(2)S) is now considered a member of a group of signaling molecules termed 'gasotransmitters'. H(2)S has been shown to be generated in the endocrine and reproductive organs and elicits various actions. H(2)S modulates insulin secretion in pancreatic islets. Adipose tissues have the ability to produce H(2)S, which regulates the local insulin sensitivity and vascular responsiveness. H(2)S also acts on the hypothalamic-pituitary-adrenal axis and is involved in stress responses. The effects of H(2)S on male and female reproductive function have also attracted great interest for their potential therapeutic implications in reproductive disorders. Alterations of H(2)S biosynthesis are associated with various endocrine disorders, and hormones can be important factors in the regulation of H(2)S production. Understanding the regulatory mechanisms for H(2)S synthesis pathways may help develop new therapeutic strategies.     

硫化氢促进结肠癌细胞的生长

<正>硫化氢(H2S)是一种具有广泛生物学效应的气体信号分子[1],我们曾报道了H2S具有促血管新生的能力[2-3],而血管新生可促进肿瘤细胞的增殖和扩散。结肠癌细胞能表达合成H2S的两个酶:胱硫醚-β-合酶(CBS)和胱硫醚-γ-裂解酶(CSE),其中CSE含量远大于CBS的含量[4]。本实验通过干扰内源性H2S的生成来探讨其对肿瘤生长的影响。     

Hydrogen sulfide inhibits human platelet aggregation

Gaseous mediators such as nitric oxide (NO) play a major regulatory role in the cardiovascular system homeostasis, including platelet aggregation. Here, we investigated whether hydrogen sulfide (H(2)S), a newly recognized endogenous mediator, can affects aggregation of human platelets, using sodium hydrogen sulfide (NaHS) as H(2)S-donor. NaHS inhibited platelet aggregation induced by ADP, collagen, epinephrine, arachidonic acid, thromboxane mimetic, U46619, and thrombin. H(2)S effect was not dependent by cAMP/cGMP generation, NO production or potassium-channels opening. NaHS concentrations (up to 10 mM) did not exert toxic effects on platelet viability. The possible protective role of endogenous H(2)S in cardiovascular system is discussed.     

Hydrogen sulfide: advances in understanding human toxicity

Hydrogen sulfide is a relatively common, frequently lethal, and unique occupational hazard for which research since 1990 has uncovered many anomalies and subtleties and a previously unsuspected physiological role for the endogenous agent. The result has been uncertainty and misunderstanding, particularly for persons new to the literature. This review addresses evidence that settles past controversies, guides practical issues in evaluating human toxicity, addresses unresolved issues involving chronic exposure, and points the way to a deeper understanding of the agent and its effects.     

Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia

Hydrogen sulfide (H₂S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H₂S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6     

Hydrogen sulfide: from physiology to pharmacology

Gaseous neutroasmitters are a growing family of enzimatically generated gaseous mediators that exert regulatory functions in mammals. It is now widely recognized that hydrogen sulfide (H(2)S), along with nitric oxide (NO) and carbon monoxide (CO), is an important signaling molecule in cardiovascular, nervous, gastrointestinal, liver and lung physiology and pharmacology. The production of H(2)S from L-cysteine is catalysed primarily by two enzymes, cystathionine γ-lyase and cystathionine β-synthase. Evidence is accumulating to demonstrate that H(2)S delivered exogenously exerts beneficial effects in animal models of inflammation and pain highlighting the potential for the therapeutic exploitation of H(2)S. Several hybrids have been developed coupling an H(2)S-releasing moiety to conventional drugs. These molecular hybrids are currently evaluated for efficacy in animal models of gastrointestinal, cardiovascular and neurogical disorders and erectile dysfunction. The anti-inflammatory activity of H(2)S has also been exploited for generating anti-platelets and anti-inflammatory agents that inhibit cyclo-oxygenases while sparing the gastrointestinal and cardiovascular tract.     

Hydrogen sulfide causes relaxation in mouse bronchial smooth muscle

We investigated the effects of NaHS, a hydrogen sulfide (H(2)S) donor, on the tension of isolated mouse and guinea-pig bronchial rings. NaHS at 0.01 - 10 mM had no effect on the tone of those preparations without precontraction. When the preparation was precontracted with carbachol, NaHS at 0.1 - 3 mM strongly relaxed the mouse rings, but produced only slight relaxation in the guinea-pig rings. The NaHS-induced relaxation in the mouse bronchus was resistant to inhibitors of ATP-sensitive K(+) channels, soluble guanylyl cyclase, cyclooxygenase (COX)-1 or COX-2, and antagonists of tachykinin receptors. Thus, NaHS evokes bronchodilation in mice, suggesting a possible role for H(2)S in the respiratory system.     

Hydrogen sulfide facilitates carotid sinus baroreflex in anesthetized rats

AIM: To study effects of hydrogen sulfide (H2S) on the carotid sinus baroreflex (CSB). METHODS: The functional curve of the carotid sinus baroreflex was measured by recording changes in arterial pressure in anesthetized male rats with perfused carotid sinus. RESULTS: H2S (derived from sodium hydrosulfide) at concentrations of 25, 50, and 100 micromol/L facilitated the CSB, shifting the functional curve of the baroreflex downward and to the left. There was a marked increase in peak slope (PS) and reflex decrease in blood pressure (RD). Effects were concentration-dependent. Pretreatment with glibenclamide (20 micromol/L), a K(ATP) channel blocker, abolished the above effects of H2S on CSB. Pretreatment with Bay K8644 (an agonist of calcium channels; 500 nmol/L) eliminated the effect of H2S on CSB. An inhibitor of cystathionine gamma-lyase (CSE), DL-propargylglycine (PPG; 200 micromol/L), inhibited CSB in male rats and shifted the functional curve of the baroreflex upward and to the right. CONCLUSION: These data suggest that exogenous H2S exerts a facilitatory role on isolated CSB through opening K(ATP) channels and further closing the calcium channels in vascular smooth muscle. Endogenous H2S may activate the activity of the CSB in vivo.     

Hydrogen sulfide protects against high-glucose-induced apoptosis in endothelial cells

Hydrogen sulfide (H2S) is the third endogenous gaseous mediator identified after nitric oxide and carbon monoxide. It has been demonstrated that H2S has protective effects on myocardial ischemia/reperfusion-induced cell apoptosis. To date, little is known about the role of H2S in the pathophysiology of diabetic vascular complications. In this study, we investigated the effects of sodium hydrosulfide on high-glucose-induced apoptosis of primary human umbilical vein endothelium cells. Exposure to high glucose (25 mmole/L) for 48 hours resulted in the induction of apoptosis by 41.6% ± 1.01%, which was attenuated by pretreatment with sodium hydrosulfide (50 μmole/L) for 30 minutes. Further investigation of the apoptotic mechanisms in the cells demonstrated that high glucose upregulated the ratio of Bax/Bcl-2 and activated caspase-3 and also increased the levels of reactive oxygen species and malondialdehyde while reducing superoxide dismutase activity. All the above responses could be prevented by pretreatment with 50 μmole/L of sodium hydrosulfide. These results indicated that the protective effects of H2S on endothelial cells in the condition of high glucose might involve an antioxidative stress mechanism.