Yuming Yang,†,§ Qiang Zhao,‡,§ Wei Feng,† and Fuyou Li*,† †Department of Chemistry and State Key Laboratory of Molecular Engineering of Polymers and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, P. R. China ‡Key Laboratory for Organic Electronics and Information Displays (KLOEID) and Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210046, P. R. China.

Luminescent chemodosimeters for bioimaging.

Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H2S from L-cysteine is catalysed primarily by two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H2S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H2S.

Hydrogen sulphide and its therapeutic potential

The important life-supporting role of hydrogen sulfide (H2S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H2S had only been known for its toxicity and environmental hazard. Physiological importance of H2S has been appreciated for about a decade. It started by the discovery of endogenous H2S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H2S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H2S. The physiological functions of H2S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H2S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes...

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Physiological Implications of Hydrogen Sulfide: A Whiff Exploration That Blossomed

Hydrogen sulfide (H₂S) is a gaseous mediator synthesized from cysteine by cystathionine γ lyase (CSE) and other naturally occurring enzymes. Pharmacological experiments using H₂S donors and genetic experiments using CSE knockout mice suggest important roles for this vasodilator gas in the regulation of blood vessel caliber, cardiac response to ischemia/reperfusion injury, and inflammation. That H₂S inhibits cytochrome c oxidase and reduces cell energy production has been known for many decades, but more recently, a number of additional pharmacological targets for this gas have been identified. H₂S activates K(ATP) and transient receptor potential (TRP) channels but usually inhibits big conductance Ca²(+)-sensitive K(+) (BK(Ca)) channels, T-type calcium channels, and M-type calcium channels. H₂S may inhibit or activate NF-κB nuclear translocation while affecting the activity of numerous kinases including p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt. These disparate effects may be secondary to the well-known reducing activity of H₂S and/or its ability to promote sulfhydration of protein cysteine moieties within the cell.

Hydrogen Sulfide and Cell Signaling

Hydrogen sulfide (H2S), a messenger molecule generated by cystathionine gamma-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H2S signals have been elusive. We now show that H2S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins.

H2S Signals Through Protein S-Sulfhydration

Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention Here we show that H2S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure

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H2S as a Physiologic Vasorelaxant: Hypertension in Mice with Deletion of Cystathionine γ-Lyase

OBJECTIVE The incidence of high dietary carbohydrate-induced type 2 diabetes is increasing worldwide. Methylglyoxal (MG) is a reactive glucose metabolite and a major precursor of advanced glycation end products (AGEs). MG levels are elevated in diabetic patients. We investigated the effects of chronic administration of MG on glucose tolerance and β-cell insulin secreting mechanism in 12-week-old male Sprague-Dawley rats. RESEARCH DESIGN AND METHODS MG (60 mg/kg/day) or 0.9% saline was administered by continuous infusion with a minipump for 28 days. We performed glucose and insulin tolerance tests and measured adipose tissue glucose uptake and insulin secretion from isolated pancreatic islets. We also used cultured INS-1E cells, a pancreatic β-cell line, for molecular studies. Western blotting, quantitative PCR, immunohistochemistry, and transferase-mediated dUTP nick-end labeling (TUNEL) assay were performed. RESULTS In rats treated with MG and MG + l-buthionine sulfoximine (BSO), MG levels were significantly elevated in plasma, pancreas, adipose tissue, and skeletal muscle; fasting plasma glucose was elevated, whereas insulin and glutathione were reduced. These two groups also had impaired glucose tolerance, reduced GLUT-4, phosphoinositide-3-kinase activity, and insulin-stimulated glucose uptake in adipose tissue. In the pancreatic β-cells, MG and MG + BSO reduced insulin secretion, pancreatic duodenal homeobox-1, MafA, GLUT-2, and glucokinase expression; increased C/EBPβ, nuclear factor-κB, MG-induced AGE, N e -carboxymeythyllysine, and receptor for AGEs expression; and caused apoptosis. Alagebrium, an MG scavenger and an AGE-breaking compound, attenuated the effects of MG. CONCLUSIONS Chronic MG induces biochemical and molecular abnormalities characteristic of type 2 diabetes and is a possible mediator of high carbohydrate-induced type 2 diabetes.

https://diabetes.diabetesjournals.org/content/diabetes/60/3/899.full.pdf

Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats

Endogenous hydrogen sulfide (H2S), generated from homocysteine metabolism mainly catalyzed by cystathionine γ-lyase (CSE), possesses important functions in the cardiovascular system. In this study, we investigated the role of H2S during the pathogenesis of neointimal formation induced by balloon injury in rats. CSE mRNA levels were reduced by 86.5% at 1 week and 64.0% at 4 weeks after balloon injury compared with the uninjured controls. CSE activity was also correspondingly reduced. Endogenous production of H2S in the injured carotid artery was significantly inhibited at 1 week and 4 weeks after balloon injury. Treatment with NaHS (a donor of H2S) enhanced methacholine-induced vasorelaxation of balloon-injured artery. More importantly, treatment with NaHS significantly inhibited neointima formation (0.15 ± 0.01 mm2 versus 0.21 ± 0.01 mm2, P < 0.001) of the balloon-injured carotid arteries and reduced the intima/media ratio (1.05 ± 0.07 versus 1.43 ± 0.06, P < 0.001). A significant decrease in vascular smooth muscle cell proliferation was demonstrated by bromodeoxyuridine incorporation at day 7 after injury. In conclusion, CSE expression and H2S production are reduced during the development of balloon injury-induced neointimal hyperplasia, and treatment with NaHS significantly reduces neointimal lesion formation.

Protective Effect of Hydrogen Sulfide on Balloon Injury-Induced Neointima Hyperplasia in Rat Carotid Arteries

The human embryonic kidney cells (HEK-293) have been widely used as one mammalian expression system in the study of voltage-gated K+ (KV) channels. Understanding the endogenous KV channels in these cells is the prerequisite for the characterization of the heterogeneously expressed KV channels in these cells. In the present study we screened the transcriptional expression of different KV genes in HEK-293 cells using reverse transcribed DNA polymerase chain reaction (RT-PCR) method. Among 16 KV genes examined in native HEK-293 cells 10 KV genes were reproducibly amplified, including those Kv a subunits encoding for the delayed rectifier (IK) [KV1.1, KV1.2, KV1.3, KV1.6, and KV3.1], and for the transient outward KV channels (IA) [KV1.4, KV3.3, KV3.4, and KV4.1] as well as a KVb2. subunit. The whole-cell outward rectifier IK currents in the native HEK-293 cells were recorded (203 ± 13 pA at +30 mV, n = 82) with the patch-clamp technique. In about 42% of the examined cells, IA coexited with IK currents. IK currents were inhibited by tetraethylammonium chloride (TEA) at 1 and 10 mM by 39.5 and 48.4%, respectively. A 39.6% inhibition of IK currents was also observed in the presence of 4-aminopyridine (4-AP, 5 mM). Interestingly, both TEA and 4-AP also inhibited IA currents. 4-acelamido-4′-isothiocyanalostilbene-2, 2′-disulfonic acid (1 mM), a Cl– channel blocker, had no effect on the endogenous outward currents. We concluded that multiple endogenous KV genes were expressed in native HEK-293 cells, which possessed significant endogenous IK and IA currents with unique pharmacological properties.

Bo Jiang

Papers

H2S as a Physiologic Vasorelaxant: Hypertension in Mice with Deletion of Cystathionine γ-Lyase

Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats

Protective Effect of Hydrogen Sulfide on Balloon Injury-Induced Neointima Hyperplasia in Rat Carotid Arteries

Endogenous KV channels in human embryonic kidney (HEK-293) cells

Attenuation of hypertension development by aminoguanidine in spontaneously hypertensive rats: role of methylglyoxal.