CJPP 2012-8 rev H2S signaling in redox regulation of cellular function

INVITED REVIEW

H 2S signaling in redox regulation of cellular functions 1

Youngjun Ju,Weihua Zhang,Yanxi Pei,and Guangdong Yang

Abstract:Hydrogen sul?de (H 2S)is traditionally recognized as a toxic gas with a rotten-egg smell.In just the last few decades,H 2S has been found to be one of a family of gasotransmitters,together with nitric oxide and carbon monoxide,and various physiologic effects of H 2S have been reported.Among the most acknowledged molecular mechanisms for the cellular effects of H 2S is the regulation of intracellular redox homeostasis and post-translational modi?cation of proteins through S -sulfhydration.On the one side,H 2S can promote an antioxidant effect and is cytoprotective;on the other side,H 2S stimulates oxidative stress and is cytotoxic.This review summarizes our current knowledge of the antioxidant versus pro-oxidant effects of H 2S in mammalian cells and describes the Janus-faced properties of this novel gasotransmitter.The redox regulation for the cellular effects of H 2S through S -sulfhydration and the role of H 2S in glutathione generation is also recapitulated.A better understanding of H 2S-regualted redox homeostasis will pave the way for future design of novel pharmacological and therapeutic interventions for various diseases.

Key words:hydrogen sul?de,cystathionine gamma-lyase,oxidative stress,S -sulfhydration,glutathione.

Résumé:Le sulfure d'hydrogène (H 2S)est traditionnellement reconnu comme gaz toxique possédant une odeur d'?ufs pourris.Ce n'est qu'au cours des dernières décennies que le H 2S s'est retrouvéparmi la famille des gasotransmetteurs avec l'oxyde nitrique et le monoxyde de carbone,et différents effets physiologiques du H 2S ont étérapportés.Parmi les mécanismes moléculaires responsables des effets cellulaires les plus reconnus du H 2S se trouvent la régulation de l'homéostasie intracellu-laire redox et la modi?cation post-traductionnelle des protéines par S -sulfhydration.D'un c?té,le H 2S peut promouvoir un effet antioxydant et est cytoprotecteur ;de l'autre,le H 2S stimule le stress oxydant et est cytotoxique.Cet article de revue résume nos connaissances des effets antioxydants et prooxydants du H 2S dans les cellules de mammifères et décrit les propriétés a `deux c?tés de ce nouveau https://www.wendangku.net/doc/bd14105771.html, régulation redox dans les effets cellulaires du H 2S par l'intermédiaire de S -sulfhydration et le r?le du H 2S dans la génération de glutathion sont aussi résumés.Une meilleure connaissance de l'homéostasie redox régulée par le H 2S pavera la route a `la conception de nouvelles interventions pharmacologiques et thérapeutiques dans différentes maladies.[Traduit par la Rédaction]

Mots-clés :sulfure d'hydrogène,cystathionine gamma-lyase,stress oxdant,S -sulfhydration,glutathion.

Introduction

Hydrogen sul?de (H 2S)is traditionally considered to be a toxic gas,and is mainly generated by industry and by bacterial metab-olism (Dorman et al.2002;Eghbal et al.2004).Now H 2S has been recognized as a third physiologically relevant gasotransmitter,along with nitric oxide (NO)and carbon monoxide (Wang 2002,2012).H 2S can be endogenously produced by pyridoxal-5=-phosphate-dependent enzymes,including cystathionine beta-synthase (CBS),cystathionine gamma-lyase (CSE),and 3-mercaptopyruvate sul-furtransferase,during cysteine metabolism (Yang et al.2008;Liu et al.2009;Wagner et al.2009;Wang 2012).The expressions of the genes for these enzymes are tissue speci?c,and it is now clear that CSE is the major H 2S-producing enzyme in the cardiovascular system,liver,kidney,and pancreas (Yang 2011).Diverse physiolog-ical roles for H 2S have been reported.H 2S is involved in the regu-lation of neuronal activity,protecting the heart from ischemic damage,inducing vasorelaxation,and altering insulin secretion and in?ammation (Abe and Kimura,1999;Wang 2002,2012;Yang et al.2008;Wagner et al.2009).Among the most acknowledged

molecular mechanisms for the cellular effects of H 2S is the regu-lation of intracellular redox homeostasis (Gadalla and Snyder 2008;Kabil and Banerjee 2010).

Maintenance of normal intracellular redox status plays an im-portant role in regulating DNA synthesis,gene expression,enzy-matic activity,etc.(Sen 1998;Benoit and Auer 2011).It is evident that the intimate balance between oxidative and reductive mole-cules determines the alterations in cellular signal transduction and functions (Oktyabrsky and Smirnova 2007).Reactive oxygen species (ROS),including the superoxide anion,hydroxyl radical,hydrogen peroxide,peroxynitrite,and others,are either of exog-enous or endogenous origin (Arrigo 1999).Generation of ROS in-volves lysosomes,NADPH oxidases,5-lipoxygenase,xanthine oxidase,and cytochrome P450(Sen 1998).One of the main sources of ROS in many cell types is the mitochondrion.A low physiolog-ical concentration of ROS is bene?cial to various processes such as the immune response,cell–cell interaction,in?ammation,metab-olism,and cell growth.High levels of oxidative stress results in oxidative damage to DNA,lipids,and proteins.The presence of an antioxidant defense system maintains intracellular concentra-

Received 20August 2012.Accepted 19September 2012.

Abbreviations:CBS,cystathionine beta-synthase;COX,cytochrome|c oxidase;CSE,cystathionine gamma-lyase;EE,ethylmalonic encephalopathy;H 2S,hydrogen sul?de;IR,ischemia–reperfusion;MDA,malondialdehyde;NaHS,sodium hydrosul?de;NO,nitric oxide;PPG,DL-propargylglycine;ROS,reactive oxygen species;SMCs,smooth msucle cells;SOD,superoxidase dismutase.

Y.Ju and G.Yang.The School of Kinesiology,Lakehead University,955Oliver Road,Thunder Bay,ON P7B 5E1,Canada.W.Zhang.Department of Pathophysiology,Harbin Medical University,Harbin,China.Y.Pei.College of Life Science,Shanxi University,Taiyuan,China.Corresponding author:G.Yang (e-mail:gyang@lakeheadu.ca ).

1This Invited Review is one of a selection of papers published in the Special Issue on the 7th Canadian Oxidative Stress Consortium

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tions of oxidative stress at a safe level (Benoit and Auer 2011).H 2S has been shown to regulate cellular functions via redox regu-lation;however,the exact role of H 2S in redox regulation is controversial,since both anti-and pro-oxidant effects have been documented (Kabil and Banerjee 2010;Yang 2011).In this review,we present a comprehensive discussion of the relation-ship between H 2S and intracellular redox homeostasis,and the underlying mechanisms of H 2S signaling in redox regulation,including direct interaction with oxidative molecules,redox-dependent S -sulfhydration regulation of proteins,and glutathione generation.

Antioxidant roles of H 2S in the cardiovascular system

H 2S has been widely proposed to protect the cardiovascular system through its antioxidant role (Table 1).The robust antioxi-dant actions of H 2S are associated with direct scavenging of ROS and (or)increased expression and functions of antioxidant en-zymes.It is well known that H 2S mediates cardiac protection through the activation of Akt and MAPK (ERK1/2and p38)path-ways,upregulation and phosphorylation of vascular endothelial growth factor,and opening the ATP-sensitive potassium channel (Papapetropoulos et al.2009;Calvert et al.2010;Yang et al.2012;Pan et al.2012).More importantly,H 2S hinders ROS production and reduces oxidative stress,which greatly contributes to cardiac protection (Table 1).

In the vascular cells and tissues,H 2S has been reported to re-duce oxidative stress by upregulating superoxidase dismutase (SOD),increasing thiol levels,and decreasing the production of ROS.SOD is one of the key enzymes that provide the ?rst line of defense against pro-oxidants,and catalyses the transformation of superoxide radicals to H 2O 2and superoxide.Sun et al.(2012)found that H 2S inhibits mitochondrial complex IV activity and increases the activities of Mn-SOD and CuZn-SOD,and decreases the levels of ROS in cardiomyocytes during ischemia–reperfusion.NaHS treatment (30and 90?mol·(kg body mass)–1·day –1)signif-

icantly increases the concentration of thiol groups in the myo-cardium,and decreases ROS production in spontaneously hypertensive rats (Shi et al.2007).Homocysteine,a sulfhydryl-containing amino acid,is an independent and graded risk factor for atherosclerosis,and H 2S has been shown to attenuate homocysteine-mediated oxidative stress and cellular damage.In vascular smooth muscle cells,low levels of NaHS (30–50?mol·L –1)reduce homocysteine-induced cytotoxicity and oxidative stress (Yan et al.2006).H 2S also protects against vascular remodeling as a result of endothelial damage,through normalizing the levels of redox stress,matrix metalloproteinase,and tissue inhibitor of metalloproteinase.H 2S decreases oxidative stress in carotid arter-ies through the decrease of the p47NADPH oxidase subunit,which is involved in the stimulation of oxidative stress via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B)pathway (Vacek et al.2010).In another study,exogenous H 2S was found to inhibit superoxide formation by decreasing the active form of Ras-related C3botulinum toxin substrate 1(Rac1)in human vascular smooth muscle cells (Muzaffar et al.2008).

H 2S also protects vascular cells from oxidative damage induced by peroxynitrite and HOCl (Whiteman et al.2004;Laggner et al.2007).H 2S directly destroys organic hydroperoxides of pathobio-logical importance,like fatty acid hydroperoxides (LOOHs).There-fore,H 2S abrogates the pathological activity of oxLDL via destroying LOOHs in oxLDL;probably a direct reduction reaction (Geng et al.2004;Muellner et al.2009).The destruction of LOOHs by H 2S can decrease the atherogenic potential of oxLDL and pre-vent the protein modi?cation of aldehydes such as malondialde-hyde (MDA).Within the cells,H 2S dissociates to yield hydrosul?de anion (HS –),which is a powerful one-electron chemical reductant capable of quenching free radicals by hydrogen atom transfer.Under speci?c conditions,H 2S can readily scavenge ROS and reac-tive nitrogen species,including hypochlorous acid,H 2O 2,lipid hydroperoxides,superoxide,and peroxynitrite.Since H 2S acts an antioxidant both directly and indirectly,many papers have re-ported that H 2S treatment combined with other agents,such as

Table 1.Antioxidant effects of H 2S in the cardiovascular and nervous systems.Cell type or animal model Treatment (conc.)Mechanisms

Reference

Cardiovascular system Cardiomyocytes

NaHS (25?50?mol·L –1)

Reduced ROS levels,direct interaction with CuZn-SOD and increased SOD activity,increased thiol group

Liu et al.2011;Shi et al.2007;Sun et al.2012Carotid arteries NaHS (30?mol·L –1)Increased SOD activity and reduced p47level

Vacek et al.2010

Smooth muscle cells NaHS (10–50?mol·L –1)Inhibited superoxide generation and NOX-1expression

Muzaffar et al.2008;Yan et al.2006

Endothelial cells NaHS (0.1–1.0mmol·L –1)Decreased lipid peroxidation Muellner et al.2009Heart

NaHS (30?mol·L –1)Reduced ROS levels Mishra et al.2010

Nervous system PC12cells NaHS (0.2?0.8mmol·L –1)Inhibited ROS generation

Lan et al.2011,Tang et al.2008,Yin et al.2009

SH-SY5Y cells

NaHS (0.03?0.25mmol·L –1)

Inhibited protein oxidation and lipid peroxidation,scavenged endogenous peroxynitrite

Schreier et al.2010,Whiteman et al.2004,2005Brain NaHS (0.1?0.5mmol·L –1)Decreased COX expression

Di Meo et al.2011

Cortex NaHS (0.1mmol·L –1)

Increased GSH,enhanced activity of

gamma-glutamylcysteine synthetase,and up-regulated cystine transport Kimura and Kimura 2004

RGC-5cells

ACS14(20?mol·L –1)Reduce ROS level and stimulate GSH production

Osborne et al.2012Brain endothelial cells NaHS (50?250?mol·L –1)Decreased ROS production and NOX-4expression,and up-regulated Trx

Tyagi et al.2009Hippocampus

NaHS (10?mol·L –1·kg –1)

Increased GSH levels,enhanced SOD,GSH-Px,and CAT activity

Jiang et al.2011

Note:ROS,reactive oxygen species;SOD,superoxide dismutase;p47,NADPH oxidase subunit p47;NOX,NADPH-oxidase;COX,cytochrome c oxidase;GSH-Px,glutathione peroxidase;Trx,thioredoxin;CAT,catalase.

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N -acetyl cysteine,glutathione,L -NAME,and (or)vitamin C,syner-gistically induces antioxidant effects and protects vascular cells from oxidative damage and cytotoxicity (Yan et al.2006).

Antioxidant roles of H 2S in the nervous system

In the mammalian central nervous system,H 2S is predominantly produced by CBS and acts as a neuromodulator (Abe and Kimura 1996;Qu et al.2006).Currently,there is a broad interest in how the neuroprotection provided by H 2S affects brain function both dur-ing development and after the onset of central nervous system disorders.It is generally recognized that H 2S may protect the cells in the central nervous system from apoptosis or degeneration following brain injury,or as a result of chronic neurodegenerative diseases,through regulation of oxidative stress (Table 1).

H 2S inhibits hypochlorous acid-induced cytotoxicity,intracellu-lar protein oxidation,and lipid peroxidation in a human-derived dopaminergic neuroblastoma cell line (SH-SY5Y)(Whiteman et al.2005).H 2S also protects PC12cells,a rat cell line derived from pheochromocytoma cells,against amyloid beta (25–35)and 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity and apopto-sis by reducing the loss of mitochondrial membrane potential and attenuating the increase of intracellular ROS (Tang et al.2008;Yin et al.2009).In another study,chronic exposure to sul?de causes accelerated degradation of cytochrome c oxidase (COX)in eth-ylmalonic encephalopathy (EE)(Di Meo et al.2011).EE is an auto-somal,recessive,fatal disorder,associated with mutations in ETHE1,a gene encoding a mitochondrial sulfur dioxygenase.Ac-cumulated sul?de in EE causes COX de?ciency and accelerates long-term degradation of COX subunits (Di Meo et al.2011),sug-gesting that H 2S may reduce ROS generation in damaged neurons via the modulation of COX.The endogenous H 2S derived from a mitochondrial H 2S-producing enzyme,3-mercaptopyruvate sul-furtransferase along with cysteine aminotransferase,was shown to reduce oxidative stress in Neuro2a cells (Kimura et al.2010).Peroxynitrite,an important mediator in brain function and dis-ease,induces cytotoxicity,intracellular protein nitration,and protein oxidation.Peroxynitrite-induced cell damage is inhibited by H 2S in SH-SY5Y cells (Whiteman et al.2004).Similar to per-oxynitrite,highly reactive alpha,beta-unsaturated aldehydes in-cluding 4-hydroxy-2-nonenal (4-HNE),induces cytotoxicity and protein modi?cation causing the inactivation of proteins.H 2S counteracts the protein modifying and cytotoxic activity of 4-HNE by directly combining 24-HNE molecules together via an S-bond at carbon 3in SH-SY5Y cells (Whiteman et al.2004;Schreier et al.2010).

In addition,H 2S ameliorates oxidative stress and apoptosis via the regulation of proteins and kinases (Tyagi et al.2009;Jiang

et al.2011;Lan et al.2011).Pretreatment of PC12cells with NaHS inhibits cobalt chloride (CoCl 2)-induced ROS production through the phosphorylation of ERK1/2and p38MAPK (Lan et al.2011).Methionine increases NADPH-oxidase-4(NOX-4)and reduces thioredoxin-1(Trx-1)expression,all of which contribute to the generation of ROS and peroxynitrite in mouse brain endothelial cells (bEnd3)(Tyagi et al.2009).H 2S enhances the activity of apo-cynin,N -acetyl-L -cysteine,glutathione,catalase,SOD,and L -NAME to inhibit ROS production in bEnd3cells when incubated with methionine by activating NOX-4and Trx-1(Tyagi et al.2009).Ex-ogenous H 2S antagonizes apoptosis and oxidative stress induced by heroin through the decrease of cleaved caspase-3and Bax (Jiang et al.2011).All of the above suggests that H 2S may directly scav-enge ROS through interaction with ROS,or indirectly reduces oxidative stress by altering redox-related enzymes in neurons.Thus,H 2S-based neuroprotective therapies against neurodegen-erative diseases,such as Parkinson and Alzheimer,may have a promising future.

Antioxidant roles of H 2S in other systems

In the liver,H 2S ameliorates carbon tetrachloride (CCl 4)-induced acute toxicity by reducing cytochorome P450(CYP)2E1activity and lipid peroxidation,and increasing levels of hepatic glutathione (Table 2).The protective effects of H 2S on CCl 4-induced cytotoxicity are abolished by DL -proparglyglycine (PPG),an irreversible inhibitor of CSE (Tan et al.2011).In addition,H 2S decreases lipid peroxidation in hepatic ischemia–reperfusion (I/R)injury in mice through the increase of reduced/oxidized glutathione ratio and TrX-1expression (Jha et al.2008).I/R causes lipid peroxidation and cell death in the kidney.The activity of CSE is not altered in the kidney upon I/R,while CBS,another enzyme responsible for endogenous H 2S generation,is signi?cantly de-creased,suggesting a protective role of H 2S towards kidney func-tion (Xu et al.2009).As expected,the administration of exogenous H 2S offers a renal protective effect from I/R injury.Oxidative dam-age to eye lens proteins and glutathione depletion play a major role in the development of senile cataract.Interestingly,Sastre et al.(2005)found that age-related de?ciency in CSE activity in the eye lens is responsible for glutathione depletion,and that the inhibition of CSE activity by PPG also causes glutathione depletion in rat lenses.Actually,a de?ciency in CSE activity is,at least in part,responsible for glutathione depletion in several physiologi-cal and pathological conditions,such as fetal longevity,cancer,AIDS,and surgical stress (Wang 2012).In a rat model of intestinal I/R injury,NaHS induces the expression of SOD and glutathione peroxidase and reduces the levels of MDA,a marker of radical injury (Liu et al.2009).In diabetic rat testes,the administration of

Table 2.Antioxidant effects of H 2S in systems other than the cardiovascular and nervous systems.Cell type or animal model Treatment (conc.)Mechanisms

Reference

HT-29Glc –/+NaHS (1mmol·L –1)

Increased UCP2and decreased COX expression

Leschelle et al.2005

Intestine NaHS (7and 14?mol·L –1·kg –1)Increased SOD and GSH-Px activity Liu et al.2009

Lung NaHS (50?mol·L –1·kg –1)Increased SOD and GSH levels,and attenuated down-regulation of Nrf2

Han et al.2011;Wang et al.2011;Wei et al.2008HaCaT cells NaHS (0.1?0.8mmol·L –1)Decreased ROS levels and COX-2expression Yang et al.2011

Liver

NaHS (10?mol·kg –1),and Na 2S (1.0mg·kg –1)Decreased CYP2E1activity and lipid

peroxidation,and increased GSH levels and Trx-1expression

Jha et al.2008;Tan et al.2011

Kidney

NaHS (100?g·kg –1)Inhibited lipid peroxidation

Xu et al.2009MC3T3-E1osteoblastic cells NaHS (0.1mmol·L –1)Increased SOD,NADPH oxidase,and MAPK activity

Xu et al.2011Diabetic rat testes NaHS (14?mol·L –1·kg –1)Increased GSH levels Sadik et al.2011Rat lenses

CSE de?ciency

GSH depletion

Sastre et al.2005

Note:HT-29Glc,human colon adenocarcinoma cell line;UCP2;mitochondrial uncoupling protein 2;COX,cytochrome c oxidase;SOD,superoxide dismustase;GSH-Px,glutathione peroxidase;Nrf2,nuclear erythroid-related factor 2;HaCaT,human skin keratinocytes;CYP2E1,cytochrome P4502E1;Trx-1,Trx,thioredoxin 1;CSE,cystathionine gamma-lyase.

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sulfurous mineral water and NaHS ameliorates the level of testic-ular glutathione by blocking apoptosis-related regulatory pro-teins such as Bax/Bcl-2,cytochrome c ,caspase-9and -3,and p53(Sadik et al.2011).

The level of H 2S in lung tissue is signi?cantly lower in the ani-mal model of oleic-acid-induced acute lung injury.Administration of NaHS induces SOD and glutathione in plasma and lung tissues,and decreases MDA levels (Wang et al.2011).Treatment with NaHS protects the lungs from tobacco-smoke-induced emphysema in mice by increasing the activity of Akt and nuclear erythroid-related factor 2(Nrf2)(Han et al.2011).Another study has shown that H 2S acts as an antioxidant,protecting cells via increased total antioxidant capacity and decreased oxidized glutathione content in hypoxic pulmonary hypertensive rats (Wei et al.2008).

CoCl 2-induced cytotoxicity and in?ammation in human skin keratinocytes (HaCaT cells)were suppressed by H 2S via inhibition of the ROS–NF-?B–COX-2pathway (Yang et al.2011).Oxidative damage is an important contributor to the morphological and functional changes in the development of osteoporosis.H 2S pro-tects MC3T3-E1osteoblastic cells against H 2O 2-induced oxidative damage via the increase of SOD activity and the decrease of ROS generation and NOX activity (Xu et al.2011).

H 2S-mediated glutathione production

Glutathione is well known for its antioxidant role in regulating intracellular redox status.It has been reported that H 2S protects neurons against glutamate-mediated oxidative stress and oxytosis through the increased generation of glutathione (Kimura and Kimura 2004).H 2S may enhance glutathione generation via the activity of gamma-glutamylcysteine synthetase/glutamate anti-porter X c–.In addition,a H 2S-releasing derivative of aspirin (ACS14)reduces glutamate-mediated oxidative stress with the stimulation of glutathione production (Osborne et al.2012).Sev-eral possibilities are proposed to contribute to the H 2S-induced glutathione level.Firstly,H 2S enhances cellular glutamate uptake and induces cystine transporter activity,and both glutamate and cysteine are the substrates for generating glutathione (Kimura and Kimura 2004).Secondly,H 2S stimulates the expression of nu-clear transcription factor Nrf2,which in turn induces the expression of glutathione-generating genes and increases glutathione synthesis and transport (Calvert et al.2010;Han et al.2011).As a signi?cant antioxidant transcription factor,Nrf2has been shown to control the expression of more than 100genes,including those for the most important antioxidant enzymes.Thirdly,H 2S also decreases the activity of glutathione-catabolizing enzymes,which will maintain the normal level of intracellular glutathione (Wang 2012).

Pro-oxidant role of H 2S

Different from its antioxidant effects,the pro-oxidant roles of H 2S have also been reported (Table 3).In isolated hepatocytes,H 2S induces ROS formation and causes cell death (Eghbal et al.2004;

Caro et al.2011).ROS formation induced by H 2S is decreased by the CYP450inhibitors cimetidine and benzylimidazole,pointing to the critical role of CYP450in H 2S-stimulated ROS formation.In another study,NaHS treatment induces glutathione depletion in isolated hepatocytes,which was prevented by several ferric chela-tors (desferoxamine and DETAPAC)and antioxidant enzymes (SOD and catalase)(Truong et al.2006).H 2S also attenuates cata-lase activity through its heme binding (Nicholls 1961).In non-transformed intestinal epithelial cells (IEC-18),H 2S suppresses mitochondrial respiratory activity and reduces the intracellular redox environment (Deplancke and Gaskins 2003).H 2S induces genomic DNA damage in Chinese hamster ovary and HT29-Cl.16E cells (Attene-Ramos et al.2006,2007,2010)via increased oxidative stress.It is now worth noting that the effects of H 2S may not always be bene?cial.

The antioxidant/pro-oxidant balance of H 2S is affected by many factors,including cell types,concentrations,administration pro-tocol,oxygen and iron level,type of H 2S donors,etc.Under certain circumstances or in speci?c cellular environment,H 2S may boost ROS generation and inhibit physiological cellular functions.

S -Sulfhydration and protein modi?cation

Since the discovery of endogenously-produced H 2S in various tissues,there has been an explosion of interest in H 2S as a biolog-ical mediator.The relatively low concentration and the consider-ably smaller size of H 2S in comparison with other low molecular weight thiols,are unlikely to afford it a quantitatively signi?cant role in cellular antioxidant function via direct interaction with ROS (Wang 2012).One of the signaling mechanisms of H 2S is through the S -sulfhydration of cysteine residues on proteins,yielding a hydropersul?de moiety (–SSH)(Mustafa et al.2009a )(Fig.1).S -Sulfhydration is now regarded as a new and important redox signaling mechanism in the regulation of different cellular and physiological functions by the post-translational modi?ca-tion of proteins (Mustafa et al.2009b ;Gadalla and Snyder 2010).S -Sulfhydration is not to be confused with S -thiolation or S -thionylation,in which a protein thiol forms a mixed disul?de with a small-molecular-weight thiol such as glutathione or cys-teine (Hurd et al.2005).The importance of S -sulfhydration is indi-cated by the large proportion of S -sulfhydrated proteins,and about 10%–25%of some major liver proteins including actin,?-tubulin,and glyceraldehyde-3-phosphate dehydrogenase are S -sulfhydrated (Mustafa et al.2009a ).The K ATP channel is a direct target for H 2S in the regulation of vasodilation and cardiopro-tection (Fig.2).In fact,H 2S S -sulfhydrates the Kir6.1subunit of K ATP channels,and dithiothreitol (DTT)reverses H 2S-mediated K ATP S -sulfhydration (Mustafa et al.2011).DTT is a strong reducing agent and can easily break the disul?de bond.H 2S also has been shown to S -sulfhydrate p65at cysteine-38and mediate the anti-apoptotic effect of NF-?B (Sen et al.2012).H 2S-induced S -sulfhydration of the phosphatase PTP1B alters endoplasmic reticulum stress response (Krishnan et al.2011).It was recently reported that H 2S modulates

Table 3.Pro-oxidant roles of H 2S.Cell type or animal model Treatment (conc.)Mechanisms

Reference

Primary hepatocytes

NaHS (0.2?0.5mmol·L –1)

Increased ROS formation,decreased mitochondrial membrane potential,and induced glutathione depletion Eghbal et al.2004;Truong et al.2006HepG2cells overexpressing CYP2E1

H 2S (0.1?0.5mmol·L –1)or CSE overexpression Increased ROS formation and depletion of ATP

Caro et al.2011

Human intestinal epithelial FHs 74int cells

Na 2S (0.1?2.5mmol·L –1)Up-regulated COX-2expression and increased DNA damage

Attene-Ramos et al.2010Rat intestinal crypt IEC-18cells NaHS (0.05?5.0mmol·L –1)Decreased cellular redox environment Deplancke and Gaskins 2003HT29.Cl0.16E cells

Na 2S (0.25?3.0mmol·L –1)

Increased DNA damage and decreased DNA repair

Attene-Ramos et al.2006,2007

Note:ROS,reactive oxygen species;HepG2,liver hepatocellular;COX-2,cytochrome c oxidase 2;DNA,deoxyribonucleic acid;HT29.C10.16E,human colonic epithelial goblet cell line.

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lecular by a vicinal forming a disul?de,antioxidant enzymes like thioredoxin.SH/SS ex-thought most likely mechanism ;Mustafa et al.2011;Pred-S -nitrosylation is well enzymatic regulation of et al.2010).At least 6to be involved in the form-?-glutamyl transpeptidase,oxidase,Wouters et al.2011;Wu regulation of H 2S and many functions and remain unclear.However,of S -sulfhydration,since many properties.Based by Marino and Gladyshev of S -nitrosylation pos-than the p K a of all cysteine of the charged residues a positive charge.These residue of proteins Even so,many questions need any other sub-under different condi-research is required and pathological implica-protein modi?cation.

enzymes and the reactivity of H 2S in unique among the regula-knowledge about antiox-steadily increasing,we are as to how,why,when,and protected by H 2S through in the ?eld of H 2S sig-function is how speci?city implications of H 2S-be investigated more in-Fig.1.Post-translational modi?cation of proteins by S -nitrosyaltion and S -sulfhydration.S -Nitrosylation is the transfer of a nitric oxide (NO)group to cysteine sulfhydryls on proteins,and S -sulfhydration is the transfer of a sulfhydryl group to cysteine sulfhydryls on proteins.

NO

Protein

Cysteine

H 2S

nNOS

iNOS

CBS

eNOS

HS

-38

Anti-apoptosis Anti-ER stress

c y s t e i n e cysteine-150p p

cysteine-215

cyste cysteine

150Enhance actin eine-43

Relax blood vessel

Enhance actin polymerization

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tensively,and the interactions of H 2S with numerous biological targets need to be widely explored.Owing to the importance of redox state in a wide range of physiological processes and dis-eases,better understanding the H 2S signaling in redox regulation may provide new opportunities for drug discovery platforms.

Con?icts of interest

The authors declare that there is no con?ict of interest associ-ated with this study.

Acknowledgements

This work was supported by a grant-in-aid from the Heart and Stroke Foundation of Canada.G.Y.was supported by a New Inves-tigator award from Heart and Stroke Foundation of Canada.

References

Abe,K.,and Kimura,H.1996.The possible role of hydrogen sul?de as an endog-enous neuromodulator.J.Neurosci.16(3):1066–1071.PMID:8558235.

Arrigo,A.P.1999.Gene expression and the thiol redox state.Free Radic.Biol.Med.27(9–10):936–944.doi:10.1016/S0891-5849(99)00175-6.PMID:10569626.Attene-Ramos,M.S.,Wagner,E.D.,Plewa,M.J.,and Gaskins,H.R.2006.Evidence that hydrogen sul?de is a genotoxic agent.Mol.Cancer.Res.4(1):9–14.doi:10.1158/1541-7786.MCR-05-0126.PMID:16446402.

Attene-Ramos,M.S.,Wagner,E.D.,Gaskins,H.R.,and Plewa,M.J.2007.Hydrogen sul?de induces direct radical-associated DNA damage.Mol.Cancer.Res.5(5):455–459.doi:10.1158/1541-7786.MCR-06-0439.PMID:17475672.

Attene-Ramos,M.S.,Nava,G.M.,Muellner,M.G.,Wagner,E.D.,Plewa,M.J.,and Gaskins,H.R.2010.DNA damage and toxicogenomic analyses of hydrogen sul?de in human intestinal epithelial FHs 74Int cells.Environ.Mol.Mutagen.51(4):304–314.doi:10.1002/em.20546.PMID:20120018.

Benoit,R.,and Auer,M.2011.A direct way of redox sensing.RNA Biol.8(1):18–23.doi:10.4161/rna.8.1.13555.PMID:21220941.

Calvert,J.W.,Elston,M.,Nicholson,C.K.,Gundewar,S.,Jha,S.,Elrod,J.W.,et al.2010.Genetic and pharmacologic hydrogen sul?de therapy attenuates ischemia-induced heart failure in mice.Circulation,122(1):11–19.doi:10.1161/CIRCULATIONAHA.109.920991.PMID:20566952.

Caro,A.A.,Thompson,S.,and Tackett,J.2011.Increased oxidative stress and cytotoxicity by hydrogen sul?de in HepG2cells overexpressing cytochrome P4502E1.Cell Biol.Toxicol.27(6):439–453.doi:10.1007/s10565-011-9198-2.PMID:21850523.

Deplancke, B.,and Gaskins,H.R.2003.Hydrogen sul?de induces serum-independent cell cycle entry in nontransformed rat intestinal epithelial cells.FASEB J.17(10):1310–1312.doi:10.1096/fj.02-0883fje .PMID:12738807.

Di Meo,I.,Fagiolari,G.,Prelle,A.,Viscomi,C.,Zeviani,M.,and Tiranti,V.2011.Chronic exposure to sul?de causes accelerated degradation of cytochrome|c oxidase in ethylmalonic encephalopathy.Antioxid.Redox.Signal.15(2):353–362.doi:10.1089/ars.2010.3520.PMID:20812865.

Dorman,D.C.,Moulin,F.J.,McManus,B.E.,Mahle,K.C.,James,R.A.,and Struve,M.F.2002.Cytochrome oxidase inhibition induced by acute hydrogen sul?de inhalation:correlation with tissue sul?de concentrations in the rat brain,liver,lung,and nasal epithelium.Toxicol.Sci.65(1):18–25.doi:10.1093/toxsci/65.1.18.PMID:11752681.

Eghbal,M.A.,Pennefather,P.S.,and O'Brien,P.J.2004.H 2S cytotoxicity mecha-nism involves reactive oxygen species formation and mitochondrial depo-larisation.Toxicology,203(1–3):69–76.doi:10.1016/j.tox.2004.05.020.PMID:15363583.

Erwin,P.A.,Mitchell,D.A.,Sartoretto,J.,Marletta,M.A.,and Michel,T.2006.Subcellular targeting and differential S -nitrosylation of endothelial nitric-oxide synthase.J.Biol.Chem.281(1):151–157.doi:10.1074/jbc.M510421200.PMID:16286475.

Forrester,M.T.,Foster,M.W.,Benhar,M.,and Stamler,J.S.2009.Detection of protein S -nitrosylation with the biotin-switch technique.Free Radic.Biol.Med.46(2):119–126.Review.doi:10.1016/j.freeradbiomed.2008.09.034.PMID:18977293.

Gadalla,M.M.,and Snyder,S.H.2010.Hydrogen sul?de as a gasotransmitter.J.Neurochem.113(1):14–26.doi:10.1111/j.1471-4159.2010.06580.x .PMID:20067586.

Geng,B.,Chang,L.,Pan,C.,Qi,Y.,Zhao,J.,Pang,Y.,et al.2004.Endogenous hydrogen sul?de regulation of myocardial injury induced by https://www.wendangku.net/doc/bd14105771.html,mun.318(3):756–763.doi:10.1016/j.bbrc.2004.04.094.PMID:15144903.

Han,W.,Dong,Z.,Dimitropoulou,C.,and Su,Y.2011.Hydrogen sul?de amelio-rates tobacco smoke-induced oxidative stress and emphysema in mice.Anti-oxid.Redox Signal.15(8):2121–2134.doi:10.1089/ars.2010.3821.PMID:21504365.

Hurd,T.R.,Costa,N.J.,Dahm,C.C.,Beer,S.M.,Brown,S.E.,Filipovska,A.,et al.2005.Glutathionylation of mitochondrial proteins.Antioxid.Redox Signal.7(7–8):999–1010.doi:10.1089/ars.2005.7.999.PMID:15998254.

Jha,S.,Calvert,J.W.,Duranski,M.R.,Ramachandran,A.,and Lefer,D.J.2008.

Hydrogen sul?de attenuates hepatic ischemia-reperfusion injury:role of an-tioxidant and antiapoptotic signaling.Am.J.Physiol.Heart Circ.Physiol.295(2):H801–H806.doi:10.1152/ajpheart.00377.2008.PMID:18567706.

Jiang,L.H.,Luo,X.,He,W.,Huang,X.X.,and Cheng,T.T.2011.Effects of exoge-nous hydrogen sul?de on apoptosis proteins and oxidative stress in the hippocampus of rats undergoing heroin withdrawal.Arch.Pharm.Res.34(12):2155–2162.doi:10.1007/s12272-011-1220-y .PMID:22210043.

Kabil,O.,and Banerjee,R.2010.Redox biochemistry of hydrogen sul?de.J.Biol.Chem.285(29):21903–21907.doi:10.1074/jbc.R110.128363.PMID:20448039.Kimura,Y.,and Kimura,H.2004.Hydrogen sul?de protects neurons from oxi-dative stress.FASEB J.18(10):1165–1167.doi:10.1096/fj.04-1815fje .PMID:15155563.

Kimura,Y.,Goto,Y.,and Kimura,H.2010.Hydrogen sul?de increases glutathione production and suppresses oxidative stress in mitochondria.Antioxid.Redox Signal.12(1):1–13.doi:10.1089/ars.2008.2282.PMID:19852698.Krishnan,N.,Fu,C.,Pappin,D.J.,and Tonks,N.K.2011.H 2S-induced sulfhydra-tion of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response.Sci.Signal.4(203):ra86.doi:doi:10.1126/scisignal.2002329.PMID:22169477.

Laggner,H.,Muellner,M.K.,Schreier,S.,Sturm,B.,Hermann,M.,Exner,M.,et al.2007.Hydrogen sulphide:a novel physiological inhibitor of LDL athero-genic modi?cation by HOCl.Free Radic.Res.41(7):741–747.doi:10.1080/10715760701263265.PMID:17577734.

Lan,A.,Liao,X.,Mo,L.,Yang,C.,Yang,Z.,Wang,X.,et al 2011.Hydrogen sul?de protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2and p38MAPK signaling pathways in PC12cells.PLoS One,6(10):e25921.doi:doi:10.1371/journal.pone.0025921.PMID:21998720.

Leschelle,X.,Goubern,M.,Andriamihaja,M.,Blottiere,H.M.,Couplan,E.,Gonzalez-Barroso,M.D.,et al.2005.Adaptative metabolic response of human colonic epithelial cells to the adverse effects of the luminal compound sul-?de.Biochim.Biophys.Acta,1725(2):201–212.doi:10.1016/j.bbagen.2005.06.002.PMID:15996823.

Liu,H.,Bai,X.B.,Shi,S.,and Cao,Y.X.2009.Hydrogen sul?de protects from intestinal ischaemia–reperfusion injury in rats.J.Pharm.Pharmacol.61(2):207–212.doi:10.1211/jpp/61.02.0010.PMID:19178768.

Liu,J.,Hao,D.D.,Zhang,J.S.,and Zhu,Y.C.2011.Hydrogen sulphide inhibits cardiomyocyte hypertrophy by up-regulating https://www.wendangku.net/doc/bd14105771.html,mun.413(2):342–347.doi:10.1016/j.bbrc.2011.08.101.PMID:21893044.Malik,M.,Shukla,A.,Amin,P.,Niedelman,W.,Lee,J.,Jividen,K.,et al.2010.S -nitrosylation regulates nuclear translocation of chloride intracellular chan-nel protein CLIC4.J.Biol.Chem.285(31):23818–23828.doi:10.1074/jbc.M109.091611.PMID:20504765.

Marino,S.M.,and Gladyshev,V.N.2010.Structural analysis of cysteine S -nitrosylation:a modi?ed acid-based motif and the emerging role of trans-nitrosylation.J.Mol.Biol.395(4):844–859.doi:10.1016/j.jmb.2009.10.042.PMID:19854201.

Mishra,P.K.,Tyagi,N.,Sen,U.,Givvimani,S.,and Tyagi,S.C.2010.H 2S amelio-rates oxidative and proteolytic stresses and protects the heart against ad-verse remodeling in chronic heart failure.Am.J.Physiol.Heart Circ.Physiol.298(2):H451–H456.doi:10.1152/ajpheart.00682.2009.PMID:19933416.

Muellner,M.K.,Schreier,S.M.,Laggner,H.,Hermann,M.,Esterbauer,H.,Exner,M.,et al.2009.Hydrogen sul?de destroys lipid hydroperoxides in oxidized LDL.Biochem.J.420(2):277–281.doi:10.1042/BJ20082421.PMID:19265508.

Mustafa,A.K.,Gadalla,M.M.,Sen,N.,Kim,S.,Mu,W.,Gazi,S.K.,et al 2009a.H 2S signals through protein S-sulfhydration.Sci.Signal.2(96):ra72.doi:doi:10.1126/scisignal.2000464.PMID:19903941.

Mustafa,A.K.,Gadalla,M.M.,and Snyder,S.H.2009b.Signaling by gasotransmit-ters.Sci.Signal.2(68):re2.doi:doi:10.1126/scisignal.268re2.PMID:19401594.Mustafa,A.K.,Sikka,G.,Gazi,S.K.,Steppan,J.,Jung,S.M.,Bhunia,A.K.,et al.2011.Hydrogen sul?de as endothelium-derived hyperpolarizing factor sulf-hydrates potassium channels.Circ.Res.109(11):1259–1268.doi:10.1161/CIRCRESAHA.111.240242.PMID:21980127.

Muzaffar,S.,Shukla,N.,Bond,M.,Newby,A.C.,Angelini,G.D.,Sparatore,A.,et al.2008.Exogenous hydrogen sul?de inhibits superoxide formation,NOX-1expression and Rac1activity in human vascular smooth muscle cells.J.Vasc.Res.45(6):521–528.doi:10.1159/000129686.PMID:18463417.

Nicholls,P.1961.The formation and properties of sulphmyoglobin and sulph-catalase.Biochem.J.81:374–383.PMID:14479446.

Nishida,M.,Sawa,T.,Kitajima,N.,Ono,K.,Inoue,H.,Ihara,H.,et al 2012.Hydrogen sul?de anion regulates redox signaling via electrophile sulfhydra-tion.Nat Chem Biol.In press.doi:doi:10.1038/nchembio.1018.PMID:22772154.Oktyabrsky,O.N.,and Smirnova,G.V.2007.Redox regulation of cellular func-tions.Biochemistry (Mosc.),72(2):132–145.doi:10.1134/S0006297907020022.PMID:17367290.

Osborne,N.N.,Ji,D.,Majid,A.S.,Del Soldata,P.,and Sparatore,A.2012.Gluta-mate oxidative injury to RGC-5cells in culture is necrostatin sensitive and blunted by a hydrogen sul?de (H 2S)-releasing derivative of aspirin (ACS14).Neurochem.Int.60(4):365–378.doi:10.1016/j.neuint.2012.01.015.PMID:22306773.

Pan,L.L.,Liu,X.H.,Gong,Q.H.,Yang,H.B.,and Zhu,Y.Z.2012.Role of cystathionine gamma-lyase/hydrogen sul?de pathway in cardiovascular dis-Ju et al.13

C a n . J . P h y s i o l . P h a r m a c o l .

D o w n l o a d e d f r o m w w w .n r c r e s e a r c h p r e s s .c o m b y S h a n g h a i J i a o T o n g U n i v e r s i t y o n 07/20/13F o r p e r s o n a l u s e o n l y .

ease:a novel therapeutic strategy?Antioxid.Redox Signal.17(1):106–118.doi:10.1089/ars.2011.4349.PMID:22017202.

Papapetropoulos,A.,Pyriochou,A.,Altaany,Z.,Yang,G.,Marazioti,A.,Zhou,Z.,et al.2009.Hydrogen sul?de is an endogenous stimulator of angiogenesis.Proc.Natl.Acad.Sci.U.S.A.106(51):21972–21977.doi:10.1073/pnas.0908047106.PMID:19955410.

Predmore,B.L.,Lefer,D.J.,and Gojon,G.2012.Hydrogen sul?de in biochemistry and medicine.Antioxid.Redox Signal.17(1):119–140.doi:10.1089/ars.2012.4612.PMID:22432697.

Qu,K.,Chen,C.P.,Halliwell,B.,Moore,P.K.,and Wong,P.T.2006.Hydrogen sul?de is a mediator of cerebral ischemic damage.Stroke,37(3):889–893.doi:10.1161/01.STR.0000204184.34946.41.PMID:16439695.

Sadik,N.A.,El-Seweidy,M.M.,and Shaker,O.G.2011.The antiapoptotic effects of sulphurous mineral water and sodium hydrosulphide on diabetic rat testes.Cell.Physiol.Biochem.28(5):887–898.doi:10.1159/000335803.PMID:22178941.

Sastre,J.,Martin,J.A.,Gomez-Cabrera,M.C.,Pereda,J.,Borras,C.,Pallardo,F.V.,et al.2005.Age-associated oxidative damage leads to absence of gamma-cystathionase in over 50%of rat lenses:relevance in cataractogen-esis.Free Radic.Biol.Med.38(5):575–582.doi:10.1016/j.freeradbiomed.2004.11.029.PMID:15683713.

Schreier,S.M.,Muellner,M.K.,Steinkellner,H.,Hermann,M.,Esterbauer,H.,Exner,M.,et al 2010.Hydrogen sul?de scavenges the cytotoxic lipid oxida-tion product 4-HNE.Neurotox Res.17(3):249256.doi:doi:10.1007/s12640-009-9099-9.PMID:19680736.

Sen,C.K.1998.Redox signaling and the emerging therapeutic potential of thiol antioxidants.Biochem.Pharmacol.55(11):1747–1758.doi:10.1016/S0006-2952(97)00672-2.PMID:9714292.

Sen,N.,Paul,B.D.,Gadalla,M.M.,Mustafa,A.K.,Sen,T.,Xu,R.,et al.2012.Hydrogen sul?de-linked sulfhydration of NF-kappaB mediates its antiapop-totic actions.Mol.Cell,45(1):13–24.doi:10.1016/j.molcel.2011.10.021.PMID:22244329.

Shi,Y.X.,Chen,Y.,Zhu,Y.Z.,Huang,G.Y.,Moore,P.K.,Huang,S.H.,et al.2007.Chronic sodium hydrosul?de treatment decreases medial thickening of in-tramyocardial coronary arterioles,interstitial ?brosis,and ROS production in spontaneously hypertensive rats.Am.J.Physiol.Heart Circ.Physiol.293(4):H2093–H2100.doi:10.1152/ajpheart.00088.2007.PMID:17630351.

Sun,W.H.,Liu,F.,Chen,Y.,and Zhu,Y.C.2012.Hydrogen sul?de decreases the levels of ROS by inhibiting mitochondrial complex IV and increasing SOD activities in cardiomyocytes under ischemia/https://www.wendangku.net/doc/bd14105771.html,mun.421(2):164–169.doi:10.1016/j.bbrc.2012.03.121.PMID:22503984.

Tan,G.,Pan,S.,Li,J.,Dong,X.,Kang,K.,Zhao,M.,et al 2011.Hydrogen sul?de attenuates carbon tetrachloride-induced hepatotoxicity,liver cirrhosis and portal hypertension in rats.PLoS One,6(10):e259431.doi:doi:10.1371/journal.pone.0025943.PMID:22022478.

Tang,X.Q.,Yang,C.T.,Chen,J.,Yin,W.L.,Tian,S.W.,Hu,B.,et al.2008.Effect of hydrogen sulphide on beta-amyloid-induced damage in PC12cells.Clin.Exp.Pharmacol.Physiol.35(2):180–186.PMID:17892504.

Truong,D.H.,Eghbal,M.A.,Hindmarsh,W.,Roth,S.H.,and O'Brien,P.J.2006.Molecular mechanisms of hydrogen sul?de toxicity.Drug Metab.Rev.38(4):733–744.doi:10.1080/03602530600959607.PMID:17145698.

Tyagi,N.,Moshal,K.S.,Sen,U.,Vacek,T.P.,Kumar,M.,Hughes,W.M.,et al.2009.H 2S protects against methionine-induced oxidative stress in brain endothe-lial cells.Antioxid.Redox Signal.11(1):25–33.doi:10.1089/ars.2008.2073.PMID:18837652.

Vacek,T.P.,Gillespie,W.,Tyagi,N.,Vacek,J.C.,and Tyagi,S.C.2010.Hydrogen sul?de protects against vascular remodeling from endothelial damage.Amino Acids,39(5):1161–1169.doi:10.1007/s00726-010-0550-2.PMID:20352463.

Wagner,F.,Asfar,P.,Calzia,E.,Radermacher,P.,and Szabó,C.2009.Bench-to-bedside review:Hydrogen sul?de–the third gaseous transmitter:applica-tions for critical care.Crit Care,13:213.doi:10.1186/cc7700.PMID:19519960.

Wang,R.2003.Signal transduction and the gasotransmitters:NO,CO,and H 2S in biology and medicine.Human Press.Totowa,New Jersey.

Wang,C.,Wang,H.Y.,Liu,Z.W.,Fu,Y.,and Zhao,B.2011.Effect of endogenous hydrogen sul?de on oxidative stress in oleic acid-induced acute lung injury in rats.Chin.Med.J.(Engl.)124(21):3476–3480.PMID:22340161.

Wang,R.2002.Two's company,three's a crowd:can H 2S be the third endoge-nous gaseous transmitter?FASEB J.16(13):17921798.doi:doi:10.1096/fj.02-0211hyp .PMID:12409322.

Wang,R.2012.Physiological implications of hydrogen sul?de:a whiff explora-tion that blossomed.Physiol.Rev.92(2):791–896.doi:10.1152/physrev.00017.2011.PMID:22535897.

Wei,H.L.,Zhang,C.Y.,Jin,H.F.,Tang,C.S.,and Du,J.B.2008.Hydrogen sul?de regulates lung tissue-oxidized glutathione and total antioxidant capacity in hypoxic pulmonary hypertensive rats.Acta Pharmacol.Sin.29(6):670–679.doi:10.1111/j.1745-7254.2008.00796.x .PMID:18501113.

Whiteman,M.,Armstrong,J.S.,Chu,S.H.,Jia-Ling,S.,Wong,B.S.,Cheung,N.S.,et al 2004.The novel neuromodulator hydrogen sul?de:an endogenous per-oxynitrite ‘scavenger’?J.Neurochem.90(3):765768.doi:doi:10.1111/j.1471-4159.2004.02617.x .PMID:15255956.

Whiteman,M.,Cheung,N.S.,Zhu,Y.Z.,Chu,S.H.,Siau,J.L.,Wong,B.S.,Armstrong,J.S.,and Moore,P.K.2005.Hydrogen sulphide:a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain?https://www.wendangku.net/doc/bd14105771.html,mun.326(4):794–798.doi:10.1016/j.bbrc.2004.11.110.PMID:15607739.

Wouters,M.A.,Iismaa,S.,Fan,S.W.,and Haworth,N.L.2011.Thiol-based redox signalling:rust never sleeps.Int.J.Biochem.Cell Biol.43(8):1079–1085.doi:10.1016/j.biocel.2011.04.002.PMID:21513814.

Wu,C.,Parrott,A.M.,Fu,C.,Liu,T.,Marino,S.M.,Gladyshev,V.N.,et al.2011.Thioredoxin 1-mediated post-translational modi?cations:reduction,transni-trosylation,denitrosylation,and related proteomics methodologies.Antioxid.Redox Signal.15(9):2565–2604.doi:10.1089/ars.2010.3831.PMID:21453190.

Xu,Z.,Prathapasinghe,G.,Wu,N.,Hwang,S.Y.,Siow,Y.L.,and O,K.2009.Ischemia–reperfusion reduces cystathionine-beta-synthase-mediated hydrogen sul?de generation in the kidney.Am.J.Physiol.Renal Physiol.297(1):F27–F35.doi:10.1152/ajprenal.00096.2009.PMID:19439522.

Xu,Z.S.,Wang,X.Y.,Xiao,D.M.,Hu,L.F.,Lu,M.,Wu,Z.Y.,et al.2011.Hydrogen sul?de protects MC3T3-E1osteoblastic cells against H 2O 2-induced oxidative damage-implications for the treatment of osteoporosis.Free Radic.Biol.Med.50(10):1314–1323.doi:10.1016/j.freeradbiomed.2011.02.016.PMID:21354302.Yan,S.K.,Chang,T.,Wang,H.,Wu,L.,Wang,R.,and Meng,Q.H.2006.Effects of hydrogen sul?de on homocysteine-induced oxidative stress in vascular smooth muscle https://www.wendangku.net/doc/bd14105771.html,mun.351(2):485–491.doi:10.1016/j.bbrc.2006.10.058.PMID:17069760.

Yang,G.2011.Hydrogen sul?de in cell survival:a double-edged sword.Expert Rev.Clin.Pharmacol.4(1):33–47.doi:10.1586/ecp.10.131.PMID:22115347.

Yang,G.,Wu,L.,Jiang,B.,Yang,W.,Qi,J.,Cao,K.,et al.2008.H 2S as a physiologic vasorelaxant:hypertension in mice with deletion of cystathionine gamma-lyase.Science,322(5901):587–590.PMID:18948540.

Yang,G.,Zhao,K.,Ju,Y.,Mani,S.,Cao,Q.,Puukila,S.,Khaper,N.,WU,L.,and Wang,R.2012.Hydrogen sul?de protects against cellular senescence via S-sulfhydration of Keap1and activation of Nrf2.Antioxid &Redox Signal.2012Nov 23.[Epub ahead of print].PMID:23176571.

Yang,C.,Yang,Z.,Zhang,M.,Dong,Q.,Wang,X.,Lan,A.,et al 2011.Hydrogen sul?de protects against chemical hypoxia-induced cytotoxicity and in?am-mation in HaCaT cells through inhibition of ROS/NF-kappaB/COX-2pathway.PLoS One 6(7):e21971.doi:doi:10.1371/journal.pone.0021971.PMID:21779360.Yin,W.L.,He,J.Q.,Hu,B.,Jiang,Z.S.,and Tang,X.Q.2009.Hydrogen sul?de inhibits MPP(+)-induced apoptosis in PC12cells.Life Sci.85(7–8):269–275.doi:10.1016/j.lfs.2009.05.023.PMID:19540852.

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C a n . J . P h y s i o l . P h a r m a c o l .

D o w n l o a d e d f r o m w w w .n r c r e s e a r c h p r e s s .c o m b y S h a n g h a i J i a o T o n g U n i v e r s i t y o n 07/20/13F o r p e r s o n a l u s e o n l y .