Hydrogen sulfide in pharmacology and medicine – An update

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PHAREP 270 1–12 Pharmacological Reports xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep 1 2

Review article

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Hydrogen sulfide in pharmacology and medicine – An update

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Q1 Jerzy

Bełtowski

Department of Pathophysiology, Medical University, Lublin, Poland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 December 2014 Accepted 5 January 2015 Available online xxx

Hydrogen sulfide (H2S) is the endogenously produced gasotransmitter involved in the regulation of nervous system, cardiovascular functions, inflammatory response, gastrointestinal system and renal function. Together with nitric oxide and carbon monoxide, H2S belongs to a family of gasotransmitters. H2S is synthesized from L-cysteine and/or L-homocysteine by cystathionine b-synthase, cystathionine glyase and cysteine aminotransferase together with 3-mercaptopyruvate sulfurtransferase. Significant progress has been made in recent years in our understanding of H2S biochemistry, signaling mechanisms and physiological role. H2S-mediated signaling may be accounted for not only by the intact compound but also by its oxidized form, polysulfides. The most important signaling mechanisms include reaction with protein thiol groups to form persulfides (protein S-sulfhydration), reaction with nitric oxide and related species such as nitrosothiols to form thionitrous acid (HSNO), nitrosopersulfide (SSNO) and nitroxyl (HNO), as well as reaction with hemoproteins. H2S is enzymatically oxidized in mitochondria to thiosulfate and sulfate by specific enzymes, sulfide:quinone oxidoreductase, persulfide dioxygenase, rhodanese and sulfite oxidase. H2S donors have therapeutic potential for diseases such as arterial and pulmonary hypertension, atherosclerosis, ischemia–reperfusion injury, heart failure, peptic ulcer disease, acute and chronic inflammatory diseases, Parkinson’s and Alzheimer’s disease and erectile dysfunction. The group of currently available H2S donors includes inorganic sulfide salts, synthetic organic slow-releasing H2S donors, H2S-releasing non-steroidal antiinflammatory drugs, cysteine analogs, nucleoside phosphorothioates and plant-derived polysulfides contained in garlic. H2S is also regulated by many currently used drugs but the mechanism of these effects and their clinical implications are only started to be understood. ß 2015 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.

Keywords: Hydrogen sulfide Gasotransmitters Non-steroidal anti-inflammatory drugs Cardiovascular diseases Inflammation

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General properties of H2S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endogenous H2S synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H2S concentration in plasma and tissues . . . . . . . . . . . . . . . . . . . . . . . . . H2S metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of H2S signaling in the cells . . . . . . . . . . . . . . . . . . . . . . . . . Interaction with thiols – protein S-sulfhydration . . . . . . . . . . . . . Reaction with NO and related species and organic electrophiles . Interaction with hemoproteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . H2S as a target for pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sulfide salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Slow-releasing synthetic H2S donors . . . . . . . . . . . . . . . . . . . . . . . Synthetic cysteine derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . H2S-releasing derivatives of other drugs . . . . . . . . . . . . . . . . . . . . Garlic and other plant-derived products . . . . . . . . . . . . . . . . . . . .

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E-mail addresses: [email protected], [email protected]. http://dx.doi.org/10.1016/j.pharep.2015.01.005 1734-1140/ß 2015 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.

Please cite this article in press as: Bełtowski J. Hydrogen sulfide in pharmacology and medicine – An update. Pharmacol Rep (2015), http://dx.doi.org/10.1016/j.pharep.2015.01.005

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PHAREP 270 1–12 2

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J. Bełtowski / Pharmacological Reports xxx (2015) xxx–xxx

Effect of currently used drugs on H2S Other compounds . . . . . . . . . . . . . . . . Conclusions and future directions. . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

metabolism and signaling. ...................... ...................... ...................... ...................... ...................... ......................

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Introduction

32 Q2 It was first proposed by Abe and Kimura in 1996 that hydrogen 33 sulfide (H2S) is the endogenously generated neuromodulator 34 [1]. During almost two decades since their seminal paper was 35 published, a large body of data about H2S in biological systems has 36 been accumulated. Currently, there is little doubt that hydrogen 37 sulfide is the third ‘‘gasotransmitter’’ in addition to nitric oxide 38 (NO) and carbon monoxide (CO) [2–4]. In 2007 we published a 39 review article about H2S in pharmacology in this journal 40 [5]. Herein, I briefly review the progress made in the field since 41 that time. Because H2S literature is now very huge, I will not 42 comprehensively cover its effects in all experimental systems but 43 will focus on general aspects of H2S biochemistry and molecular 44 signaling mechanisms as well as its potential application in 45 pharmacotherapy. 46

General properties of H2S

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H2S is a colorless flammable gas with a strong odor of rotten eggs. It is easily soluble in both water and lipids. At physiological pH (7.4) less than 20% of H2S exists in the solution as the undissociated compound and the rest is dissociated to HS (hydrosulfide anion) and H+. Further dissociation of HS to sulfide anion (S2) occurs only at high pH and is insignificant at physiological conditions. Since both H2S and HS always coexist in aqueous solution, it is not possible to separate their effects and to conclude which of them is involved in signaling processes [6]. From the chemical point of view, H2S is the simplest thiol and as such is a reductant. It should be noted that pKa of H2S (6.8) is by 1–2 units lower than of most allylthiol species (R–SH) present in vivo such as glutathione (GSH) or protein cysteine thiols (CysSH); consequently, a greater portion of H2S exists in the dissociated form than of other thiols. Hydrosulfide anion (HS) is easily oxidized to hydrosulfide radical (HS) which is the oxidizing species [6]. It has been known for a long time that so called sulfane sulfur, that is sulfur atoms at zero oxidation step usually bound only to other sulfur atoms, exists in tissues [7,8]. One of the forms of sulfane sulfur are protein persulfide (perthiol, hydrodisulfide, Cys–SSH) and hydropolysulfide (CysSnH, n > 2) groups, glutathione persulfide (GSSH) or polysulfide (GSnH) as well as inorganic polysulfides (HSnH). Some recent studies suggest that these forms of sulfane sulfur may contribute to H2S signaling (see below) [9].

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Endogenous H2S synthesis

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Four enzymatic pathways of H2S production have been described so far. Two of them are catalyzed by cystathionine b-synthase (CBS) and cystathionine g-lyase (CSE) which are pyridoxal 50 -phosphate (vitamin B6)-dependent cytosolic enzymes of the transsulfuration pathway in which homocysteine is metabolized to cysteine. In the transsulfuration pathway L-homocysteine is condensed by CBS with L-serine to produce L-cystathionine and H2O. However, L-serine may be replaced in this reaction by L-cysteine with L-cystathionine and H2S being the

products (Table 1). Nevertheless, because L-cysteine is less abundant in the intracellular compartment than L-serine and Km of CBS for L-serine is lower than for L-cysteine, H2S production is less efficient than canonical transsulfuration reaction catalyzed by this enzyme [10]. CBS may also catalyze the alternative reactions between two cysteine and two homocysteine molecules to form H2S and lanthionine (two cysteine molecules connected by thioether –S– bond) or homolanthionine (two homocysteine molecules connected by the –S– bond), respectively [11]. CBS is a tetrameric protein; each subunit consist of N-terminal catalytic domain containing heme, substrate-, and PLP-binding sites, whereas C-terminal regulatory domain binds the positive allosteric regulator, S-adenosylmethionine. NO and CO reduce CBS activity by binding to its heme group which is the important mechanism of interplay between these gasotransmitters. In particular, CO binds to the CBS heme moiety with high affinity [12–14]. In the transsulfuration pathway, CSE breaks down L-cystathionine to L-cysteine, a-ketobutyrate and ammonia. Some of the reactions catalyzed by CBS in which H2S is produced are also shared by CSE, but the main mechanisms of H2S production by this enzyme seems to be b-elimination of L-cysteine or g-elimination of L-homocysteine to ammonia, H2S and pyruvate or a-ketobutyrate, respectively (Table 1) [15]. Because L-cysteine concentration exceeds that of L-homocysteine, cysteine desulfhydration is the main mechanism of H2S production by CSE under physiological conditions [16]. Importantly, increase in homocysteine concentration increases total H2S production by CSE and the contribution of homocysteine-involving reactions [15]. In contrast, CBS-catalyzed H2S production is not affected by homocysteine concentration. However, these relationships were mainly examined in the in vitro models. Although H2S has been demonstrated to ameliorate some of the negative effects of homocysteine, the impact of hyperhomocysteinemia on H2S production in vivo has not been studied so far. In general it is suggested that CBS is the main H2S synthase in the nervous system whereas CSE plays this role in most peripheral tissues except the liver and kidney which contain both enzymes in substantial amounts. The role of CBS may be underestimated in experiments in which only L-cysteine is used as the substrate because, to produce H2S, CBS requires both L-cysteine and L-homocysteine to be present simultaneously [11]. Recently, it has been demonstrated that both CBS and CSE can break down L-cystine (cysteine disulfide) to thiocysteine (CysSSH, cysteine persulfide), pyruvate and ammonia [17]. Through further exchange reactions between CysSSH and glutathione or protein cysteine thiols, the respective persulfide species (GSSH and protein-CysSSH) may be formed. It is suggested that this kind of sulfane sulfur may operate as the signaling species instead of H2S itself and that H2S may just be the marker of persulfide compounds released through their reaction with reductants [17]. However, because cytosolic L-cystine/L-cysteine ratio is normally very low, the contribution of this reaction to overall H2S/sulfane pool is unclear. Nevertheless, as L-cystine may be transported to the cell through cystine-glutamate antiporter, it can achieve significant concentrations at the vicinity of plasma membranes. In addition, L-cystine/L-cysteine ratio increases in oxidative stress-related

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PHAREP 270 1–12 J. Bełtowski / Pharmacological Reports xxx (2015) xxx–xxx Table 1 Enzymatic reactions relevant for H2S production. Substrates

Products

Enzyme(s)

L-Homocysteine + L-serine

L-Cystahionine + H2O

L-Homocysteine + L-cysteine

L-Cystahionine + H2S

L-Cysteine + L-cysteine

L-Lanthionine + H2S

L-Homocysteine +

L-Homolanthionine

CBS CBS, CSE CBS, CSE CBS, CSE

+H2S

L-homocysteine

a-ketobutyrate +

L-Cystathionine

L-Cysteine + NH4+

L-Cysteine

Pyruvate + H2S + NH4+ a-Ketobutyrate + H2S + NH4+ L-Thiocysteine + pyruvate + NH4+ 3-Mercaptopyruvate + a-ketoglutarate 3-Mercaptopyruvate + NH4+ Pyruvate + H2S

L-Homocysteine L-Cystine L-Cysteine + glutamate D-Cysteine

3-Mercaptopyruvate

CSE CSE CSE CBS, CSE CAT DAO 3-MST

138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168

conditions. It is unclear if CBS and CSE can also catalyze the analogous reaction using L-homocystine (L-homocysteine disulfide) as the substrate. The third pathway of H2S generation requires two enzymes, cysteine aminotransferase (CAT, aspartate aminotransferase) and 3-mercaptopyruvate sulfurtransferase (3-MST). In contrast to CBS and CSE, this pathway operates mainly in mitochondria. CAT catalyzes the transamination reaction between L-cysteine and aketoglutarate to produce 3-mercaptopyruvate and L-glutamate, whereas 3-MST in the presence of dithiol-containing reductants such as thioredoxin or dihydrolipoic acid, converts 3-mercaptopyruvate to pyruvate and H2S. In the absence of reductants, 3-MST synthesizes sulfane sulfur instead of H2S [18–21]. Finally, in the cerebellum and the kidney H2S may be synthesized from D-cysteine by the concerted action of Daminoacid oxidase (highly expressed in peroxisomes of these organs) and 3-MST. D-Aminoacid oxidase oxidizes D-cysteine to 3mercaptopyruvate which is the achiral metabolite and may be used by 3-MST as the substrate [22]. Although D-cysteine is not endogenously produced, it may be provided from food. This pathway has important implications for both H2S research and potential therapeutic applications. First, L-cysteine is often used in experimental studies to augment endogenous H2S production and then D-cysteine is frequently used as the negative control being not CBS, CSE or CAT substrate. Data discussed above indicate that Dcysteine is clearly not a suitable negative control for D-aminoacid oxidase-containing tissues [22]. In addition, D-cysteine could be useful to increase H2S production in the brain and kidney for therapeutic purposes. Indeed, at equimolar concentrations Dcysteine is much more efficient H2S substrate than L-cysteine in these organs [22].

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H2S concentration in plasma and tissues

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Early studies suggested that H2S is present in plasma and tissues at relatively high concentrations; values up to 50–60 mM have been reported in plasma and even >100 mM in the brain. However, it was the artifact resulting from using colorimetric methylene blue method which has multiple disadvantages [6]. This method measures not only free H2S/HS but also other sulfide pools in the sample including sulfane sulfur and acid-labile sulfur; the latter mostly includes iron–sulfur clusters in proteins [23]. However, both these bound sulfur pools are H2S storage forms from which the gasotransmitter may be released and, as stated previously, a subfraction of sulfane sulfur may even be directly synthesized by CBS and CSE. Thus, although high micromolar H2S values are clearly overestimated, relative differences in ‘‘H2S’’ concentrations between, for example, control and

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experimental groups may be of significant relevance for H2S signaling. The true free H2S concentration is low micromolar or even nanomolar [24].

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H2S metabolism

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H2S has been known for decades as one of the most important poisons in human toxicology. The main mechanism of its toxicity is inhibition of mitochondrial respiratory chain by binding to cytochrome c oxidase. Indeed, H2S is the second most potent inhibitor of this enzyme after cyanide [25]. However, one of the most exciting findings of the recent years in the H2S field was that it may also be enzymatically metabolized in mitochondria. H2S is the first and until now the only known inorganic substrate for mitochondrial respiratory chain which may provide energy for ATP generation [26–28]. First, H2S is oxidized by specific enzyme, sulfide:quinone oxidoreductase (SQR) [29], which transfers electrons to ubiquinone (coenzyme Q) from which they are further transported to cytochrome c by ubiquinol:cytochrome c oxidase (complex III) and finally to molecular oxygen by cytochrome c oxidase (complex IV) [30–32]. Thus, SQR is the third source of electrons for mitochondrial respiratory chain in addition to NADH dehydrogenase (complex I) and succinate dehydrogenase (complex II); two latter enzymes being involved in oxidation of organic substrates. SQR oxidizes H2S to sulfane sulfur incorporated into the enzyme itself to form persulfide –SSH group. This sulfane sulfur atom is then transferred to reduced glutathione to form glutathione persulfide (GSSH), and then may be either oxidized to sulfite (SO32) by sulfur dioxygenase (persulfide dioxygenase, protein deficient in ethylmalonic encephalopathy, ETHE1) or transferred to sulfite by thiosulfate:cyanide sulfurtransferase (TST, rhodanese) to form thiosulfate (SSO32) [31,33]. Sulfite is further oxidized to sulfate (SO42) by sulfite oxidase, whereas thiosulfate may be converted to H2S and sulfite by thiosulfate reductase (TR) using GSH as the reductant, or by 3-MST with thioredoxin and dihydrolipoic acid as the reductants (Table 2). Thiosulfate is considered the most specific marker of H2S metabolism. Although different tissues may convert H2S to thiosulfate and sulfate in different proportions, most of the sulfate is derived from H2S-independent sources such as cysteine oxidation by cysteine dioxygenase. The key H2S-metabolizing enzyme, SQR, is present in most tissues except the brain where the related enzyme called SQR-like protein (SQRLP) is expressed [34]. It is suggested that mitochondria of eukaryotic cells originate from ancient H2S-oxidizing bacteria living in sulfide-rich environments. Indeed, the ability to oxidize sulfide in common also nowadays in many microorganisms and invertebrates. In general, it is unlikely that H2S is a quantitatively significant energy substrate for the mammalian cells. H2S oxidation is associated with unfavorable ratio between the amount of electrons provided for respiratory chain and oxygen consumption because all steps of H2S oxidation beyond SQR do not provide electrons for the respiratory chain while spent a lot of O2 [35,36]. The exception may be epithelial cells of the colon where large amounts of H2S are produced by anaerobic bacteria; it is estimated that quantitatively

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Table 2 Enzymatic reactions involved in H2S metabolism. Substrates

Products

Enzyme(s)

H2S

SQR persulfide GSSH GSH + SO32 GSH + SSO32 SO32 + H2S SO42

SQR

GSSH GSSH + SO32 SSO32 GSH SO32

ETHE1 Rhodanese Thiosulfate reductase Sulfite oxidase

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J. Bełtowski / Pharmacological Reports xxx (2015) xxx–xxx

H2S may be the dominant energy substrate for colonocytes [37]. This microbiota-derived H2S is produced without any energetic costs for the host and does not require any transport mechanism or ‘‘biochemical preparation’’ before oxidation. Mitochondrial H2S oxidation plays an important role in H2S detoxification; again, it is especially vital for colonocytes exposed to high luminal sulfide concentration. It should be stressed that mitochondria can oxidize H2S only at low concentrations (in general less than 10 mM). Higher concentrations of H2S inhibit cytochrome c oxidase, similarly to other gasotransmitters such as CO and NO as well as cyanide. Addition of sulfide at low concentration to isolated mitochondria increases O2 consumption and ATP synthesis, whereas higher sulfide concentrations have the opposite effects. Deficiency of ETHE1 results in the rare autosomal recessive disorder, ethylmalonic encephalopathy, characterized by neuronal developmental delay, diffuse vascular damage and gastrointestinal dysfunction associated with high plasma and tissue H2S, sulfane sulfur and thiosulfate concentrations; most patients with this disorder die within the first decade of life [33,38,39]. The similar phenotype is observed in Ethe1 knockout mice further supporting the important role of mitochondrial H2S detoxification. Whereas ETHE1 deficiency results in toxicity of endogenous sulfide, more subtle changes in H2S oxidation regulate its tissue level and signaling [40]. The main factor which regulates the rate of H2S oxidation is oxygen concentration. It is suggested that H2S mediates many physiological effects of hypoxia such as vasodilation of systemic and vasoconstriction of pulmonary arteries. Effects of hypoxia on vascular tone are often mimicked by H2S donors and abolished by inhibitors of H2S synthesis. H2S may contribute to oxygen sensing in blood vessels, arterial chemoreceptors and central respiratory neurons [41–43]. Renal medulla is a highly hypoxic environment even under physiological conditions. This tissue is characterized by high energy expenditure accounted for by active sodium reabsorption and relatively poor oxygen supply. H2S concentration in the renal medulla is higher than in the renal cortex despite lower expression of H2S-synthesizing enzymes because mitochondrial H2S oxidation is slow. Renal medullary oxygen balance must be carefully regulated because any further decrease in pO2 results in damage of tubular cells. H2S may play an important role as the oxygen sensor in this tissue because it inhibits Na+ transport. Thus, hypoxia-induced increase in H2S inhibits Na+ reabsorption-dependent oxygen consumption and restores oxygen balance [44]. It is well-known that moderate transient hypoxia increases resistance of many tissues to subsequent more severe episodes of ischemia; the phenomenon referred to as ‘‘ischemic preconditioning’’. H2S exerts protective effects against ischemia–reperfusion injury similar to ischemic preconditioning and may even mediate preconditioning phenomenon in myocardium, kidney and liver [45]. Perivascular adipose tissue (PVAT produces H2S which dilates adjacent blood vessels by activating ATP-sensitive potassium channels in smooth muscle cells. Obesity, metabolic syndrome and arterial hypertension are associated with PVAT dysfunction. However, short-lasting obesity not associated with insulin resistance, increases anticontractile properties of adipose tissue by increasing H2S. This effect results from adipose tissue hypoxia which occurs in obesity due to enlargement of adipocytes and prolongation of oxygen diffusion pathway from blood vessels. Up-regulation of PVAT-derived H2S may be a protective mechanism which maintains vascular tone despite endothelial dysfunction [46–48]. Addition of H2S to isolated mitochondria or cells increases electron transport and ATP synthesis not only by directly entering the oxidation process. In addition, H2S stimulates mitochondrial oxidation of organic substrates in the cAMP-dependent manner. Indeed, H2S increases intramitochondrial cAMP concentration by

inactivating phosphodiesterase [49]. Significant intramitochondrial H2S production by the CAT/3-MST pathway suggests an important role of the gasotransmitter in this organelle [50].

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Mechanisms of H2S signaling in the cells

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Biological effects of H2S result from its interactions with three groups of targets: (1) thiols, (2) reactive oxygen and nitrogen species as well as oxidation products of macromolecules, (3) metals and metalloproteins. Below these three targets are briefly characterized.

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Interaction with thiols – protein S-sulfhydration

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It is widely accepted that he main molecular mechanism of H2S signaling is S-sulfhydration (or sulfuration) of protein cysteine residues; that is conversion of thiol (–SH) to persulfide (perthiol, hydrodisulfide –SSH) groups [51]. S-sulfhydration of many proteins including receptors, ion channels and enzymes have been described [51–62] (Table 3). Initially, it was suggested that Ssulfhydration always results in the increase in protein activity, however, inhibitory effect of sulfhydration was also demonstrated. H2S cannot directly sulfhydrate protein thiol groups; this reaction becomes possible after previous oxidation of either thiol group or H2S itself. Oxidation of protein thiols to disulfides or sulfenic acid (–SOH) is a common signaling mechanism of reactive oxygen species such as hydrogen peroxide, and protein cysteinesulfenate becomes a good substrate for H2S-mediated sulfhydration [63]. Alternatively, H2S is readily oxidized in biological systems to polysulfides (HSnH) containing 2–8 sulfur atoms, which may then sulfhydrate intact protein thiol groups. Polysulfides are also formed spontaneously in the solution containing NaHS commonly used as the H2S donor, and it is now increasingly appreciated that polysulfides rather than H2S itself are relevant signaling molecules [64,65]. S-sulfhydration-induced changes in protein activity result

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Table 3 Protein S-sulfhydration and its functional consequences. Protein

Effect on activity

Consequences

KATP channels

"

SKCa, IKCa channels

"

Voltage-sensitive K+ channel Kv4.3 VEGFR1 Parkin GAPDH Actin NF-kB Keap1 eNOS PKG PTP1B PTEN Phospholamban

#

Vasorelaxation Protection of myocardium from I/R Hyperpolarization of endothelial cells, vasorelaxation Contraction of gastric smooth muscle cells

MEK1

"

" " " " " # " " # # #

Angiogenesis Neuroprotection ? " action polymerization # apoptosis Activation of Nrf2 " NO production, vasorelaxation Vasorelaxation " PERK activity, # ER stress ? Inactiavtion of SERCA, decrease in myocardial relaxation PARP-1 activation, improved DNA repair

KATP – ATP-sensitive potassium channels, I/R – ischemia/reperfusion, SKCa – smallconductance calcium-activated K+ channels, IKCa – intermediate-conductance calcium-activated K+ channels, Kv – voltage-sensitive K+ channels, VEGFR1 – vascular endothelial growth factor receptor 1, GAPDH – glyceraldehydes 3phosphate dehydrogenase, Keap1 – Kelch-like ECH-associated protein 1, Nrf2 – NFE2 related factor 2, eNOS – endothelial NO synthase, PKG – protein kinase G, PTP1B – protein tyrosine phosphatase 1B, PERK – protein kinase-like endoplasmic reticulum kinase, PTEN – phosphatase and tensin homolog, SERCA – smooth endoplasmic reticulum Ca2+-ATPase, MEK1 – mitogen-activated protein kinase 1, PARP-1 – poly (ADP-ribose) polymerase 1.

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from the differences in chemical properties between thiol and persulfide groups. In particular, persulfide groups are generally more acidic than respective thiols (pKa lower by 1–2 units), and a larger fraction of them exist in dissociated form (perthiolate anion, R–SS). Both undissociated hydropersulfides (R–SSH) and perthiolate anions are also better reductants than the respective thiols or thiolate anions. Finally, hydropersulfide groups are better electrophiles than the respective thiols [63]. It is suggested that more complex protein hydropolysulfides (R–SnH) may also be generated but the role of this process in H2S-mediated signaling has not been characterized in more detail.

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Reaction with NO and related species and organic electrophiles

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Although H2S is the reductant and has been demonstrated to protect cells from detrimental effects of various reactive oxygen species, direct ROS scavenging does not play an important role in H2S signaling because its concentration is much lower than of other antioxidants such as glutathione. However, recent studies suggest that H2S may interact with nitric oxide and related species. Nitrosothiols (R–S–NO) originate as the result of reaction between NO and protein cysteine thiol groups. Protein Snitrosylation is the important signaling mechanism of NO, in addition, nitrosothiols are the storage form of NO from which it may be released. H2S reacts with free NO to form thionitrous acid (HSNO) which is the smallest nitrosothiol [66,67]. This reaction, associated with NO scavenging, has been suggested to be responsible for vasoconstricting effect of H2S at low concentrations observed in some experiments [68]. However, H2S may also react with protein or low molecular weight nitrosothiols such as S-nitroso-glutathione (GSNO) and restore thiol group or to release free NO thus potentiating its effects on soluble guanylate cyclase [69] or to form HSNO which is easily transported across plasma membranes and thus facilitates transnitrosation reactions again potentiating the NO signaling [66]. Another product of the reaction between nitrosothiols and H2S is nitrosopersulfide (SSNO), a very stable (T1/2 > 30 min) activator of soluble guanylate cyclase. SSNO decomposes to nitrosonium cation (NO+) and disulfide (S22); in this way NO catalyzes polysulfide formation from H2S with consecutive protein S-sulfhydration [70]. In the presence of excess H2S, HSNO may react with it forming hydrogen disulfide (H2S2) and nitroxyl (HNO); the reduced form of nitric oxide [71]. Nitroxyl has been suspected for a long time to be produced endogenously although this has not been definitely proven. HNO has very interesting pharmacological properties. Similarly to NO, it induces vasorelaxation by activating soluble guanylyl cyclase. However, in contrast to NO, it is resistant to degradation by ROS and does not induce tolerance after prolonged administration. In addition, HNO, in contrast to NO, increases myocardial contractility. During contraction of cardiomyocytes, HNO increases intracellular Ca2+ concentration by activating endoplasmic reticulum ryanodine receptor, however, HNO also facilitates relaxation by activating Ca2+-ATPaser [72]. This is a very beneficial property since most agents which increase intracellular Ca2+ during the contraction including b-adrenergic agonists do so also during the relaxation thus impairing diastolic function. In addition, HNO increases myocardial contractility by enhancing the sensitivity of contractile apparatus for Ca2+ [73]. Combined vasodilating, positive inotropic and lusitropic effects make HNO donors excellent drugs for the treatment of heart failure. Recently, it has been demonstrated that H2S increases HNO formation in cultured endothelial cells by interacting with NO and/or nitrosothiols, and that HNO induces vasorelaxation by activating transient receptor potential ankyrin 1 (TRPA1) channels in perivascular sensory nerves and stimulating release of calcitonin gene-related peptide (CGRP) [74].

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Nitrites (NO2) and nitrates (NO3) are stable NO metabolites and their measurement is often used as a marker of NO production. However, nitrites may also be reduced to NO under hypoxic conditions [75]. The reaction may be catalyzed by various proteins including xanthine oxidase, cytochrome c oxidase, deoxyhemoglobin, deoxymyoglobin, as well as nonenzymatically by protein thiol groups or metal centers. Spontaneous reaction of nitrites with H2S to form NO and/or HNO is very slow, however, this reactions proceeds efficiently in the presence of cultured cells [76]. Rapid disappearance of H2S and NO2 are observed in the presence of Jurkat cells with concomitant NO and HNO formation. The reaction is most likely catalyzed by iron–heme centers of mitochondrial respiratory chain enzymes [76]. Whether H2S-dependent mechanism contributes to endogenous synthesis of NO from nitrites, remains to be established. Nitric oxide overproduced by iNOS in nitrosative stress-related conditions reacts with cGMP to form 8-nitro-cGMP [77]. Biological activity of 8-nitro-cGMP is different than of its unnitrosated counterpart. For example, at low concentrations (<10 mM), 8-nitro-cGMP not only does not induce vasorelaxation but augments phenylephrine-induced vasoconstriction [78]. 8-NitrocGMP impairs dimerization of endothelial NO synthase and induces enzyme uncoupling leading to generation of O2 rather than NO. In addition, 8-nitro-cGMP reacts with protein thiol groups forming protein–cGMP adducts; the process referred to as protein S-guanylation. This irreversible posttranslational modification activates of Ras proteins involved in growth factor receptor signaling and contributes to the development of myocardial hypertrophy and dysfunction [79]. Under oxidative/nitrosative stress conditions, intracellular 8-nitro-cGMP concentration may be higher than of cGMP since the former is resistant to degradation by phosphodiesterases. H2S and polysulfides react with 8-nitro-cGMP to form 8-SH-cGMP thus preventing protein S-guanylation and other deleterious effects of 8-nitro-cGMP mediated signaling [80]. Apart from 8-nitro-cGMP, H2S sulfhydrates other electrophilic peroxidation products such as nitrated fatty acids or 4-hydroxynonenal, but the role of these reactions has not been studied in detail [80].

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Interaction with hemoproteins

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H2S easily reacts with transition metals;. in the biological systems the most prominent target being hemoproteins. Binding of H2S to cytochrome c oxidase in the main mechanism of its toxicity. In addition, H2S binds to hemoglobin and myoglobin forming sulfhemoglobin and sulfmyoglobin, respectively [81]. Although reaction between H2S and hemoproteins is mainly considered as the molecular basis of its toxicity, it may be also involved in some physiological/protective effects. Exposure of mice to low H2S concentration in the ambient air induced ‘‘hibernation-like’’ state characterized by hypometabolism, reduced body temperature, decrease in oxygen consumption and heart rate [82]. This effect results from the inhibition of nonshivering thermogenesis, that is heat production from uncoupled mitochondrial electron transport not associated with ATP synthesis. Consequently, H2S exposure protected animals from detrimental effects of subsequent hypoxia [83]. Although these findings seem specific for small animals, inhibition of cytochrome c oxidase may contribute to some protective effects of H2S in other models such as renal ischemia– reperfusion injury [84]. Transient decrease in ATP production may contribute to activation of ATP-sensitive potassium channels and H2S-induced vasorelaxation [85]. Recently, it has been demonstrated that H2S inhibits myeloperoxidase (MPO) at concentrations as low as 1 mM [86]. Myeloperoxidase – the enzyme of polymorphonuclear leukocytes – catalyzes the reaction of H2O2 with chloride (Cl) to form hypochlorite (HOCl), a potent killer of

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invading microorganisms, and plays an essential role of inflammatory response. In addition, low-grade long-lasting excess of MPO is associated with cardiovascular and other oxidative stressrelated diseases. In addition to inhibiting catalytic turnover of MPO, H2S may be oxidized by this enzyme to polysulfides, important H2S-derived signaling molecules [86]. Regarding nonheme metals, H2S reacts with copper in copper–zinc superoxide dismutase (SOD1) increasing its catalytic activity [87].

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H2S as a target for pharmacotherapy

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Although excess H2S may contribute to the pathogenesis of some diseases such as cancer [88,89], septic shock [90] or acute pancreatitis [91] and pharmacological or genetic inhibition of H2S production is protective in some models, application of H2S donors and/or augmenting endogenous H2S attracts most attention as the possible therapeutic approach for several reasons. First, protective effects of H2S or its donors were demonstrated more convincingly in many experimental models. Potential targets for H2S donors include arterial hypertension, atherosclerosis, myocardial hypertrophy, heart failure, ischemia–reperfusion injury of various organs such as the heart, brain, kidney, lung, liver or intestine, erectile dysfunction, preeclampsia, diabetic nephron- and retinopathy, chronic inflammatory diseases, peptic ulcer disease, and enhanced uterine contractility [92–95]. Second, even if detrimental effect of H2S was observed in some models, the results are controversial. For example, proinflammatory effect was observed mainly when inorganic sulfide salts were used as the H2S donors. Sulfide salts increase H2S to supraphysiological concentrations and can induce toxic effects. In addition, sulfide salts are easily oxidized to various sulfur species which may have H2S-independent effects. Thus, such proinflammatory effect could be not specific for H2S. Third, even if reducing H2S could be protective in some instances, currently we have no effective approach to do it. The available CBS and CSE inhibitors have limited membrane permeability and are not very specific. In addition, there is no 3-MST inhibitor available. Inactivation of genes encoding H2S-synthesizing enzymes has also H2S-independent consequences such as hyperhomocysteinemia, decrease in cysteine (and consequently glutathione synthesis), etc. In addition, CBS, CSE or 3-MST knockout mice exhibit many abnormalities which precludes considering such approach in humans. Therefore, in the subsequent section I will focus only on approaches aimed to increase H2S signaling.

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Sulfide salts

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In most studies about H2S inorganic sulfide salts such as sodium hydrosulfide (NaHS) and sodium sulfide (Na2S) are used. These compounds increase H2S/HS concentration due to dissociation and pH-dependent balance between HS and H2S in aqueous solutions. Inorganic sulfide salts have several important disadvantages: (1) induce rapid but short-lasting increase in H2S concentration to supraphysiological concentration, (2) are easily oxidized even spontaneously; it is suggested that most if not all commercial preparation contain some amount of polysulfides, elemental sulfur or even sulfite, (3) can change pH of the if used in the non-buffered solution. Rapid increase in H2S induces proinflammatory effects in contrast to slowreleasing H2S donor [96]. NaHS has been demonstrated to be protective in many experimental models of ischemia –reperfusion injury. However, pharmacokinetic profile of NaHS suggests that it could induce short-lasting metabolic inhibition followed by restoration of mitochondrial electron transport; the effect which mimics ischemia and reperfusion. It cannot be excluded that some of protective effects did not result from binding of H2S to specific molecular targets but rather from a kind of ‘‘ischemic

preconditioning’’ mimicked by H2S-induced hypometabolism. Interestingly, many mechanisms reported to be involved in the protective effect of NaHS such as activation of KATP channels, protein kinase B/Akt, Nrf2-induced signaling or increase in antioxidant enzymes are also induced by ischemic pre- and postconditioning. Despite these limitations, Sulfgenix has recently started a randomized, double-blinded, placebocontrolled trial to assess the safety and bioactivity of sodium polysulthionate (SG1002) in patients with heart failure [97].

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Slow-releasing synthetic H2S donors

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To overcome the limitations of sulfide salts, several organic slow-releasing H2S compounds have been synthesized; the most popular of them being GYY4137 (morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate). GYY4137 is a water soluble compound which spontaneously decomposes to release H2S over 3–4 h after dissolving [98]. GYY4137 induces vasorelaxation in vitro and decreases blood pressure in vivo [98]. It reduced secretion of proinflammatory cytokines (TNF-a, IL-1b, IL-6) as well as decreased COX-2 and iNOS expression in LPS-stimulated RAW264.7 macrophages [96]. In the experimental model of LPS-induced septic shock, GYY4137 attenuated hypotension, reduced plasma concentration of NO metabolites, decreased C-reactive protein, L-selectin and lung myeloperoxidase activity [99]. In addition, GYY4137 decreased proliferation and/or induced apoptosis of many cancer cell lines while having no effect at nonmalignant cells at the same concentrations [100]. All these effects were H2S-dependent as evidenced by lack of effects of ‘‘decomposed’’ GYY4137 predissolved before the experiment to exhaust H2S. Importantly, the product of GYY41347 decomposition is believed to be biologically inert. In addition, GYY4137 protected cultured cardiomyocytes from hyperglycemia-induced injury [101], was beneficial in the experimental model of joint inflammation [102], inhibited platelet aggregation in vitro and thrombus formation in vivo [103], attenuated opioid dependence [104], restored fetal growth in mice model of preeclampsia [105], reduced atherosclerotic lesions in apolipoprotein E knockout mice [106] and was protective in the experimental model of hyperoxiainduced neonatal lung injury [107].

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Synthetic cysteine derivatives

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L-Cysteine is widely used in the experimental studies to augment endogenous H2S production. However, L-cysteine is not a good H2S precursor because is metabolized in many other pathways such as glutathione synthesis, taurine synthesis or oxidation to sulfate. Several synthetic cysteine derivatives such as S-propyl-cysteine (SPC), S-allyl-cysteine (SAC) and S-propargylcysteine (SPRC) are good substrates for CBS and CSE and are enzymatically converted to H2S. In addition, these compounds augment the expression of CSE through the as yet unknown mechanism. Intraperitoneally administered SPC, SAC or SPRC protected rat heart from coronary artery ligation-induced ischemia–reperfusion injury as evidenced by reduced infarct size, decrease in mortality, reduced lipid peroxidation and increase in GSH, SOD and GPx in hypoperfused myocardium [108,109]. SPRC attenuated LPS-induced deficit in spatial learning and memory; the effect accompanied by decrease in TNF-a and its receptor, reduced activity of NF-kB and amyloid precursor protein processing to amyloid b in the hippocampus [110,111]. SPRC was also demonstrated to exhibit anticancer effect both in vitro and in vivo. This compound reduced tumor growth in nude mice transplanted with human SGC-7901 gastric cancer cells [112]. SPRC reduced NF-kB activity, decreased intracellular ROS production,

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TNF-a synthesis, iNOS and ICAM-1 expression in LPS-treated rat neonatal ventricular cardiomyocytes [113], inhibited TNF-a induced inflammatory response in endothelial cells [114], reduced cerulein-induced acute pancreatitis and the associated lung inflammation in mice [115]. SPRC administered for 6 weeks improved myocardial contractility, reduced cardiomyocyte apoptosis and improved myocardial antioxidant enzyme activities in rats with myocardial infarction-induced heart failure [116]. Finally, SPRC stimulated angiogenesis in a mouse model of hindlimb ischemia and in a rat model of myocardial ischemia [117].

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H2S-releasing derivatives of other drugs

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The other approach to increase H2S is conjugation of H2S-releasing moiety such as anethole dithiolethione (ADT) and its metabolite, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH) with drugs currently used in pharmacotherapy. In particular, several H2S-releasing derivatives of nonsteroidal antiinflammatory drugs (NSAIDs) have been synthesized including S-aspirin (ACS14), S-diclofenac (ACS15, ATB-337) and S-naproxen (ATB346). Each of them is hydrolyzed to H2S and the respective parent compound both in vitro and in vivo [118]. One of the most important adverse effects of NSAIDs is gastric mucosal damage. Most, if not all, H2S-releasing NSAIDs are characterized by improved gastrointestinal safety profiles in comparison to compounds not containing the sulfide-releasing moiety [119–121]. ACS14 has strong antithrombotic [122,123] and antioxidant [124] properties. ACS14 reduced hypertension induced by administration of buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis [125], and protected retinal ganglion cells (RGC-5) from glutamate and BSO-induced toxicity [126]. In addition, ACS14 reduced atherosclerosis in apolipoprotein E knockout mice [127] and decreased hyperglycemia-induced oxidative stress in vascular smooth muscle cells [128]. S-Diclofenac reduced LPS-induced lung and liver inflammation [129] and carrageenan-induced hindpaw edema formation in the rat [130], ameliorated lung inflammation in the course of ceruleaninduced acute pancreatitis [131], protected isolated perfused rabbit heart against ischemia–reperfusion injury [132], inhibited vascular smooth muscle cell proliferation [133], reduced breast cancer-induced osteolysis [134], and attenuated cardiotoxic effect of doxorubicin [135]. H2S-releasing naproxen accelerated recovery from experimental spinal cord injury [136], was more potent than naproxen in experimental model of carrageenan-induced synovitis [137] and inhibited the development of experimental colorectal cancer [138]. Finally, H2S-releasing mesalamine (ATB429) was more effective than mesalamine itself in experimental models of inflammatory bowel disease [139]. H2S-releasing derivatives of NSAIDs inhibited growth of cancer cell lines originating from different tissues 30–3000 more potently than respective NSAIDs not conjugated with H2S-donating moiety [140]. L-Dihydroxyphenylalanine (L-DOPA), the precursor of dopamine, is widely used in the treatment of Parkinson’s disease. LDOPA is taken up by nigrostriatal neurons and converted to dopamine, the deficiency of which is responsible for symptoms of PD. However, L-DOPA may induce dyskinesis, becomes ineffective in later stages of the disease when progressive neurodegeneration makes neurons unable to process it, and even may contribute to disease progression by inducing oxidative stress. ACS85, ACS83 and ACS84 are H2S-releasing L-DOPA derivatives which contain ADT-OH analogs, ACS5, ACS48 and ACS50, respectively. All three compounds increase L-DOPA and H2S concentration in the brain and reduce inflammatory response of microglial cells and their toxic effect on co-cultured SH-SY5Y neuroblastoma cells

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[141]. H2S-releasing L-DOPA derivatives may slow-down neurodegeneration process in the course of PD due to antiinflammatory and antioxidant effects of sulfide. Indeed, in a recent study, ACS84 relieved movement dysfunction and alleviated the loss of tyrosine hydroxylase positive dopaminergic neurons in the substantia nigra and decline in dopamine concentration in striatum in 6-hydroxydopamine-induced rat model of PD [142]. Phosphodiesterase 5 (PDE5) inhibitors such as sildenafil induce vasorelaxation by inhibiting cGMP breakdown and are commonly used in the treatment of erectile dysfunction. PDE5 inhibitors have therapeutic potential also in pulmonary hypertension and heart failure. H2S-releasing sildenafil (ACS6) relaxed rabbit corpus cavernosum [143], and decreased NADPH oxidasedriven superoxide anion production in endothelial cells [144]. Because H2S relaxes corpus cavernosum as well [145], the contribution of H2S-releasing moiety to the effect of ACS6 may be significant. Moreover, ACS6 protected cultured rat pheochromocytoma PC12 cells from homocysteine-induced mitochondrial dysfunction and apoptosis suggesting neuroprotective potential of this compound [146]. Neurotoxic effect of homocysteine is partially associated with down-regulation of paraoxonase-1, a calcium-dependent esterase which reduces detrimental consequences of oxidative stress by metabolizing fatty acid peroxidation products and hydrolyzing toxic homocysteine derivative, homocysteine thiolactone. ACS6 improved PON1 expression and activity in homocysteine-treated PC12 cells and its protective effect was attenuated by PON1 inhibitor, 2-hydroxyquinoline [147].

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Garlic and other plant-derived products

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Garlic (Allium sativum) has been known for a long time to improve cardiovascular risk by decreasing oxidative stress, plasma cholesterol concentration, platelet aggregation and blood pressure. At least part of these protective effects may be mediated by H2S. Garlic cloves contain allin, a sulfur aminoacid which during clove crunching is converted to diallyl thiosulfinate (allicin) by the enzyme allinase. Then, allicin spontaneously decomposes to organic polysulfides, diallyl disulfide (DADS) and diallyltrisulfide (DATS). Upon reduction by reduced glutathione, DADS and DATS release H2S [148–150]. Isothiocyanate group (–N5 5C5 5S) -containing compounds such as sulforafane, allyl isothiocyanate, erucin and iberin are contained in vegetables such as broccoli, rocket salad, wasabi, mustard and horseradish. Although these compounds have beneficial health effects similar to H2S and could provide H2S in biological systems by nonenzymatic thiol-mediated reduction or sulfurtransferase (TST or 3-MST) catalyzed reaction, this possibility has not been studied so far [151].

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Effect of currently used drugs on H2S metabolism and signaling

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Angiotensin-converting enzyme inhibitor, ramipril [152,153], calcium channel antagonist, amlodipine [154], atorvastatin [155], digoxin [156], vitamin D3 [157], aspirin [158] and metformin [158] increase H2S concentrations in at least some tissues. Statins may increase H2S synthesis by up-regulating CSE [160] and/or reduce its degradation by decreasing coenzyme Q concentration [161,162]. Lipophilic atorvastatin but not hydrophilic pravastatin increased H2S in perivascular adipose tissue and augmented its vasodilating effect most likely because this lipophilic statin accumulates in triglyceride-rich adipocytes [161]. In contrast, both statins had comparable effects on H2S in the liver. Interestingly, the effect of statins was not associated with decrease in mitochondrial oxidation of organic substrates and thus had no detrimental effect on cellular bioenergetics [162]. The mechanisms

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through which other drugs mentioned above affect H2S metabolism is unclear. Paracetamol has a tissue-specific effect with increase in H2S observed in heart, liver and kidney, and decrease in the brain [163]. A non-selective a- and b-adrenergic receptor antagonist, carvedilol, decreased H2S in the brain but increased its concentration in the heart and the liver [164]. Its effect in the kidneys was dose-dependent with decrease in H2S at low and increase at higher doses. Classic NSAIDs decrease H2S synthesis in gastric mucosa which may be the important mechanism of their gastrointestinal toxicity. PDE5 inhibitor, tadanafil, up-regulates CSE-H2S pathway in the heart in cGMP-dependent manner [165]. Both testosterone [166] and 17b-estradiol [167,168] increase H2S synthesis in the vascular wall. Interestingly, thiol group-containing ACE inhibitor, zofenopril, restored impaired acetylcholine-induced endothelium-dependent vasorelaxation in spontaneously hypertensive rats and decreased blood pressure more efficiently than another ACE inhibitor, enalapril. The effect of zofenopril but not of enalapril was accompanied by the increase in H2S concentration in plasma and vascular wall. Zofenoprilat, an active metabolite of zofenopril, released H2S in a cell-free assay and induced vasorelaxation; the effect reproduced also by R-stereoisomer which does not inhibit ACE. These results suggest that H2S release may be one of the cardiovascular protective mechanisms of zofenopril [169].

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Other compounds

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D-Cysteine may be the H2S donor specific for D-aminoacid oxidase-expressing tissues such as the kidney. Indeed, as the H2S precursor, it may ‘‘bypass’’ reduced CSE and CBS expression observed in some experimental models. Indeed, D-cysteine is more effective in reducing kidney ischemia–reperfusion injury than L-cysteine [22]. Thiosulfate was also used as the H2S donor in some experimental studies [171,172]. It may be converted to H2S by thiosulfate reductase or 3-MST especially under hypoxic conditions. Sodium thiosulfate had protective effect in acute inflammatory lung injury [171] and decreased blood pressure, myocardial hypertrophy and fibrosis in rats with angiotensin II-induced hypertension [172]. Adenosine- and guanosine 5-monophosphorothioates (AMPS and GMPS) are synthetic AMP and GMP analogs with one oxygen atom of the phosphate group replaced by sulfur. Both AMPS and GMPS are hydrolyzed to H2S and AMP or GMP, respectively, by isolated Hint1 and Hint2 proteins – ubiquitously expressed histidine triad-containing enzymes contained in cytosol and mitochondria, respectively [173–175] as well as by cell lysates with intact but not with knocked-down Hint1 [176]. Recently, we have demonstrated that AMPS and GMPS are hydrolyzed to H2S and AMP or GMP, respectively, by isolated kidney glomeruli after being transported to the cells through plasma membrane purinergic P2X7 receptors/channels. A significant H2S production from nucleoside phosphorothioates was observed only in the presence of P2X7 agonist and was inhibited by the antagonist of this receptor. In addition, AMPS and GMPS relaxed angiotensin IIpreconstricted renal glomeruli and increased glomerular filtration rate following infusion into the renal artery, which is consistent with relaxing effect of H2S on glomerular mesangial cells [177]. AMPS and GMPS have some interesting features as the potential H2S precursors. First, they are hydrolyzed to H2S and AMP or GMP, non-toxic endogenous compounds. Second, they are enzymatically hydrolyzed to H2S only in the intracellular space and thus could be much more focused and effective than donors spontaneously releasing H2S. Third, receptor-mediated entry provides potential opportunity for tissue-specific or regulated

delivery. However, the disadvantage of AMPS and GMPS is that only a small fraction of them enter the cells and high concentration/doses of these compounds must be used.

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Conclusions and future directions

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A significant progress has been made in recent years in the H2S field. The mechanisms of H2S synthesis by CBS and CSE were explained and it was demonstrated that it can be formed not only from cysteine but also from homocysteine. The new 3-MSTdependent pathways of H2S production have been described and its mitochondrial metabolism is now quite well characterized. Several molecular signaling mechanisms have been demonstrated. Many new methods of H2S measurements such as polarographic sensors, gas chromatography and selective fluorescent probes are available and allow better characterization of endogenous H2S production, including real-time monitoring in living cells. Slowreleasing H2S donors provide more reliable data about physiological effect of H2S and provide potential opportunity for drug discovery together with H2S-releasing derivatives of drugs currently used in clinical practice. However, there are also significant challenges for future research. Most studies about physiological effects of H2S are still performed with sulfide salts and more data obtained with more physiological donors are required. The relative role of H2S versus polysulfides in signaling processes must be investigated. There are still few studies available in which free H2S was measured in humans by specific methods. Inhibitors of H2S-synthesizing enzymes currently available have serious limitations which often preclude better understanding of the role of endogenous H2S. Role of H2S in some diseases (beneficial vs. detrimental) is still controversial; the best example of them being cancer. All available H2S-releasing drugs have been until now examined only in preclinical experiments. Finally, the effect of currently used drugs and natural products on H2S system is in the early stage of research.

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Conflict of interest

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None declared. Uncited references

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Q4

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[159,170].

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Acknowledgements

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Author’s own studies cited in this paper were supported by grant DS 476 from Medical University, Lublin, Poland, as well as by Q5 EU Project ‘‘The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases’’ within the Operational Program Development of Eastern Poland 2007–2013, Priority Axis I Modern Economy, Operations I.3 Innovation Promotion.

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References

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Please cite this article in press as: Bełtowski J. Hydrogen sulfide in pharmacology and medicine – An update. Pharmacol Rep (2015), http://dx.doi.org/10.1016/j.pharep.2015.01.005

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