Hydrogen sulfide in hemostasis: friend or foe?

CBI 7027

No. of Pages 8, Model 5G

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Contents lists available at ScienceDirect

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Hydrogen sulfide in hemostasis: Friend or foe?

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Beata Olas ⇑ Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland

a r t i c l e

i n f o

Article history: Received 12 November 2013 Received in revised form 2 April 2014 Accepted 6 April 2014 Available online xxxx Keywords: Hydrogen sulfide Cardiovascular system Hemostasis Blood platelet activation

a b s t r a c t Hydrogen sulfide (H2S) is a well known toxic gas that is synthesized from the amino acids: cysteine (Cys) and homocysteine (Hcy) by three enzymes: cystathionine-b-synthase (CBS), cystathionine-c-lyase (CSE) and mercaptopyruvate sulfurtransferase (3-MST). Hydrogen sulfide, like carbon monoxide (CO) or nitric oxide (NO) is a signaling molecule in different biological systems, including the cardiovascular systems. Moreover, hydrogen sulfide plays a role in the pathogenesis of various cardiovascular diseases. It modulates different elements of hemostasis (activation of blood platelet, and coagulation process) as well as proliferation and apoptosis of vascular smooth muscle cells. However, the biological role and the therapeutic potential of H2S is not clear. This review summarizes the different functions of hydrogen sulfide in hemostasis. Ó 2014 Elsevier Ireland Ltd. All rights reserved.

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Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism of endogenous hydrogen sulfide. . . . Biological properties of hydrogen sulfide . . . . . . . Regulation of hemostasis by hydrogen sulfide . . . Effects of hydrogen sulfide on the cardiovascular Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . Transparency Document . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

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Hydrogen sulfide (H2S), noted for its smell of rotten eggs, is traditionally known as an air pollutant and a poisonous gas [1,2]. It is moderately soluble in water. Aqueous solutions of hydrogen sulfide have a slightly acidic pH, because hydrogen sulfide dissociates in two-step process into H+ and hydrogen sulfide anion (HS) and then into sulfide (S2). In physiological pH (pH = 7.4, at 37 °C) less than 1/5 of H2S is undissociated, and the remaining 4/5 are mainly HS (pKa1 = 6.98, at 25 °C) with a small admixture of sulfide ions (pKa2 = 19 ± 2) [3–6]. The physiological relevance of hydrogen sulfide gained more attention as it was detected in different mammalian tissues such

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as: brain, liver, kidney, heart, aorta and also lungs, mediating pleiotropic effects [7,8]. Endogenous concentrations of H2S in human plasma are described with range from 34 lM to 65 lM [9]. Its physiological level in the brain is up to threefold higher than in serum [10,11]. However, H2S concentration in human tissues depends on the method used for measurement and the donor’s age [9,12]. Moreover, most methods, like the spectrophotometric measurement of hydrogen sulfide with the use N0 N-dimethyl-p-phenylenediamine, monitor not only hydrogen sulfide, but also other species as S2 and HS. Endogenous concentration of H2S is regulated by many metabolic pathways, such as mitochondrial oxidation and cytosine methylation. Hydrogen sulfide can be scavenged by methemoglobin or metallo- or disulfide-containing molecules, i.e. oxidized glutathione – GSSG [13–16].

E-mail address: [email protected] http://dx.doi.org/10.1016/j.cbi.2014.04.006 0009-2797/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: B. Olas, Hydrogen sulfide in hemostasis: Friend or foe?, Chemico-Biological Interactions (2014), http://dx.doi.org/ 10.1016/j.cbi.2014.04.006

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Therapeutic and toxic effects of hydrogen sulfide depend on the concentration. Exposure to H2S (>700 ppm) causes loss of consciousness (syncope), paralysis of respiratory system and may also lead to death. In concentration 300–700 ppm hydrogen sulfide causes syncope and can sometimes lead to death if the exposition of the H2S is longer than 30 min. A few breaths of air containing high levels of >H2S (200–300 ppm) and an exposition of more than 1 h cause to the paralysis respiratory system. Hydrogen sulfide is present in effluent from hydrothermal vents and sulfur springs (at very low concentrations), which have been proposed to act as ‘‘pores’’ in the Earth surface, providing a source of energy in the form of reducing equivalents and of iron–sulfur centers [17]. H2S has special therapeutic effects in treatment of some diseases: arteriosclerosis, arterial hypertension, chronic heavy metal toxicity, skin diseases or rheumatism [7].

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2. Metabolism of endogenous hydrogen sulfide

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Hydrogen sulfide is the final product of amino acids metabolism, which contain sulfur (homocysteine (Hcy) and cysteine (Cys), which is synthesized from L-methionine through the transsulfuration pathway with Hcy as an intermediate, or liberated from endogenous proteins). The substrate for the generation of endogenous H2S is L-cysteine. However, 3-mercaptopyruvate sulfurtransferase together with D-amino acid oxidase emerged as the fourth way for endogenous hydrogen sulfide production from D-cysteine, predominantly in the kidney and the cerebellum [18]. There are two main pathways of L-cysteine catabolism: (1) thiol group of Cys is oxidized by cysteine dioxygenase (CDO) to cysteine sulfinate, which may be decarboxylated to taurine or converted to pyruvate and sulfite, afterward oxidized to sulfate by sulfite oxidase (SO); (2) cysteine sulfur atom is removed without its oxidation which results in H2S production – process of ‘‘desulfhydration’’. Desulfuration may be catalyzed by the two enzymes, which take part in Hcy transsulfuration pathway: cystathionine b-synthase (CBS) and cysthationine c-lyase (CSE). CBS and CSE are vitamin B6-dependent (pyridoxal 50 -phosphate-dependent). H2S production by CBS involves the condensation of Hcy with Cys to yield cysthationine; and during this reaction the H2S is liberated [19]. CSE catalyzes the conversion of L-cysteine to pyruvate, thiocysteine and ammonia. Then, thiocysteine nonenzymatically decomposes to cysteine and hydrogen sulfide. Recently it has been shown that 3-mercaptopyruvate sulfurtransferase (3-MST) also takes part in endogenous H2S generation. 3-MST produces H2S in conjunction with cysteine aminotransferase (CAT) from L-cysteine in the presence of a-ketoglutarate. CAT catalyses the transformation between L-cysteine and a-ketoglutarate. The products of this reaction are 3-mercaptopyruvate and L-glutamate. 3-MST transfers sulfur from 3-mercaptopyruvate into sulphurous acid and in the reaction are produced pyruvate and thiosulfate, and the later is reduced to hydrogen sulfide in the presence of reduced form of glutathione (GSH) [17,20]. The CBS pathway is reported to contribute to endogenous H2S production in the central nervous system, CSE is a major H2S-producing enzyme in the cardiovascular system and 3-MST in the myocardium [21,22]. During the enzymatic pathway, H2S can be immediately released or stored in the cells. Pathways of synthesis of endogenous hydrogen sulfide are shown on Fig. 1. There are two mechanisms for the release of hydrogen sulfide. First, H2S is immediately released after its enzymatical formation. Second mechanism is that the produced H2S is stored intracellular in a sulfane sulfur bond and is released in response to a physiological signal [23,24]. Sulfane sulfur has regulatory effects in biological systems. These functions include activation or inactivation of enzymes, posttranscriptional modification of transfer RNA and synthesis of the sulfur-containing cofactors or vitamins [25–27].

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3. Biological properties of hydrogen sulfide

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The physiological effects of endogenous H2S may be multifaceted. In different animal disease models, hydrogen sulfide exerts a classical pleiotropic profile with anti-inflammatory, cytoprotective, and anti-apoptotic action [28–31]. Other experiments have reported that hydrogen sulfide inhibits smooth muscle cell proliferation by promoting apoptosis, i.e. in human aortic smooth muscle. H2S (in a concentration-dependent manner) induces apoptosis through activation of the mitogen activated protein kinase (MAPK) pathway [32]. Moreover, H2S stimulates the expression of heme oxygenase 1 (HO-1) through a signaling pathway depending on extracellular signal-regulated kinase (ERK) (Fig. 2). In addition, HO-1 reduces production of NO by inhibiting the expression of inducible nitric oxide synthase (iNOS). H2S prevents phosphorylation of IjB and subsequent degradation. As a consequence the NF-jB mediated transcription is decreased. H2S not only activates ERK 1/2, but also stimulates phosphorylation p-38 MAPK (mitogen activated kinase) [33–35]. Hydrogen sulfide plays also a role in vascular homeostasis [11,29], because it has anti-adhesive and anti-inflammatory properties [36]. The action of H2S influence on vascular inflammatory process is of particular interest because H2S has an antiinflammatory influence on macrophages [34] and it has an proinflammatory effect on vascular smooth muscle cells [35]. Various groups have demonstrated the effect of H2S on organ injury and postischemic reperfusion disorders [1]. Moreover, anti-aggregatory, anti-coagulatory and anti-thrombotic properties of H2S were observed [2,24,37]. Hydrogen sulfide may decrease arterial pressure (about 125 lM H2S) [38], hyperpolarize blood vessels in vivo by KATP channels activation (about 200 lM H2S) [32]. The relaxing properties of hydrogen sulfide was shown in endothelial cells and in smooth muscle cells of gastrointestinal system and airways. The results of Mazza et al. [39] indicate that Akt/eNOS signaling and S-sulfhydration of cardiac proteins are involved in H2S-dependent cardiac relaxation in frog and rat. The experiments of Castro-Piedras and Perez-Zaghbi [40] have shown that hydrogen sulfide inhibits Ca2+ release through inositol-1,4,5-trisphosphate receptors and relaxes airway smooth muscle. Other results have reported that hydrogen sulfide plays an important function in the peripheral nervous system [41]. Qu et al. [42] have observed that H2S concentration in the cerebral cortex is increased in stroke. The authors suggest that high concentration of cysteine, probably is associated with high concentration of hydrogen sulfide and inversely correlates with clinical outcome of patients which suffer from ischemic stroke [43]. The role of H2S in oxidative stress is still uncertain. Recent studies have demonstrated that hydrogen sulfide reacts with reactive oxygen and nitrogen species, i.e. hydrogen peroxide (H2O2), super oxide anion radical (O 2 ), peroxynitrite (ONOO ) and hypochlorite [44–48].

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4. Regulation of hemostasis by hydrogen sulfide

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The hemostatic system consists of a complex array of processes that maintains blood flow under physiological conditions. Hemostasis involves an explosive reaction, designed to curtail blood loss, restore vascular integrity and ultimately preserve life. The rapid transformation of blood from its fluid state into a localized thrombus at the site of tissue damage is controlled by an intricate interplay of four key components – the vascular endothelium, blood platelets, the coagulation pathway and fibrinolysis. Disruption of this tightly regulated hemostatic process can result in pathological thrombosis or hemorrhage, both a frequent complication of surgery, illness and trauma. Blood platelets circulate in close contact

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Pyruvate + thiosulfate +

L-cysteine + α-ketobutyrate + NH4+

H2 S

Mercaptopuryvate sulphurtransferase

Cystathionine-γ-lyase

3-mercaptopyruvate

Cystathionine + Cysteine aminotransferase

L-glutamate

H2 S

Cystathionine-β -synthase

Homocysteine

α-ketobutyrate L-cysteine

Cysteine dioxygenase

L-cysteinylosulfinate

Cystine Cystathionine - β -synthase

α-ketobutyrate Hipotaurine

L-glutamate

Pyruvate + thiocysteine + NH4+

β-sulfinatopyruvate Taurine Pyruvate + sulfite

L-cysteine +

H2 S

Sulfite oxidase

Sulfate Fig. 1. Pathways of synthesis of endogenous hydrogen sulfide. The substrate for the production of endogenous H2S is L-cysteine, which may be metabolized by three enzymes: cystathionine-b-synthase, cystathionine-c-lyase and mercaptopyruvate sulfurtransferase [[17–20,96,97], modified].

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with the endothelial wall of blood vessels, facilitating rapid recognition of a disrupted or injured endothelial cell surface. Later, the formation of a platelet and fibrin hemostatic plug is observed. The process of platelet plug formation is called primary hemostasis, as opposed to the secondary events of the procoagulant system. Primary hemostasis consists of several platelet events; adhesion, secretion and aggregation [49]. Platelets are multiresponding cells, both with respect to the different number of agonists and compounds. They can be activated by several physiologically important compounds including collagen, ADP and thrombin. Platelet aggregation under physiological conditions is an important process to stop bleeding, but it is considered that excessive platelet aggregation causes thrombosis and atherosclerosis. Recent studies have shown that H2S acts antithrombotic, thereby inhibiting different steps of platelet activation (i.e. platelet adhesion, secretion and aggregation) and thrombus formation [2,37,50–52] (Fig. 3). The total inhibition of platelet aggregation was observed at 10 mM NaHS concentration, independently from the agonists in vitro. Studies conducted by Zagli et al. [37] showed that NaHS prevented in a concentration-dependent manner platelet aggregation induced by different agonists: ADP, U46619, collagen, epinephrine, thrombin and arachidonic acid. The highest

concentration by 2 lM ADP, thus excluding the possibility that NaHS acts via endogenous NO generation. Inhibition of adenylyl cyclase by SQ 22,536 (100 lM) and of guanylyl cyclase by ODQ (100 lM) did not affect NaHS-induced inhibition of ADPstimulated aggregation (2 lM). Significant inhibition of platelet aggregation induced by a moderate ADP concentration (0.8 lM), was also obtained with NaHS concentrations as low as 30 lM. Results of Nishikawa et al. [50] have demonstrated that H2S suppresses rabbit platelet aggregation (induced by collagen and ADP) by interfering with both upstream and downstream signals of cytosolic Ca2+ mobilization in a cAMP-dependent manner. The effective concentration range of NaHS was 0.1–0.3 mM in platelet-rich plasma and 1–3 mM in washed platelets. However, the potency of H2S to inhibit platelet aggregation depends on the strength of the stimulus, and H2S concentrations close to those found in human plasma exhibited antiaggregating effects. Thus, it could be theorized that physiological H2S concentrations in plasma may be sufficient to prevent platelet aggregation induced by moderate stimulation. Moreover, experiments of Grambow et al. [2] suggest that the anti-aggregatory effect of hydrogen sulfide might be due to S-sulfhydration of blood platelet proteins with concomitantly reduced granule exocytosis and shape change upon


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Fig. 2. Hydrogen sulfide-mediated pathways. H2S may stimulate the expression of heme oxygenase 1 (HO-1) through a signaling pathway depending on extracellular signal-regulated kinase (ERK). H2S may also stimulate phosphorylation mitogen activated kinase (p-38 MAPK). The HO-1 reduces production of NO by inhibiting the expression of inducible nitric oxide synthase (iNOS).

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activation. Other results of Grambow et al. [2] showed that hydrogen sulfide also reduces intracellular calcium levels in blood platelets, leading to both reduced exocytosis and shape changes. Next experiments demonstrated the inhibitory action of hydrogen sulfide on blood platelet adhesion [51]. Moreover, H2S modifies the adhesive properties of collagen and fibrinogen [52]. The authors assume that the interaction of modified adhesive proteins may cause impaired adhesion [52]. Flow cytometry of TRAP (peptide which is ‘‘tethered’’ ligand domain of thrombin receptor; peptide with the sequence Ser-Phe-Leu-Leu-Arg-Asn; SFLLRN) -activated blood platelets revealed that hydrogen sulfide exposure decreased adhesion molecule expression (i.e. P-selectin expression) in a dose dependent manner [2]. Studies of Morel et al. [51] indicated that H2S seems to display multiple effects of blood platelet activation since it inhibits action of both, the thrombin-mediated proteolytic cleavage of PAR(s) and non-proteolytic agonist – TRAP, but reduction of platelet responses causes by thrombin is stronger than by TRAP. These results suggest that NaHS–H2S donor may inhibit the activation cascade downstream of G-protein activation. Moreover, the tested concentrations (0.00001–0.1 mM) of NaHS did not cause the lyses of blood platelets determined as a leakage of lactic dehydrogenase into the extracellular medium [51]. During agonist induced blood platelet activation, a signal is transmitted into the platelet that produces different biochemical events, including reactive oxygen/nitrogen species (ROS/RNS) formation. ROS/RNS may behave as second messengers and may regulate blood platelet activation [41,53]. H2S may have pro- and antioxidative effects, which depend on its concentration. Inactive nitrozothiols are the products of a chemical reaction between H2S with nitric oxide. H2S decreases NO production during inflammation and limits his bioavailability of NO in physiological levels. Low concentrations of NaHS (30–50 lM) potentiate the protective antioxidative role of N-acetylcysteine, glutathione, superoxide dismutase, catalase or vitamin C.

Morel and co-workers [51], using NaHS as H2S donor, demonstrated in vitro that NaHS inhibits O 2 generation in blood platelets. The authors suppose that NaHS reacts with O 2 in resting blood platelets and thrombin- or TRAP-activated platelets. They showed that the strongest inhibitory action of NaHS on O 2 generation takes place in blood platelets activated by thrombin. Antioxidative properties of NaHS may be involved in the antiplatelet action of this compound. Platelet stimulation by thrombin causes the activation of phosphoinositides 3-kinase (PI 3-K), which phosphorylates the D3 position of the phosphatidylinositol ring to produce phosphatidylinositol (3,4) – bisphosphate (PI3, 4 P2) and phosphatidylinositol (3,4,5) – triphosphate (PI3, 4, 5 P3) [54,55]. The generation of PI3, 4 P2 would be required for the prolonged activation of integrin aIIbb3 and stabilization of platelet aggregates [54,55]. PI 3-kinase is also involved in receptor-mediated ROS production in blood platelets (activated by thrombin) and supports the importance of ROS signaling in platelet functions [56]. Hu et al. [57] demonstrated that cardioprotection induced by hydrogen sulfide involves PI 3-kinase pathway, therefore Morel et al. [51] postulate that PI 3-kinase may be involved in the mechanism(s) of H2S action in blood platelets. The effects of hydrogen sulfide on the complex coagulation system and fibrinolysis are manifold due to its pleiotropic character. We have observed that NaHS (at concentration 0.00001–0.1 mM) prolonged clotting time, decreased the maximal velocity of fibrin polymerization and stimulated the fibrinolysis in human plasma. The obtained in vitro results indicate the anticoagulant activities of H2S [58]. Therefore, we suppose that hydrogen sulfide may be a promising compound to prevent thrombosis in pathological processes where plasma procoagulant activity is observed. We suppose that modifications of various proteins of hemostatic system (including fibrinogen, plasminogen and thrombin) induced by H2S may be associated with changes of coagulation process and fibrinolysis. Experiments of Li et al. [59] showed that H2S promotes sulfhydrylation of protein cysteine. Results of other authors demonstrated that compound with thiol group(s) enhances plasma factor XIII-mediated fibrinogen cross linking [60,61]. It is possible that H2S is involved in this process.

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5. Effects of hydrogen sulfide on the cardiovascular system

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Hemostasis is a complex process that regulates in vivo the flowing properties of blood. However, changes in hemostatic process may play a very important role in the modulation of cardiovascular system and in the pathogenesis of cardiovascular diseases. Experiments performed on many various animals, and tissues or cells defined the functional role of H2S in the cardiovascular system [13]. It has known that H2S induces vasorelaxation in arterial hypertension. Researches on some animal models have shown that plasma H2S concentration, aortic CSE expression and enzymatic activity are lower in spontaneously hypertensive rats (SHR) in comparison with Wistar–Kyoto rats. In other words, chronic administration of NaHS lowers blood pressure in SHR but not in normotensive rats [62]. The CSE inhibitor D,L-propargylglicyna (PAG) decreases plasma H2S concentration and increases blood pressure in normotensive rats but not in SHR. This indicates that vascular H2S is involved in the regulation of vascular tone under baseline conditions thus H2S-generating system is suppressed in the hypertensive strain [63]. Other experiments have shown that low doses of NaHS increase the mean arterial pressure in anesthetized rats [64]. On the other hand, a transient dose-dependent decrease in mean arterial pressure in anesthetized rats is induced by intravenous bolus injection of hydrogen sulfide [11]. Moreover, NaHS relaxed rat thoracic aorta and portal vein preconstricted with norepinephrine, in vivo. H2S

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H2 S

S-sulfhydration

Blood platelet proteins

inhibition

O2 generation changes adhesive properties of collagen

Blood platelet activation

Collagen

Cellular injury Tissue factor

Contact system Blood platelet adhesion Blood platelet secretion

inhibition inhibition

H2 S

inhibition

Blood platelet aggregation Fibrinogen

Fibrin

Thrombus

changes biological properties of fibrinogen

H2 S

Fig. 3. The role of H2S in hemostatic system. H2S may display multiple effect on hemostasis. H2S may inhibit different steps of blood platelet activation: platelet adhesion, secretion and aggregation. H2S also modifies the adhesive properties of collagen and fibrinogen. Moreover, H2S inhibits O 2 production in blood platelets and induces Ssulhydration of platelet proteins.

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relaxed also rat mesenteric arteries which are peripheral resistance vessel. This effect exerted hydrogen sulfide at concentrations lower than required to relax the aorta. Results of Zhu et al. [65] showed that H2S plays an important role in myocardial ischemia in experimental rats. Animals were randomly divided into three groups and received either vehicle, 14 lmol/kg of NaHS or 50 mg/kg PAG everyday for 1 week before surgery, and the treatment was continued for a further 2 days after myocardial ischemia when the animals were killed. The authors observed that endogenous H2S was cardioprotective in the rat model of myocardial ischemia. PAG reduced endogenous H2S generation after myocardial ischemia by inhibiting cystathionine-gamma-lyase. The mechanisms of action explicated by hydrogen sulfide are multiple and range from vasodilatation and activation of KATPchannels to the differential regulation of pro- and anti-inflammatory genes [1,24]. Other experiments suggest that the interaction between NO and H2S is involved in regulation of not only cellular functions, inflammatory/immune function, but also cardiovascular responses [1,6,16,28]. There is a synergy of NO and H2S on vascular smooth muscle relaxation and the cysteine residues of hydrogen sulfide producing enzyme CSE are potential targets for NO-induced S-nitrosylation, thereby enhancing the activity of CSE [24,66]. Beside the action of NO on CSE protein, nitric oxide may stimulate CSE by increasing the activity of cGMP-dependent kinases [11,24]. On the other hand, hydrogen sulfide upregulates the NO generation from endothelial nitric oxide synthase (eNOS) through Akt kinasedependent Ser 1177 phosphorylation [67]. Moreover, hydrogen

sulfide augments NO production by potentiating the IL-1b-induced NFjB activation in rat vascular smooth muscle cells [35]. Results of Minamishima et al. [68] have demonstrated that hydrogen sulfide increases the phosphorylation of eNOS in the left ventricle of mice undergoing cardiac arrest and resuscitation. Issa et al. [69] demonstrated that NaHS when given before reperfusion protects against the effects of haemorrhage-induced ischemia–reperfusion by acting primarily through a decrease in both proinflammatory cytokines and inducible nitric oxide synthase pathway. Experiments of Huang et al. [70] indicate that endogenous H2S in the early reperfusion phase is the key mechanism of cardioprotection induced by ischemic postconditioning. Studies of Sun et al. [71] have shown that pretreating rat neonatal cardiomyocytes with NaHS reduced the level of ROS during the hypoxia/reoxygenation condition. They found that H2S inhibited mitochondrial complex IV activity and increased the activities of superoxide dismutases, including Mn-SOD and CuZn-SOD. Experiments of Kram et al. [24] have shown that H2S has antithrombotic action, i.e. prolonging the time until both initial occlusion of blood flow. The anti-thrombotic efficacy of H2S involves the NOS pathway. The recent studies have demonstrated that hydrogen sulfide may have some direct effects on the vascular wall [62,63,72]. Hydrogen sulfide causes apoptosis of human aortic smooth muscle cells [73,74] and reduces the growth of artherosclerotic lesions. A novel H2S releasing derivative of the non-steroidal anti-inflammatory drug – ‘‘S-diclofenac’’ has pro-apoptotic effects in human aortic smooth muscle cells over-expressing the H2S synthesizing


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enzyme CSE. Exogenous H2S induces apoptosis in the concentration-dependent manner through activation of MAPK pathway in human aortic smooth muscle cells. Surprisingly, this proapoptotic properties of hydrogen sulfide may be important for the prevention of cell proliferation in some diseases, such as: vascular graft occlusion, neointimal hyperplasia and atherosclerosis [13,75]. However, it was confirmed that hydrogen sulfide has antiatheroscerotic effects in different ways (Fig. 4). Decreased endogenous H2S production predisposes the animals to vascular remodeling and early development of atherosclerosis. Results of Mani et al. [76] suggest that the CSE/H2S pathway is an important therapeutic target for protection against atherosclerosis. Some facts support the hypothesis that H2S deficiency might contribute to atherogenesis and if it’s feasible, one should focus on patients who suffer from hyperhomocysteinemia. Despite elevated plasma Hcy, the risk of acute cardiovascular effects is not increased in humans with reduced activity of methylenetetrahydrofolate reductase (MTHFR) [77]. As proven previously, MTHFR deficiency should increase the level of H2S which may partly attenuate the proatherogenic effect of Hcy. The risk of cardiovascular events is increased in patients with homocystinuria, which were treated with vitamin B6, but is not as high as in patients with mild hyperhomocysteinemia, even though plasma Hcy is much greater in the former group [78]. To sum up, progression of atherosclerosis is slower in patients with Down syndrome, a state of H2S overproduction [79]. In in vivo experiments it was shown the pro-angiogenic effects of H2S in endothelial cells and this action was inhibited by the inhibitor of phosphoinositide 3-kinase. Several studies indicated that H2S is involved in the pathogenesis of hyperhomocysteinemia. Yan et al. [80] demonstrated that H2S plays a protective role on hyperhomocysteinemia-induced cell injury by its anti-oxidative stress effect. It was demonstrated that low concentrations of H2S (30 and 50 lM) increased homocysteine (100 lM)-incubated cell survival by 7% and 61%, respectively. It was also shown that H2S (30 lM) attenuated Hcy (100 lM)induced overproduction of O 2 by 55.8%. Chang et al. [81] observed that injection of H2S reduced the concentration of Hcy in plasma, and decreased lipid peroxidation. These results suggest that there is a protective role of H2S in hyperhomocysteinemia induced by anti-oxidative stress, which may interfere with the promoting effect of hyperhomocysteinemia on cardiovascular disease. Some studies have demonstrated the role of hydrogen sulfide as therapeutic agent in various diseases, including cardiovascular diseases. An injectable Na2S (IK-1001), which is an H2S donor, has been developed for clinical use. It is currently undergoing phase I and II trials for therapy in ischemia reperfusion injury and renal injury [82]. S-allylcysteine, which may derive with garlic reduced blood platelet aggregation, and this action may be mediated through H2S [83,84]. Table 1 has shown hydrogen sulfide as therapeutic agent.

H2 S oxidative stress

adhesion

vascular remodeling

inflammation

Ox-LDL Fig. 4. Anti-atherosclerotic actions of hydrogen sulfide. H2S has a number of antiatherosclerotic effects, like reducing inflammation, attenuating oxidative stress, inhibiting blood platelet adhesion and preventing proliferation of vascular smooth muscle cells [[98], modified].

Table 1 Hydrogen sulfide as therapeutic agent [83,84,91–95]. Therapeutic agent

Functions

Na2S (IK-100)

Phase I and II trials for therapy in ischemia reperfusion injury and renal injury Anti-inflammatory role

Morpholin-4-ium-4methoxyphenyl(morpholino) phosphinodithioate (GYY4137) 5-Amino-2-hydroxybenzoic acid 4(5-thioxo-5H-[1,2]dithiol-3yl)phenyl ester (ATB-429; mesalazine) 2-(6-Methoxynapthalen-2-yl)propionic acid 4thiocarbomylphenyl ester (ATB3346; naproxen derivative) 2-Acetyloxybenzoic acid 4-(3-thioxo3H-1,2-dithiol-5-yl) ester (ACS-14; aspirin derivative) 4-(3-Thioxo-3H-1,2-dithiol-4-yl)benzoic acid (ACS48; dopamine derivative) [2-Methoxy-4-3-thioxo-3H-1,2dithiol-5-yl)-phenoxy] acetic acid (ACS50; dopamine derivative) 1,3-Dithiolate-2-thioxo-4-caboxylic acid (ACS5; dopamine derivative) 3-(Prop-2-en-1-yldisufanyl) propanoic acid (ACS81; dopamine derivative) Garlic derived compounds (at dietary doses) – S-allylcysteine

Crohn’s disease and ulcerative colitis treatment

Inhibits activity of cyclooxygenase-2 and protects gastrointestinal mucosa

Plays anti-inflammatory and analgestic role Parkinson’s disease

Parkinson’s disease

Parkinson’s disease Parkinson’s disease

Cardioprotective effects by inhibition of blood platelet aggregation

6. Conclusions

452

Endogenous metabolism and physiological functions position H2S in the novel family of endogenous gaseous transmitters – called ‘gasotransmitters’, besides NO and CO. So H2S is another inorganic gasotransmitter in the cardiovascular and nervous system [15]. Because there are some controversies in the field surrounding the physiologically significant H2S concentrations and its biological effects is in the midst of the lively expansion [85,86]. H2S has been demonstrated to stimulate or inhibit certain intracellular transduction pathways, to stimulate [87] or inhibit [72,88] cell proliferation, to active [73,74] or block [29] apoptosis, to be pro- [32] or anti-inflammatory [89], active or block hemostasis [17]. Some of this effects are still controversial [15]. Only few studies have shown alterations in H2S level in human diseases (e.g. Down syndrome, septic shock or ischemic stroke) and what is important, in most cases it was done indirectly by measuring H2S-related compounds – thiosulfate or sulfhemoglobin [90] rather than H2S itself. Due to its vasorelaxative and also vasoprotective properties, H2S might be useful in treating arterial hypertension by decreasing peripheral resistance [86]. Novel exciting and important aspects of H2S research continuously emerge. For example, considering the role of oxidative stress in many diseases (such as atherosclerosis, Alzheimer’s disease, etc.) one might wonder if excessive ROS production may cause H2S deficiency [45]. Its effect on hemostasis: blood platelet activation or hemostatic proteins is still unknown? Recognition of H2S role (the friend or the foe) in hemostasis may bring benefits in prophylaxis and treatment many diseases, such as: cardiovascular diseases, which are the highest risk of death. Researchers speculate the positive role of hydrogen sulfide (as the friend) in the cardiovascular system.

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Conflict of Interest

482

The authors declare that there are no conflicts of interest.


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Acknowledgements

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Special thanks goes to A. Morel, J. Malinowska and J. Tadeusiewicz (Department of General Biochemistry, University of Lodz) for help in preparing of the manuscript.

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Homocysteine: Friend or Foe?

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KIM-1: friend or foe?

Pericytes in wound healing: friend or foe?

Autophagy: Friend or Foe in Lung Disease?

Erythropoietin in stroke therapy: friend or foe.

Serotonin in liver tumor: Friend or foe?

microRNAs in mycobacterial disease: friend or foe?

YAP in tumorigenesis: Friend or foe?

Big data in nephrology: friend or foe?

Protein phosphorylation in neurodegeneration: friend or foe?

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Internal thoracic vein: friend or foe?

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Computer-assisted personalized sedation: friend or foe?