Cellular Physiology and Biochemistry

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Atherosclerosis and the Hydrogen Sulfide Signaling Pathway – Therapeutic Approaches to Disease Prevention

Wang Z.-J.a,b · Wu J.b,c · Guo W.b · Zhu Y.-Z.a,b

Author affiliations

aSchool of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science & Technology, Macau, China
bShanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
cDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China

Corresponding Author

Yi-Zhun Zhu and Wei Guo

Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng

Road, Shanghai 201203 (China)

E-Mail zhuyz@fudan.edu.cn/yzzhu@must.edu.mo/guowei@fudan.edu.cn

Key Words: H2SAtherosclerosisCSEApoEGasotransmitter

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https://doi.org/10.1159/000478628

Abstract

Hydrogen sulfide (H2S) is now admitted as a third gasotransmitter together with nitric oxide (NO) and carbon monoxide (CO), albeit it was originally considered as a foul and poisonous gas. Endogenous H2S production in mammalian cells is counting on the three enzymes acting on cysteine. Involvement of H2S in various physiological and pathological processes has been extensively studied in the last fifteen years. Mounting evidence suggests that H2S is able to protect against atherosclerosis development and progression. Exogenous H2S supplement has salutary effects on atherogenesis, and reduction of the endogenous H2S level accelerates atherosclerosis. The anti-atherosclerotic mechanisms of H2S have been descried in different aspects, including endothelium preservation, antioxidative action, anti-inflammatory responses, vasorelaxation, regulation of ion channels, etc. However, further investigation is still needed to help us gain more insights into the fundamental underlying mechanisms, and that will allow us to design better therapeutic applications of H2S in the treatment of atherosclerosis.

© 2017 The Author(s). Published by S. Karger AG, Basel

Introduction

H2S made its landfall in gasotransmitter field 15 years ago [1], being recognized as the third gasotransmitter alongside with nitride oxide (NO) and carbon monoxide (CO). Like NO and CO, H2S is widely implicated in the physiological and pathophysiological processes in both prokaryotes and eukaryotes. It is known that these anaerobic gases ubiquitously existed and may serve as an energy source in the ancient earth where considering amount of oxygen was available. So it is reasonable that these three gasotransmitters profoundly affect the lives on earth now since their entire involvement in our evolutionary process.

Atherosclerosis, characterized with fatty of cholesterol build up in the large- or medium-sized vessels and artery trees [2], is developed from a continuous process that involves numerous pathophysiological processes that influence each other. These include vascular inflammation, endothelial dysfunction, smooth muscle cell (SMC) proliferation and migration, lipoproteins accumulation monocyte recruitment and adhesion and macrophage differentiation. Since the precise roles of each of processes contributed to the disease are not fully understood, it’s difficult to reveal drug targets and develop corresponding therapeutic approaches for intervention. Recently, it was reported that alteration of H2S production is highly associated with atherosclerosis acceleration, and H2S intervention could significantly prevent the emergence and progression of atherosclerosis which may become a whole new target for atherosclerosis treatment, drawing much of our attention now. But how H2S exerts this beneficial effects haven’t been fully elucidated.

In this review article, we discuss the endogenous production and elimination of H2S, with its usual physiological actions and mechanisms related to vasculature, and how H2S participates in atherosclerosis development.

H2S production and elimination

The production of H2S in mammalian cells is constitutive of both endogenous enzyme catalysis and nonenzymatic pathways (e.g., degradation of thiols and thiol-containing molecules). However, more studies are focusing on the enzymatic generation of H2S, which may be crucial for the regulation in specific cells under special conditions. H2S generated from molecule reservoirs with bound sulfane sulfur by enzymes can interact with cysteine thiols to form stabilized persulfides which may be one of the mechanisms by shedding light on the protective effects of the gas.

As to enzymatic pathways of generating H2S, four critical enzymes are required, including cystathionine γ lyase (CSE, EC 4.4.1.1), cystathionine β synthase (CBS, EC 4.2.1.22), cysteine aminotransferase (CAT, EC2.6.1.3) and 3-mercaptopryruvate sulfurtransferase (3-MST, EC 2.8.1.2). These four enzymes compose three chemical pathways to generate H2S in mammalian cells. CSE, which is normally localized in cytosol catalyzes L-cysteine to thiocysteine and then rearranges to form H2S. CBS acts on L-cysteine to generate H2S and L-serine. In addition, CBS is the rate-limiting enzyme to consume homocysteine and serine to train cystathionine. 3-mercaptopyruvate is produced by CAT with L-cysteine and keto acids and is then catalyzed by 3-MST to form H2S. Additionally, it is useful to mention that cysteinelyase (CL, EC 4.4.1.10) can convert L-cysteine and sulfite into cysteate and H2S, contributing to part of endogenous H2S production. Recent researches reported a novel pathway to produce H2S by utilizing D-cysteine, which introduced a new enzyme named D-amino acid oxidase (DAO, EC 1.4.3.3). DAO metabolizes D-Cysteine to achiral 3-mercaptopyruvate which is a substrate of 3-MST to produce H2S [3]. Interestingly, DAO is localized in peroxisomer, whereas 3-MST is located at mitochondria and DAO is only found in brain and kidney, which limits the effects of DAO/3-MST pathway, whereas the H2S concentration is 7- and 80-fold higher in cerebellum and kidney than that in other tissues, which may indicate significance of H2S in related regions [4]. Pyridoxal 5’-phosphate (PPP) is requisite for CSE, CBS, CAT and CL as a cofactor, but 3-MST is zinc dependent. The elimination of H2S is constitutive of oxidation, methylation, scavenging together with expiration and excretion. Specific catalytic reaction pathways can be transmitted to Fig. 1.

Fig. 1.

Mammalian metabolic pathways involved in H2S biosynthesis and catabolism.

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Distribution of endogenous H2S producing enzymes in mammalian tissues is complicated. CSE is generally located in cardiovascular system [5], liver [6], kidney [7] and gastrointestinal tract [8-10]. CBS protein expression is dominant in the brain [11], and its existence in other tissue has been confirmed (e.g., liver, kidney, uterus and gastrointestinal tract [12-14]). 3-MST is detected mostly in the central nervous system [15], other tissues include vasculature [16], especially coronary artery [17], kidney and liver [15, 18].

Physiological effects of H2S and related molecular mechanisms associated with atherosclerosis preventing effect

H2S exerts distinct physiological effects on different organs and tissues, varying from heart to brain and from vasculature to neurons. In consideration of the chemical nature of H2S, it can easily reach its molecular targets since H2S is a gasotransmitter which are dissolved in extracellular fluid, on the plasma membrane, within the cytosol or inside the intracellular organelles, mirroring its wide scope of physiological and biological effects. However, this peculiar chemical reactive ability with certain types of molecular targets that make it as a selective and multifunctional signaling molecule [19].

Interactions with ion channels

H2S, as an endothelium-derived hyperpolarizing factor (EDHF) being recently identified, exerts vasorelaxant effects by influencing many ion channels, partially explained by sulfhydrating vasorelaxation related ion channels [20]. To date, it activates small- and intermediate-conductance calcium-activate potassium channels (SKCa and IKCa channels, respectively) and induces endothelium-dependent smooth muscle hyperpolarization, which can be stopped by the co-application of charybdotoxin and apamin [21]. The mechanism of H2S playing a role as an EDHF is partly elucidated by H2S sulfhydrating IKCa channels in primary human aortic endothelial cells [20]. Not limiting to SKCa and IKCa channels, it has been reported that H2S dilates phenylephrine (PE)-constricted rat mesenteric arteries by activating endothelial big-conductance calcium-activated potassium channels (BKCa) [22] and CYP2C and then triggers vascular smooth muscle cells (VSMCs) Ca2+ sparks, which can be inhibited by ryanodine (ryanodine receptor blocker), iberiotoxin (BKCa blocker), endothelium denudation and sulfaphenazole (CYP2C inhibitor) [23].

Besides conductance calcium activated potassium channels, H2S also activates ATP-sensitive potassium channels (KATP channels) to mediate H2S-evoked vasodilation [5]. The stimulation of KATP channels in VSMC partially demonstrates the vasorelaxant effects of H2S [24, 25]. As the molecular target of H2S, the sulfonylurea receptor 1 (SUR1) subunit of KATP channels through mutagenesis in HEK-293 cells [26] and the SUR2B subunit of KATP channels in colonic smooth muscle cells [27] can be sulfhydrated by H2S. KATP channels, 4-Aminopyridine (4-AP)-sensitive potassium channels are also contributed to NaHS-induced relaxation in rat coronary artery [28]. Besides, H2S mediates rat mesenteric arteries vasorelaxation through the release of neurotransmitters by sensory nerves’ transient receptor potential ankyrin 1 (TRPA1) channels activation [29].

H2S plays synergistically with NO to form polysulfides (H2Sn) to act as TRPA1 channel activator in vasodilation [30]. Meanwhile, ZYZ-803, a slow-releasing H2S-NO hybrid molecule, could exert vasorelaxant effect [31] and angiogenesis [32] activity better than S-Propargyl-Cysteine (SPRC) and furoxan alone or together. And as reported recently, H2S could upregulate and stabilize the endothelial nitric oxide synthase by facilitating miRNA-455-3p expression [33]. And H2S could down regulate inducible NOS (iNOS) expression in LPS-induced acute lung injury [34].

Interactions with second messengers

Considering the wide scope of influence of H2S, inevitably H2S affects second messengers although it can also directly affect the target protein alone. Cytosol free calcium is a classical second messenger in cellular signal transduction. Effects of H2S on calcium handling in specific cells differ. In endothelial cells, H2S can raise intracellular calcium levels by either triggering calcium influx [35] or stimulating an ATP- and 4-CEP sensitive intracellular calcium pool [36], thus activating many calcium-dependent signaling pathways such as endothelial cells migration [37] and metabolism or adjusted function ensuing. H2S triggers calcium sparks in VSMCs in rat mesenteric arteries [23] and pig cerebral arterioles [38]. Calcium sparks stimulate transient KCa channels and consequent plasma membrane hyperpolarization which concretely manifests vasodilation. Actions on cardiomyocytes of H2S are biphasic, not only inhibiting L-type and T-type VDCCs but also increasing calcium release from intracellular calcium pool [39], of which the realistic functional consequence has not been clarified. In turn, calcium-sensing receptor (CaSR) regulates the endogenous CSE/ H2S pathway to achieve the inhibition of proliferation of VSMCs in diabetic models [40] and the protective effects in high glucose-induced cardiotoxicity via inhibition of nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3 (NLRP3) inflammasome activation [41] and NADPH oxidase 4 (NOX4) inhibition [42].

Besides, H2S inhibits adenylyl cyclase and stimulates phosphodiesterases (PDEs) to make the concentration of cyclic AMP decline [43]. However, it has been reported that H2S inhibits PDEs in many studies [44, 45]. How this contradiction occurs will raise the issue of whether the effect of H2S is tissue specific.

Post-translational modification: proteins sulfhydration

Protein S-sulfhydration is ubiquitous in vivo. It has been reported that S-sulfhydration can be detected by biotin-switch assay [46] and tag-witch method [47, 48]. For instance, Kelch-lick ECH-associated protein 1 (KEAP1), a negative protein factor of nuclear factor erythroid 2-related factor 2 (NRF2), can be sulfhydrated at the Cys151, but not Cys273, by H2S to dissociate with NRF2, hence, the NRF2-related antioxidant responses was enhanced [49, 50] and subsequent diabetes-accelerated atherosclerotic progress was ameliorated [51].

H2S and antioxidant defences

Redox includes oxidation and reduction processes, where electrons migrate from the reductant to oxidant. Redox balance shift reflects the homeostasis change, more specifically, higher oxidant stress and/or lower reductive ability contributes to numerous pathological processes and molecule and cell damage. The antioxidant effects of H2S have been clearly established, not only because of its reductive chemical nature, but also its ability of regulating lots of protein and signaling pathways [52]. H2S destroys lipid hydroperoxides in oxidized low-density lipoprotein (ox-LDL) [53]. In addition to hydroperoxides, H2S scavenges oxidants including superoxide [54], H2O2, HOCl/-OCl and ONOOH/ONOO- [55], although the low physiological concentration of H2S can not fully account for the antioxidant effects of H2S [55, 56], indicating another mechanism rather than its chemical redox nature plays a role in it. As to signaling pathway, KEAP1-NRF2 pathway S-sulfhydration [49] could serve as an example to modulate redox balance homeostasis. Schematic graph of H2S related physical molecular mechanisms could be referred to Fig. 2.

Fig. 2.

Cystathionine γ lyase and cystathionine β synthase (CBS) use L-cysteine as the substrate to produce H2S within mammalian tissues. In addition, 3-mercaptopyruvate sulfurtransferase (3-MST/MST) acts on 3-mercaptopyruvate (3-MP), produced by cysteine aminotransferase (CAT) from L-cysteine, to produce H2S. 3-MP can also synthesised from D-cysteine by the catalytic action of D-aminoacid oxidase (DAO). Interestingly, CSE is usually located within the cytosol however recent evidence suggests that this enzyme can also translocated to mitochondrion under stress conditions (e.g. pO2↑ or [Ca2+]↑). Both CAT and MST can be found both in cytosol and mitochondrion. CBS is mostly located in cytosol. Hcy, homocysteine; PDE, phos-phodiesterase; pO2, partial pressure of oxygen.

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H2S epigenetic regulation atherosclerosis is an important factor in the pathogenesis of atherosclerosis

Sirtuin 1 (SIRT1) and H2S

Although evidence has been pointed to the direct actions of H2S to hamper the development of atherosclerosis, whether other molecular mechanisms are involved in anti-atherogenesis effect of H2S is well worth considering. SIRT1, functions as a NAD+-dependent histone deacetylase, is highly distributed in the vasculature [57] and is implicated in the field of aging, metabolism [58]. Previous studies have demonstrated that SIRT1 played a major role in regulating the vascular tone [59-61] and down regulation of atherosclerosis [61, 62]. It has been reported that mice overexpression of SIRT1 preserved the endothelium function comparing with that of WT littermates fed with high-fat diet and overexpression of SITR1 in ApoE-/- mice developed less atherosclerotic lesions compared with the ApoE-/- controls [61]. The mechanism of SIRT1 improving atherosclerosis may include dilating arteries [59], preserving function of endothelium [60] and preventing endothelial senescence [63], downregulating neointima formation [64] and vascular modeling [65], decreasing Lox-1-induced foam cell formation [62] and protecting against DNA damage [66]. It has been reported that H2S upregulated SIRT1 to exert some of its protective effects. For example, H2S upregulated SIRT1 to inhibit endoplasmic reticulum stress in PC12 cells [67] and to prevent H2O2-induced [68] or nicotinamide-induced [69] senescence in human umbilical vein endothelial cells (HUVECs). Besides HUVECs, previous studies from our group demonstrated that H2S increased SIRT1 expression to abolish the oxidative stress induced apoptosis in H9c2 cardiomyocytes [70] and previous studies from our group demonstrated [6] found that H2S attenuated inflammatory hepcidin partially by promoting SIRT1-mediated STAT3 deacetylation. SIRT3, one of the isoforms of SIRT family, has also been reported that it could be regulated by H2S to protect endothelial cells in an antioxidant manner [71].

DNA damage and H2S

DNA damage accumulation is one of the notable features of atherosclerosis [72]. Mitochondrial DNA (mtDNA) damage has been reported as a risk factor independent of reactive oxygen species (ROS) to accelerate atherosclerosis by acing on VSMCs and monocytes [73]. In addition to mtDNA damage, VSMC DNA damage, including double-stranded breaks (DSBs) and DNA damage response activation, could alter plaque phenotype and inhibits fibrous cap areas, making it a novel target to exert salutary effects on plaque stability [74]. Interestingly, H2S ameliorates DNA damage in endothelial cells and fibroblasts via S-sulfhydration of MEK1 which leads to activation of PARP-1, thus attenuating cell senescence [75]. Besides, H2S maintains mtDNA replication and copy number by demethylation of mitochondrial transcription factor A (TFAM) [76]. Not limited to DNA itself, H2S can also remodel chromatin to modulate cytokine production [77]. Interestingly, CSE gene promoter was methylated by ox-LDL treatment in macrophages and in ApoE KO mice, which was recently reported by Du et al. [78]. It will be an interesting question whether H2S plays its anti-atherosclerotic role via repairing DNA both in nuclear and mitochondria. As to the role of VSMC in atherosclerosis, recently Feil [79] et al. reported that VSMC could transdifferentiate to macrophage-like cell during atherosclerosis, which had a significant effect of plaque stability because of loss of the balance of atherosclerotic composition. It will be just an question that whether any link exists between DNA damage, VSMC transdifferentiation and H2S. S-Propargyl-Cysteine (SPRC), an endogenous H2S initiator derived from garlic, could ameliorate DNA damage in doxorubicin-induced cardiotoxicity [80]. Schematic figure of H2S-exerted therapeutic effects could be transmitted to Fig. 3.

Fig. 3.

Exogenous and endogenous H2S can reduce the progression of atherosclerosis via amelioration of platelet aggregation, inhibition of inflammation, reduction of foam cell formation, vasorelaxation, and prevention of vascular smooth muscle cell (VSMC) proliferation, migration, calcification and senescence, and induction of VSMC apoptosis. These therapeutic effects are partly attributed to the S-sulfhydration at Cys151 of NRF2, which can trigger HO-1 upregulation and induce cellular antioxidative defences.

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Evidence related to atherosclerosis prevention and treatment

Atherosclerosis, a chronic progression from very early stage [2], inflammatory, cholesterol-rich lipids piling up disease, can principal morbidity and mortality worldwide [81]. Main therapeutic strategy to lower or reverse atherosclerosis is statins, but the clinical benefits of statins is somehow limited [82]. Surprisingly, recent reports have mentioned that treatment of statins can improve the H2S production, but it is the lipophilic atorvastatin, but not the hydrophilic pravastatin that increases the net H2S production [83-88]. Recently, It is reported that estrogen evoked anti-atherosclerotic effects was mediated through CSE-generated H2S [89]. Meanwhile, H2S has been proved to protect arteries from atherogenesis via various mechanisms.

Evidence has been piling up that H2S, a new star of gasotransmitter, plays a significant role in protecting susceptible arteries from atherogenesis via a variety of actions on certain types of cells. Detailed information could be referred to Table 1.

Table 1.

H2S exerted therapeutic effects in prevention of atherosclerosis

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In vivo evidence of H2S preventing atherosclerosis

Philip K. Moore et al. [106] reported that C57/Bl6 mice fed with a high fat diet up to 16 weeks showed a decrease of H2S producing enzymes which may contribute to later reducing endogenous H2S production and increased levels of plasma IL-6, IL 12p40 and G-CSF, though that of lipid deposition in aortae was inconspicuous and serum amyloid A (SAA) and C-reactive protein (CRP) did not change. CSE down regulation in atherosclerosis may partially attributed by microRNA-186 upregulation in THP-1 macrophages [107]. These evidence indicated that a high fat diet may trigger endogenous H2S production decline which is prior to apparent atherosclerotic disease.

Exogenous H2S treatment in apolipoprotein E (ApoE) knock out (KO) mice inhibits plaque progression. Hart et al. [108] reported that chronic treatment of sodium hydrosulfide in the final 4 weeks of 16-week high fat diet inhibited the development of vascular lesions and reduced systolic blood pressure whilst protected endothelium via causing reduction in vascular superoxide anion generation. However, inhibiting endogenous H2S generation with DL-propargylglycine (PAG) did not aggravate the lesion progression leading to the result that endogenous H2S is insufficient to abolish the atherogenesis. It is worth mentioning that PAG mediated CSE inhibition came at an incredibly high dosages (e.g., 50 mg/kg) and nonspecific effects [109-112].

Other researchers have reported the results in consist with aforementioned protective effects. Plasma H2S decreased and plasma and aortic intercellular adhesion molecule-1 (ICAM-1) increased in ApoE KO mice fed with a high fat diet, while size of atherosclerotic plaque shrank in NaHS treated ApoE KO mice and plaque size increased in ApoE KO mice administered with PAG [113]. Besides, NaHS inhibited ICAM-1 expression induced by tumor necrosis factor (TNF)-α stimulation via hampering IκB degradation in HUVECs [113]. Furthermore, Wang et al. [114] suggested that H2S inhibited progression of atherosclerosis in ApoE KO mice with high-fat diet via downregulating CX3CR1 and CX3CL1 expression on macrophages in the lesion plaque in vivo. In addition, exogenous NaHS achieved its beneficial effects on diabetes accelerated atherosclerosis by inducing KEAP1 sulfhydration and NRF2 activation [51]. Interestingly, NaHS exerted its anti-atherosclerosis effects through inducing protein S-nitrosylation [115]. Recent report unveiled that NaHS-induced anti-atherosclerotic effects could also be partially through up-regulating ATP-Binding Cassette Transporter A1 (ABCA1) [116]. In addition to the therapeutic effects of H2S, H2S could be a biomarker for ST-elevation myocardial infarction and unstable angina [117].

Exogenous H2S exerts anti-atherosclerosis effect, but whether exogenous H2S can be physically translated to endogenous H2S in vivo is not clear. Knock out of CSE, CBS or 3-MST may be a feasible approach to estimate the effect of endogenous H2S on tissues and organs. CSE knock out (CSE KO) mice was first reported by Wang et al. and the gene deletion resulted in diminished endothelium-dependent vasorelaxation and profound hypertension [118]. Besides, deficit of CSE led to multiple pathological changes, including VSMCs overproliferation [119], redox imbalances and apoptosis under hypoxia [101], macrophage enhanced releasing of TNF-α induced by oxLDL (CSE knockdown) [120]. Furthermore, Mani et al. [121] reported that early fatty-streak lesions occurred in CSE KO mice fed with an atherogenic paigen-type diet for 12 weeks, together with increased oxidation stress, increased expression of adhesion molecules and exacerbated aortic intimal proliferation. However, wild-type mice fed with an atherogenic paigen-type diet or CSE KO mice fed with a normal chow diet did not develop any distinct atherosclerotic damage. Fed with a regular diet for 24weeks, ApoE KO mice and ApoE-/-/CSE-/- (DKO) mice developed atherosclerosis, whereas CSE KO mice and WT mice appeared normal [121]. Though ApoE KO mice and DKO mice shared several similar biomarkers including plasma cholesterol and LDL-cholesterol levels, DKO mice showed an accelerated atherosclerotic plaque rather than CSE KO mice. NaHS intervention reduced the atherosclerotic progress without affecting plasma lipid levels compared with ApoE KO mice, prompting that CSE may be a risk factor independent of plasma lipid homeostasis. Recently, ApoE KO mice overexpressing CSE (Tg/KO) showed an increased H2S generation in aortic tissue, reduced atherosclerotic plaque, alleviated plasma lipid profiles and down-regulated oxidative stress, supporting the assumption that CSE was a plausible approach to prevent atherogenesis [122].

CBS KO mice showed mild and severe homocysteinemia because it is rate-limited enzyme consuming homocysteine to generate precursor of H2S. Besides, homozygous mutants suffered from severe growth retardation and the bulk of them died within 5 weeks after birth [123]. The plasma homocysteine level of homozygous and heterozygous mutants was 40 times and 2 times of that of WT mice, respectively. Considering high mortality of homozygous mice, heterozygous mice will be a feasible model for homocysteinemia [123]. In addition to homocysteinemia, CBS KO mice showed an abnormal lipid profiles, including markedly raised triglyceride and nonesterified fatty in serum and liver and serum elevated apolipoprotein B100 and very low density lipoprotein, which may be one of the causable factors of hepatic steatosis [124]. CBS deficit-induced homocysteinemia is involved in various pathogenesis. Hyperhomocysteinemia (HHcy) impairs EDHF induced relaxation in CBS deletion mice small mesenteric arteries by inhibiting SK/IK activities via imbalanced oxidative stress and tyrosine nitration-related mechanisms [125]. By introducing ApoE mutation into CBS KO mice (ApoE-/-/CBS-/- and ApoE-/-/CBS+/- mice), aortic lesions developed even without dietary manipulation, which indicated endogenous hyperhomocysteinemia was an independent factor for atherogenesis [126]. Interestingly, CBS homozygous mutant mice with zinc-inducible metallothionein promoter (Tg-hCBS) can circumvent the neonatal lethality of homozygous mutants [127]. By crossing ApoE KO mice with Tg-hCBS mice to create the Tg-hCBS ApoE-/- CBS-/- mice, fed with a high fat diet, severe HHcy exacerbated atherosclerosis and macrophages accumulation in lesions [128]. Additionally, homocysteine could in turn trigger inflammatory effects through inhibiting CSE expression via DNA hypermethylation on CSE promotor [129].

Introducing endogenous deficiency of H2S, whether by knocking out of CSE or CBS, atherosclerosis accelerates, even early stage of atherosclerosis develops in ApoE-/-CSE-/-, ApoE-/-CBS-/- and Tg-hCBS ApoE-/-CBS-/- mice without diet manipulations. These in vivo evidence fully stress the importance of endogenous H2S in preventing atherogenesis.

Anti-atherosclerotic effect of H2S-releasing drugs

Considering short half-time period and dramatic blood concentration fluctuation of NaHS, it would be more ideal to apply H2S-releasing drugs to circumvent the defects of NaHS. GYY4137 exhibits anti-atherosclerotic effects in high-fat fed ApoE KO mice by downregulating vascular inflammation and oxidative stress, preserving endothelial function and reduced plaque formation achieved. Besides, GYY4137 could protect against myocardial fibrosis [130]. GYY4137 could also dilate arteries [131, 132] and attenuate fibrosis of myocytes [130], which might also be implicated in atherosclerosis prevention [51]. S-aspirin (ACS14), another H2S-releasing chemical, also protects 12-week high-fat fed ApoE KO mice from atherosclerosis by 12-week treatment of ACS14 via reducing CX3CR1 expression in lesions and impeding atherogenesis and progress of atherosclerosis [133]. ACS14 also inhibits human platelet aggregation [105] and has strong antithrombotic effects [134]. In addition, Diallyl disulfide (DADS), organic sulfide donor which is derived from garlic, abolishes the deleterious effects of ox-LDL on NO production of eNOS [135] and suppresses ox-LDL-induced VCAM-1 and E-selectin expression [136], which may somehow possesses the potential to improve atherosclerosis. Our recent investigation revealed that SPRC could prevent methionine and choline deficient diet-induced fatty liver through antioxidant pathways that were consistent with via which H2S exerted its antiatherosclerotic effects (Fig. 4) [51], and H2S could be promising in preventing atherosclerosis [137].

Fig. 4.

NaHS and SPRC, a CSE initiator, significantly improved the MCD diet-induced NAFLD in mice. (A) H&E staining of liver after scheduled administration. (B) Oil Red-O staining aortas from high fat diet-induced mice model treated with or without NaHS. (C) Pathways involved in prevention of NAFLD of SPRC. (B) is adapted from [116] and (A) and (C) are derived from [136].

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Conclusion and perspectives

We have summarized the known knowledge of H2S distribution, production and metabolism, physiological effect and molecular mechanisms related to vasculature, and profound significance of H2S in atherosclerotic progress and development. Finally, we point out some additional insights of mechanisms H2S may involve in, shedding new light of how H2S works to protect the precise architecture of the body. Although the full picture of this gas remains to be investigated into and the underlying mechanisms await to be further elucidated, the therapeutic effects of H2S and H2S-releasing chemicals are extremely promising. Drawbacks, rapid degradation and dramatic fluctuation, and whether the therapeutic effects in animal studies can be translated into clinical studies require to be considered discreetly. However, a steady H2S-releasing donor will be improved, not only for the research purpose but also for the safe and controlled therapeutic application based on H2S. In short, a better understanding of how H2S works to protect from atherosclerosis and the development of promising H2S-based therapy may pave the way for treating atherosclerosis in the future.

Abbreviations

H2S, hydrogen sulfide; NO, nitric oxide; CO, carbon monoxide; SMC, smooth muscle cell; CSE, cystathionine γ lyase; CBS, cystathionine β synthase; CAT, cysteine aminotransferase; 3-MST, 3-mercaptopryruvate sulfurtransferase; CL, cysteine lyase; DAO, D-amino acid oxidase; EDHF, endothelium-derived hyperpolarizing factor; SKCa channels, small- conductance calcium-activate potassium channels; IKCa channels, intermediate-conductance calcium-activate potassium channels; PE, phenylephrine; BKCa channels, big-conductance calcium-activated potassium channels; VSMCs, vascular smooth muscle cells; KATP channels, ATP-sensitive potassium channels; SUR1,sulfonylurea receptor 1; 4-AP, 4-Aminopyridine; TRPA1, transient receptor potential ankyrin 1; VDCCs, voltage-dependent calcium channels; CaSR, calcium-sensing receptor; phosphodiesterases (PDEs); KEAP1, Kelch-lick ECH-associated protein 1; NRF2, nuclear factor erythroid 2-related factor 2; PGC, proliferator-activated receptor-γ coactivator; PPRC, peroxisome proliferator-activated receptor-γ coactivator-related protein; ox-LDL, oxidized low-density lipoprotein; SAA, serum amyloid A; CRP, C-reactive protein; ApoE, apolipoprotein E; PAG, DL-propargylglycine; ICAM-1, intercellular adhesion molecule-1; TNF, tumor necrosis factor; ABCA1, ATP-Binding Cassette Transporter A1; HHcy, Hyperhomocysteinemia; SIRT1, Sirtuin 1; HUVECs, human umbilical vein endothelial cells; mtDNA, mitochondrial DNA; reactive oxygen species (ROS); DSBs, double-stranded breaks; TFAM, transcription factor A; SPRC, S-Propargyl-Cysteine; KO, knock out; H2Sn, polysulfides; NLRP3, nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3; NOX4, NADPH oxidase 4.

Acknowledgements

This work was kindly supported by the National Scientific and Technological Major Project (No.2012ZX09501001-001-003, 2012ZX09103101-064), National Natural Science Foundation of China (No. 81573421, 81330080, 81173054), Shanghai Committee of Science and Technology of China (No. 14JC1401100), and the Key Laboratory Program of the Education Commission of Shanghai Municipality (No. ZDSYS14005).

Disclosure Statement

The authors claim no conflict of interests of the publication of this paper.


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Author Contacts

Yi-Zhun Zhu and Wei Guo

Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng

Road, Shanghai 201203 (China)

E-Mail zhuyz@fudan.edu.cn/yzzhu@must.edu.mo/guowei@fudan.edu.cn

Article / Publication Details

First-Page Preview
Abstract of Review

Received: March 21, 2017
Accepted: April 11, 2017
Published online: June 23, 2017
Issue release date: October 2017

Number of Print Pages: 17
Number of Figures: 4
Number of Tables: 1

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: https://www.karger.com/CPB

Open Access License / Drug Dosage / Disclaimer

This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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2017, Vol.42, No. 3

October 2017

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Z. Wang and J. Wu contributed equally to this work.
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