Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells. Z Altaany Hydrogen sulfide and endothelial dysfunction: relationship with nitric oxide. Hydrogen Sulfide (H2S) and Nitric Oxide (NO) have become recognized as important gaseous signaling molecules with enormous. PL16 Relationship between Hydrogen Sulfide and Nitric Oxide . OP15 Hydrogen sulfide protects endothelial function under conditions of oxidative stress.
Modulated macrophage infiltration decreased inflammation, diminished interstitial fibrosis and improved cardiac remodeling and dysfunction Nahrendorf et al.
Recently, our study demonstrated that exogenous H2S treatment increased macrophage infiltration into the infarcted myocardium at the early stage of MI in both wild type and CSE-deficient mice Miao et al. In this study, exogenous H2S treatment promoted the migration of macrophages in vitro. In our very recent study, we further demonstrated that exogenous H2S treatment ameliorated post-MI pathological cardiac remodeling and dysfunction in wild-type and CSE-deficient mice, decreased infarct size and mortality, and promoted M2 polarization of macrophages at the early stage of MI Miao et al.
Notably, adoptive transfer of exogenous H2S-treated bone marrow-derived macrophages into wild-type and CSE-deficient mice with depleted macrophages also improved MI-induced cardiac dysfunction. A similar profile was also observed by Ji et al. Further mechanistic investigations demonstrated that exogenous H2S-induced M2 polarization of macrophages was achieved by enhanced mitochondrial biogenesis and fatty acid oxidation Miao et al.
The immunomodulatory role of H2S in myocardial ischemia. In addition to regulatory effects of H2S on immune cell infiltration and phenotype switch, it also directly inhibits inflammatory responses in ischemic myocardium.
In addition, Toldo et al. Heart Failure Heart failure is an inability of the heart to adequately meet the metabolic needs of the body, a clinical disease causing significant morbidity and mortality.
Heart failure is the final outcome of conditions with varying etiologies. Atherosclerosis, risk factors, and comorbidities such as diabetes and obesity, many of which have an inflammatory component, typically precede MI injury Odegaard and Chawla, The smoldering immune-inflammatory response impedes infarct healing by interfering with resolution of local inflammation and delaying the reparative phase Swirski and Nahrendorf, Although the prognosis of patients with acute MI is largely determined by the extent of myocardial tissue loss, immune-inflammation also plays a critical role in the evolution of MI-induced cardiac remodeling and may tip the balance in favor of heart failure.
In addition, they found that CSE-deficient mice exhibited greater cardiac dilatation and dysfunction compared to wild-type mice after transverse aortic constriction. In contrast, cardiac-specific CSE transgenic mice maintained cardiac structure and function after transverse aortic constriction. All these data suggest that both exogenous and endogenous H2S exhibit cardioprotective effects in heart failure.
In heart failure, accumulating experimental and clinical evidence points to a gradual state of immune-inflammatory activation accompanied by the progression of ventricular dysfunction with leukocyte activation and release of inflammatory mediators.
Our previous study demonstrated that exogenous H2S administration markedly inhibited inflammatory cytokine expression in an in vivo model of heart failure associated with improving cardiac function and attenuating myocardial fibrosis Pan et al. In addition, H2S also inhibited chronic inflammatory responses and attenuated myocardial hypertrophy in experimental models of myocardial infarction and pressure overload induced via transverse aortic constriction Nishida et al.
These findings support the emerging view that H2S has potent immuno-inflammatory regulatory activities in ischemia-induced heart failure, resulted in reduced interstitial fibrosis, cardiac hypertrophy as well as improved overall survival Figure 3. The immunomodulatory role of H2S in heart failure A H2S administration induced cardioprotection in chronic MI by improving cardiac function, attenuating myocardial fibrosis, and inhibiting chronic inflammatory mediators.
Interaction of Hydrogen Sulfide with Nitric Oxide in the Cardiovascular System
C H2S induced M2 macrophage polarization and recruitment in myocardial infarction, thereby contributing to angiogenetic factor release and subsequent angiogenesis. Angiogenesis is a complex biological process that leads to increased blood flow and promotes cardiac repair and myocardium survival during heart failure. Therefore, promoting myocardial angiogenesis is a novel therapeutic strategy for the treatment of heart failure Bao et al.
In recent years, the gasotransmitter H2S has become apparent that it is capable of mediating angiogenesis and improving cardiac function after heart failure Givvimani et al. In a mouse model of transverse aortic constriction-induced heart failure, chronic H2S treatment with diallyl trisulfide improved left ventricular remodeling and function by inducing angiogenesis via upregulation of VEGF and endothelial NO synthase.
One proposed explanation for these observations is that distinct macrophage subpopulations may mediate inflammatory M1 and reparative M2 macrophage activities Lavine et al.
Although there is no direct evidence that H2S modulates macrophage phenotype in heart failure, Kolluru et al. However, the contribution of M1 vs. M2 macrophages in H2S-mediated angiogenetic responses in heart failure has yet to be clarified in future investigation.
Likewise, depletion of dendritic cells disturbs resolution of inflammation Hofmann et al. There is still lack of direct evidence for an immunoregulatory role of H2S on immune cell phenotypes in heart failure.
Given that leukocytes play a key role in heart failure, the immunoregulatory function of H2S on different immune cell subsets merits further investigations. Taken together, preclinical evidence suggests that H2S significantly improve cardiac function in the setting of heart failure via immunoregulatory activities, including modulating immune cell phenotypes, suppressing inflammatory responses and inflammatory cell infiltration, which represents a therapeutic strategy for heart failure Figure 3.
Atherosclerosis Atherosclerosis, a vascular disease at the susceptible sites in medium and large-sized arteries, is the pathological basis of coronary heart disease and the major cause of death in developed countries. The development of atherosclerosis is a complex multifactorial process that involves vascular inflammation, VSMC proliferation and migration, thrombus formation, as well as abnormal immune responses including monocyte infiltration and differentiation, and lesion-resident macrophage conversion into foam cells Pan et al.
Through the factors that initiate plaque formation and are currently being debated, it is no longer news that atherosclerosis is more than a mere cholesterol storage disease. Immune inflammation in the pathogenesis of atherosclerosis has now gained widespread recognition Libby and Hansson, Recent studies have suggested that dysfunctional CSE and reduced endogenous H2S levels are linked to the pathogenesis of atherosclerosis Wang et al.
At the same time, CSE expression and H2S production were reduced during neointimal hyperplasia in carotid artery in rats, and that exogenous H2S treatment markedly reduced neointimal formation Meng et al. Furthermore, Wang et al. Initially, exploration of the immune-inflammatory aspects of atherogenesis focused on the intima, the site where atheromata take root. As probing has deepened, researchers have come to recognize that influence arising from all three layers of arteries can affect the pathophysiology of this disease Libby and Hansson, ; Gistera and Hansson, Indeed, immune-inflammatory responses participate in atherosclerosis by modifying the arterial tree at various levels Libby and Hansson, Accumulating evidence has indicated that H2S is involved in the immune-inflammatory processes in atherosclerosis in a number of preclinical models of atherosclerosis Figure 4.
The vascular endothelial dysfunction, characterized by the loss or dysregulation of the homeostasis, is considered an important early event in the development of atherosclerosis Mani et al. Endothelial dysfunction is associated with increased oxidative stress, adhesion molecules expression, synthesis of inflammatory and pro-thrombotic factors, and abnormal modulation of vascular tone Mani et al.
Similarly, Feng et al. In contrast, Zanardo et al. The immunomodulatory role of H2S in atherosclerosis. B H2S inhibited monocyte activation and foam cell formation, thereby contributing to inflammatory cytokine release, VSMC proliferation and subsequent atherosclerotic plaque formation. Macrophage is thought to play an important role in atherosclerosis by generating lipid-laden foam cells and by secreting inflammatory mediators Moore and Tabas, However, H2S plays an inhibitory role in macrophage-derived foam cell formation.
In vitro, Wang et al. The protective effect of H2S can be, at least in part, attributed to Nrf2 activation via Keap1 S-sulfhydration at Cys However, PPG demonstrated the opposite effect: In vivo, Zhang et al. Lastly, they identified that plasma H2S level was negatively correlated with the proportion of Mon2 monocyte subsets, suggesting that impaired endogenous H2S synthesis in ACS may facilitate monocyte subset conversion from Mon1 to Mon2 or Mon3, leading to atherosclerotic plaque instability, and the development of ACS Gao et al.
However, the precise mechanism by which H2S regulates monocyte phenotypes in CAD remains to be better understood. T-helper Th cells play a critical role in mediating adaptive immunity. Accumulating evidence has shown that peripheral activation of Treg and subsequent recruitment to atherosclerotic plaque limit the lesion progression in experimental models by down-regulating inflammatory responses which include multiple mechanisms Libby et al.
More recently, Yang et al.
H2S also enhances T cell proliferation and lineage determination via altering cytoskeletal actin dynamics and increasing the reorientation of the microtubule-organizing center Miller et al. Therefore, it may be a novel therapeutic approach for chronic immune-inflammatory responses in atherosclerosis via targeting H2S metabolism. Mechanisms underlying H2S signaling have been uncovered; however, a lot of unknowns on how H2S influences cardiovascular homeostasis remain to be further investigated.
Immune-inflammatory responses play a decisive role in different phases of cardiovascular diseases Gistera and Hansson, ; Jones et al. Data from basic studies support immunoregulatory functions of H2S and therefore the potential of H2S to modulate the immune-inflammatory response to prevent cardiovascular disorders, including ischemic heart disease, atherosclerosis, heart failure, and so on.
In other cardiovascular diseases such as hypertension, H2S has been demonstrated to play an important role Yang et al. As arterial inflammation and immune dysregulation are involved in the pathogenesis of the disease Smith and Ferguson, and H2S has been shown to maintain immune homeostasis, it could be postulated that H2S may play a positive role in such condition. So far literature has been limited to provide further evidence and hence is not covered in the current review, which merit future investigation and verification.
Both pro- and anti-inflammatory effects of H2S have been reported. In numerous studies including our studies, H2S has been characterized for its anti-inflammatory role Cao and Bian, ; Zhou et al. In contrast, recent work from different groups has shown a key role of H2S as an inflammatory mediator Li et al.
Endothelial dysfunction: the link between homocysteine and hydrogen sulfide.
Biochemistry of NO-H2S Interaction The biological and chemical reactivities of H2S have been discussed thoroughly in some excellent review papers previously [ 4243 ].
H2S can form chemical complexes with nitrate, nitrite, S-nitrosothiols, and peroxinitrates [ 45 ]. In a previous work, Whiteman et al. The study revealed that the addition of H2S to various NO donors not only inhibits the release of NO, but also alters the expected NO-based biological function. The aerobic conditions maintained during these experiments might be responsible for NO oxidation leading to the formation of nitrosating species.
HNO can react with thiol groups in the cysteine residues to form N-hydroxysulfenamide RSNHOH [ 52 ] or helps to form a reversible disulfide bond if there are two thiols residing in the near vicinity [ 53 ].
Hydrogen sulfide and endothelial dysfunction: relationship with nitric oxide.
These modifications may induce conformational change and therefore the functions of the targeted proteins Figure 2. The pharmacological effects of HNO donors have already brought attention of many research groups towards their potential therapeutic value against many cardiac ailments such as congestive cardiac failure.
There are several types of HNO releasing compounds. In the upcoming sections of this paper, we have discussed the effects of HNO on various aspects of cardiovascular physiology. Simplifying depiction of chemical interaction between H2S and NO. HNO may modify the functions of proteins by converting their reactive thiols thiolates in cysteine residues to N-hydroxysulfenamide RSNHOH or forming disulfide bond between two thiol groups in the near vicinity.
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- Hydrogen sulfide and endothelial dysfunction: relationship with nitric oxide.
Role of H2S-NO Interaction in the Regulation of Heart Contractility NO both exogenous and endogenous has concentration-dependent bimodal action on basal contractile state of cardiomyocytes. At low concentrations, NO exerts positive inotropic action [ 55 ]. The resultant increase in is mainly responsible for positive inotropic action.
On the other hand, the negative inotropic effect by higher NO concentration is mediated chiefly through cGMP dependent pathway. The increased intracellular cGMP is further shown to downregulate myofilament calcium sensitivity increasing cardiac relaxation [ 58 ]. It is interesting to know that the mechanisms of action of NO depend upon the origin of endogenous NO as well. Accumulating evidences suggest that there is a cross-talk between H2S and NO in the heart. H2S may directly interact with NO during pathological situations like oxidative stress and alter cardiac functions.
We were among the first groups to observe that H2S reversed the negative inotropic and lusitropic effects of NO. To explain this phenomenon, we proposed the formation of new thiol sensitive molecule as they found that thiols abolished the effects of the mixture of NO and H2S in their experimental setup [ 949 ]. It is also possible that H2S reacts with either oxidized forms of NO e.
Due to the strong reducing capability of H2S [ 16566 ], Yong et al. The interaction of H2S with NO and the resultant synthesis of thiol-sensitive compounds may also provide the justification behind the elusive bimodal effect of NO on cardiac contractility as mentioned in the beginning of this section. In fact, the redox dependent mechanism is important for the positive inotropic effect of HNO. HNO can enhance the myofilament calcium sensitivity through formation of an actin—TM heterodimer.
With mass spectrometry MS and a modified biotin switch assay, Gao et al. HNO can also modulate the thiol groups in EC-coupling proteins and regulate the functions of these proteins. In addition, Paolocci et al. Exogenous NO is believed to act via direct phosphorylation of LTCC and cardiac contractile proteins such as troponin 1.
The effect of endogenous NO depends on the source. Interestingly, the intermediate product, nitroxyl HNOproduces positive inotropic effect. Role of H2S-NO Interaction in the Cardioprotection Myocardial ischemia occurs when cardiac myocytes are insufficiently provided with the oxygenated blood via coronary arteries, resulting in cardiovascular morbidity and mortality [ 76 ].
Ischemic injury is a complex process involving the action and interaction of many factors. NO is one of these factors to protect heart against ischemic injury. Similarly, the cardioprotective effects of H2S also involve multiple mechanisms Figure 3. This was described in detail in our previous review article [ 64 ].
Downregulation of endogenous H2S production was found to increase myocardial infarct size, suggesting an important role of endogenous H2S in maintaining the normal heart function [ 87 ]. The contribution of antiapoptotic signaling activation was demonstrated by the modulation of proteins expression including Beclin-1 [ 89 ], Bcl-2, Bax, caspase 3 [ 90 ], and HSP [ 91 ]. H2S is also known to preserve mitochondrial functions by modulating cellular respiration [ 92 ].
We and other groups revealed that the cardioprotective effect of H2S preconditioning involves the activation of PKC and sarcolemmal channels, Akt, and eNOS pathways [ 93 — 96 ].
H2S and NO may act in concert to protect the heart against ischemic injury. Administration of NaHS alleviated isoproterenol-induced toxic cardiomyopathy through elevation of myocardial and serum NO levels [ 98 ].
We showed previously that H2S pretreatment activates eNOS pathway to confer protective effect against ischemic injury [ 93 ]. However, some conflicting effects were also reported. The data collected from rat and mouse aortic rings demonstrated that H2S directly inhibited recombinant bovine eNOS activity [ ]. In yet another study, both exogenous and endogenous H2S inhibited eNOS transcription and activity [ ]. Thus it is highly possible that the nature of effect of H2S on eNOS is dependent on many factors including H2S concentration and experimental setup.
Overexpression of iNOS and the subsequent excessive formation of NO may cause cytotoxic effects and exacerbate myocardial injury [ ]. Inhibition of iNOS may produce beneficial effects in heart [ ]. Taken together, NO is an important player in the cardioprotection induced by H2S, despite different mechanisms that may be involved in various pathological situations.
A previous study showed that exogenous application of an NO donor, sodium nitroprusside, and upregulated the expression of CBS and CSE, culminating in augmented H2S production in rat tissues [ ]. These data suggest that H2S and NO may influence the production of each other by altering their generating abilities during ischemic situations. However, the role of HNO, the direct interaction product from these two gases, in ischemic reperfusion injury is still debated. Preconditioning with HNO also grants a protection similar to that afforded by classical ischemic preconditioning [ ].
This protective effect was not from NO, as it cannot be achieved with equimolar amounts of the NO donors. The mechanisms underlying HNO-induced cardioprotection may involve mitochondrial channel m [ ] Figure 4.
However, it is also worth noting that higher concentration perfusion of HNO may also produce detrimental effects during ischemic reperfusion caused by recruitment of neutrophils [ ]. There are multiple underlying mechanisms for cardioprotective effect of H2S.
Furthermore, NO also plays an important role in the cardioprotective effect of H2S. The resultant inhibition of mitochondrial permeability transition MPT is responsible for decreased cytochrome C release and apoptosis in cardiomyocytes.
HNO, depending on the concentration, can be either cardioprotective or cardiotoxic.
Role of H2S-NO Interaction in the Maintenance of Vascular Tone The identification of NO as an endothelium derived relaxing factor [ 3 ] is a milestone in the field of gasotransmitters biology research. NO is now established as an important regulator of vascular tone. Physiologically, NO is a powerful vasodilator exerting its effect on various arteries, resistance vessels, and veins. The underlying signaling pathway is mainly cGMP dependent [ ]. NO can also mediate vasodilation in a cGMP independent manner .
H2S has a biphasic effect on vascular tone in the cardiovascular system by mediating both vasorelaxation and vasoconstriction Figure 5. It is suggested that the vasodilatory effect of endogenous H2S is mainly responsible for the maintenance of basal tone in vasculature which in turn controls physiological blood pressure [ ]. H2S targets channels to produce its vasodilatory effect [ 16]. Interestingly, Ali et al. The mechanisms underlying the vasoconstrictive effects of low concentration of H2S involve downregulation of endothelial NOS, decrease of intracellular cAMP level in smooth muscle cells, and production of ROS.
This was discussed in details in our previous review [ 64 ]. Depending upon the concentration, H2S exerts biphasic response on vascular tone.
NO, by itself, is a strong vasodilator. NO signaling is also stimulated by high concentration of H2S, contributing to its vasodilatory effect. Various experimental studies provided evidence for the interaction between H2S and NO and the vasoregulatory role of this interaction.
The first report of summation effect between H2S and NO on vasorelaxation came from the findings of Hosoki et al. Furthermore, pharmacological blockade of endogenous NO production or physical removal of the endothelium, attenuated H2S-induced relaxation [ 16 ]. These data suggest that the vasorelaxant effect of H2S is mediated by NO. The interplay between these two gases is different for the observed effect of vasoconstriction.
In line with this finding, Ali et al. Interestingly, H2S only induced vasoconstriction in endothelium-intact vessels but not in endothelium-denuded vessels. The contractile effect of H2S is therefore not a direct action on vascular smooth muscle cells but an indirect effect involving endothelial cells.
Furthermore, they demonstrated that NaHS, in a dose-dependent manner, significantly downregulated vasorelaxant effect induced by chemically different NO donor molecules e. Similarly, NaHS reversed vasorelaxation induced by endogenous NO from vascular endothelial cells in a concentration dependent manner.
This indicates that H2S may induce vasoconstriction via direct quenching of NO. Interestingly, this group also hypothesized the formation of a new compound, nitrosothiol.
Since copper sulfate, which converts nitrosothiol to nitrite and nitrates, prevented the contractile of aortic rings without influencing the vasorelaxant effect of NaHS, the generation of nitrosothiols was proved. This nitrosothiol molecule might have contributed to the modulatory effect of H2S on vascular tone [ ]. Similarly, we found that H2S may also stimulate anion exchanger-2 activity which transports in exchange of to inactivate NO and thus inducing stronger vasoconstriction.
These findings indicate that H2S may induce vasoconstriction via inactivation of NO. Recently, Berenyiova et al. HNO is produced endogenously in vascular tissue [ — ]. It induces vasodilatory effect via multiple mechanisms. Previous reports showed that HNO may dilate vascular vessels as an endothelium-derived relaxing and hyperpolarizing factor , via activation of a cGMP-dependent pathway [ ] and via activation of TRPA1 receptor channels of trigeminal fibres inducing CGRP release [ ].
In addition to the direct interaction, H2S and NO are also known to affect mutual production. NO can increase H2S production in the normal vascular tissues. Incubation with NO donors increased H2S production rate in the rat vascular tissues [ 16].
In pulmonary hypertension, higher H2S production and upregulated CSE level were found in the presence of L-arginine [ ].
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In aortic tissues, Geng et al. In a recent study, Eberhardt et al. Consequently, calcitonin gene-related peptide CGRP was released inducing potent local and systemic vasodilation [ ].
Thus it can be proposed that the H2S and NO homeostasis is of the prime importance in maintaining vascular tone. However, Huang et al. Role of H2S-NO Interaction in Angiogenesis The formation of new blood vessels from preexisting vasculature through process of angiogenesis is the means by which cells can meet an elevated need of metabolites and in pathological conditions such as ischemia.
Endothelial cells ECs play a pivotal role in the process by migrating towards and proliferating at the site of angiogenesis . Accumulating evidences suggest that gasotransmitters NO and H2S are important factors to influence ECs and angiogenesis [ 8 ].
The relationship between NO and neovascularization is very well established [ ] and found to involve cGMP transduction pathway [ 8 ].