[Frontiers in Bioscience E3, 736-749, January 1, 2011]
Role of sulfur-containing gaseous substances in the cardiovascular system.
School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora West 3083, Victoria, Australia
TABLE OF CONTENTS
1. ABSTRACT
Gaseous mediators are important signaling molecules with properties that differ from other, larger signaling molecules. Small gaseous mediators readily cross cell membranes and can access sites on target molecules that would be inaccessible to bulkier molecules. They have a variety of signaling mechanisms, some well understood, some not. The family of gasotransmitters is growing, well known members include nitric oxide (NO) and carbon monoxide (CO). Newer candidates include the sulfur containing gases hydrogen sulfide (H2S), which has been shown to have a wide range of physiological functions, and more recently sulfur dioxide (SO2) has been studied as a potential new gasotransmitter. This review explores the production, regulation and role of the sulfur-containing gases H2S and SO2 at the level of the endothelial and vascular smooth muscle cells as well as the broader effects on the cardiovascular system under both physiological and pathophysiological conditions.
Gaseous mediators are important signaling molecules that regulate a variety of physiological functions. There has recently been considerable interest in the expanding field of gaseous mediators or gasotransmitter molecules. They are implicated in many physiological and pathophysiological processes including neurological, cardiovascular and inflammatory events. The most well known molecule of this class is nitric oxide (NO); its discovery marked the beginning of a whole new paradigm for cellular signaling. Since then other gaseous mediators have been identified and are involved in a broad range of physiological functions. Their involvement in the cardiovascular system is well documented and there is good evidence that pathways involving gaseous mediators may play a role in the development of a range of cardiovascular diseases. The most recent additions to the family of gaseous mediators are the sulfur containing gases H2S and SO2 which have drawn considerable scientific interest. The focus of this review is to examine the evidence for physiological and pathophysiological roles of these sulfur containing gases in endothelial and vascular smooth muscle cell function, vascular regulation and in the pathology of cardiovascular disease.
3. Gaseous mediators as signaling molecules
Gaseous mediators or gasotransmitters are a relatively new class of signaling molecules, although the discovery that gases are involved in neurotransmission dates back to 1980 (1). Examples include nitric oxide, carbon monoxide, hydrogen sulfide, and possibly sulfur dioxide, carbonyl sulfide (2), nitrous oxide (3) and carbon dioxide (4). These gases share many features in their production and action but differ from classical signaling molecules. The concept that a short-lived, endogenous gas could act as a signaling molecule was discovered by Furchgott, Ignarro and Murad and was rewarded with the Nobel Prize for Physiology or Medicine in 1998. The terminology and characterization criteria for gasotransmitters were first introduced in 2002 (5). For a molecule to be considered to be a gasotransmitter, all of the following criteria should be met:
- It must exist as a gas.
- It is freely permeable to membranes and does not rely on a specific transporter or on a membrane receptor.
- It is endogenously and enzymatically generated by a regulated process.
- It has well defined and specific functions at physiologically relevant concentrations.
- Its cellular effects may be direct or be mediated by second messengers, but it has specific cellular and molecular targets. The effects of the endogenous gas can be mimicked by exogenous application.
Advantages of gases as signaling molecules include their small size which allows easy access to a variety of target sites that would not be accessible by larger molecules. They easily cross membranes, are labile with short half-lives and are made on demand. They are not stored in their native form as they can't be constrained by vesicles and need to be bound for storage or rely upon de novo synthesis. They can have endocrine, paracrine, autocrine or even intracrine effects. As an endocrine regulator, gasotransmitters can enter the blood stream, be transported to remote targets by carriers and released there to modulate functions of remote target cells. As a paracrine or autocrine mediator they do not need a carrier, but the effects are short-lived. There are a number of examples of gaseous mediators acting as intracrine regulators, modulating the activity of the cell that produced it. It is also interesting that all the molecules confirmed as gasotransmitters (NO, CO, H2S) were all considered only as toxic molecules until their endogenous production and effects were determined.
Like NO, H2S was first considered a toxic gas and notable for its distinctive "rotten egg" odour. It now qualifies as a gasotransmitter according to the above criteria (see Table 1), which will be expanded upon below. At moderate-high concentrations it is a mitochondrial poison, which inhibits cytochrome oxidase and prevents utilization of O2 and causes uncoupling of oxidative phosphorylation (6). Additionally it can bind to haemoglobin and interfere with oxygen transport (6). However it is now reported to be involved in a wide variety of physiological processes including memory (7), nociception (8-9), insulin secretion (10-11), liver function (12), kidney function (13), gastrointestinal function (14) as well as playing a role in the cardiovascular system (15). Another intriguing role for H2S is in eliciting metabolic inhibition and endowing a state of suspended animation (16-17). There are a number of anti-oxidant and anti-inflammatory effects associated with H2S which are reported to endow it with cytoprotective (18) and immunomodulatory effects (19). The field of research into the endogenous effects if H2S is growing rapidly and promises potential targets for future therapeutic exploitation.
H2S is a weak acid with a pKa ~6.9. Its aqueous solubility is ~80mM at 37�C. At physiological pH the ratio of HS-:H2S is 3:1 and this would suggest a lower capacity for transport through membrane compared to other gases (e.g. NO), although it does permeate membranes without a transporter (20). It is not known whether HS- and H2S have differential effects and the combination of HS- and H2S are considered to be the effects of hydrogen sulfide by most authors as currently it is not possible to discriminate between the two species. In most studies either dissolved H2S gas, or a solution of NaHS is used as an H2S donor, although newer compounds with the capacity to release H2S are being developed.
There are three documented enzymatic pathways for H2S production (see Figure 1). The enzymes involved have multiple enzymatic functions, with the physiological importance of their H2S-producing ability currently uncertain, although initially CO and NO could have been considered by-products of haem and arginine metabolism, respectively. H2S is produced by the metabolism of amino acids such as cysteine and homocysteine via the transulfuration pathway, predominantly by the pyridoxal 5'-phosphate (vitamin B6) dependent enzymes; cystathionine-β-synthase (CBS EC 4.2.1.22) and cystathionine-γ-lyase (CSE EC 4.4.1.1) (21). The third pathway is by the catabolism of cysteine via cysteine aminotransferase (CAT EC 2.6.1.3) and 3-mercaptopyruvate sulfurtranferase (3MST EC 2.8.1.2) (21-22). CBS is expressed mainly in the brain and liver and does not seem to account for cardiovascular H2S production (23). CSE is found in large amounts in the liver, and also in the vasculature and in non-vascular smooth muscle (24). CSE is generally considered to be the cardiovascular source of H2S although it has been localised in the brain (7, 24-26), but in much lesser quantities than CBS. 3MST is a mitochondrial enzyme and expressed in a range of tissues, including the myocardium (27), brain (28) and endothelium (29).
Other mechanisms for H2S production include reduction of sulfate or elemental sulfur. Mammals lack the ability to reduce elemental sulfur, but this can occur via sulfur-reducing bacteria or by release of H2S from thiols and sulfides. Notably, the mammalian gut has evolved specialised enzyme systems to degrade H2S from bacterial sources to sulfates (30). H2S can also be derived from inorganic sources, such as non-enzymatic reduction of elemental sulfur, achieved by utilising reducing equivalents from the oxidation of glucose (31). In addition, sulfur stores have been identified in cells, and these may release H2S when pH varies. There are two forms of these stores, acid labile and bound sulfur (32). Acid labile sulfur is localised mainly in the mitochondria, and not considered to be a physiological source of H2S since mitochondria are not normally acidic. Bound sulfur is localised to the cytoplasm and can release H2S in reducing and alkaline conditions (32).
H2S levels are tightly controlled in vivo and maintained at low levels through absorption and storage as bound sulfur or metabolism, thus the half-life of H2S in plasma is short. The most important metabolic pathways for H2S include scavenging by methaemoglobin to form sulfhaemoglobin, which may act as a sink for circulating H2S. H2S is scavenged by oxidised glutathione, oxidised in mitochondria or methylated in the cytosol via thiol-S-methyltransferase (30). Excretion is then via the kidney as free or conjugated sulfate (33). Endogenous circulating H2S levels are reported anywhere from 3-300�M in the literature, however the actual tissue concentrations are probably much lower (sub-�M) as these �M order values are due to the measurement of both bound and the free sulfide together (34) and additionally without considering the balance of tissue production and metabolism (35). More recent estimates of the actual H2S concentration in plasma suggest it is more likely to be in the nM range (35). This will be clarified as better assay techniques for H2S become readily available.
4.1. Cardiovascular effects of H2S
H2S is a well documented vasorelaxant of both large and small blood vessels in animal and human models. Despite considerable effort the molecular mechanism of this effect remains unclear but seems to involve K+ and Ca2+ channels. H2S has been reported to activate KATP channel currents (36), and more recently the molecular basis of this effect has been reported to be via sulfydration of either the KIR subunit (37) or the SUR component (38) of the vascular KATP channel. These effects at the molecular level are interesting; however a closer examination of the data obtained from in vitro vasorelaxation studies show that the H2S donor NaHS retains considerable vasorelaxant effect in the presence of KATP channel inhibition. For example in isolated rat aorta in the presence of 10�M glibenclamide (standard concentration used to inhibit KATP channels in vascular preparations) there remains a 40% vasorelaxation response to the H2S donor NaHS (39) and in the isolated rat mesenteric bed 10�M glibenclamide elicited a 10-fold rightward shift and only a 20% suppression of the maximum vasodilatation elicited by H2S-saturated solution (40). These data do not support the notion that H2S elicits all its vasorelaxant effects via KATP channels. There is also a recent report of H2S inhibiting another K+ channel subtype, the BKCa channel in human cells (41) and KV channels in rat coronary arteries (42). L-type Ca2+ channels are inhibited by H2S in rat cardiomyocytes (43) and blocking vascular L-type Ca2+ channels with nifedipine inhibits NaHS-mediated vasorelaxation in isolated vessel experiments (44). A recent paper reports of the ability of H2S to modulate intracellular Ca2+ concentrations in endothelial cells (45). Others have proposed metabolism-related mechanisms for H2S-induced vasorelaxation, including a decrease in intracellular pH (via the Cl-/HCO3 exchanger) (46) or via metabolic inhibition (47). Currently it appears that there is heterogeneity in H2S-induced vascular effects. An important advance in the field will be the actual determination of the molecular basis for vasorelaxation elicited by H2S.
H2S was first reported to have hypotensive effects when administration of H2S donors in vivo to anaesthetised rats was found to induce a transient hypotensive effect (39). The CSE-L-cysteine pathway is downregulated in spontaneously hypertensive rats and treating them with an H2S donor was protective, reducing blood pressure and vascular remodeling (48). The most compelling evidence for the importance of H2S in blood pressure regulation is that mice deficient in CSE develop endothelial dysfunction and hypertension within 8 weeks of birth and that H2S replacement decreases systolic blood pressure in both CSE-/- and CSE+/- mice (49). Further actions of H2S are that it regulates plasma renin levels (50) and inhibits angiotensin converting enzyme activity in endothelial cells. The latter effect was caused by H2S interaction with the Zn at the active centre of the enzyme and inhibiting its function, without affecting expression of the enzyme (51). This would enhance any hypotensive effect by reducing angiotensin II production and inhibiting bradykinin degradation and suggests a regulatory role for H2S in the maintenance of a healthy blood pressure. Finally, H2S regulates renal function in rats by increasing renal blood flow, glomerular filtration rate and urinary sodium and potassium secretion. Conversely, inhibiting CSE and CBS decreased all these parameters, and infusing L-cysteine had similar effects to NaHS (13), suggesting a role for endogenous H2S in kidney function, and subsequently regulation of blood pressure.
An important consideration of H2S biology is its relationship with fellow gaseous mediator NO. NO has been shown to increase both expression and activity of CSE in vascular smooth muscle cells (39, 52), whilst chronic nitric oxide synthase (NOS) inhibition has been shown to decrease CSE expression and activity (53). Conversely, H2S treatment decreased NO formation, endothelial NOS (eNOS) activity and expression as well as L-arginine transport (54). Additionally, H2S was found to directly inhibit eNOS as well as the other NOS isomers iNOS and nNOS (55). Finally, H2S interacts directly with NO to form a novel nitrosothiol molecule in vitro, which was determined using a range of techniques including electron paramagnetic resonance, amperometry and measurements of nitrite concentrations (56). These studies raise the possibility that a nitrosothiol molecule may act as a store for both H2S and NO.
H2S is a strong reductant and reacts with many reactive oxygen and nitrogen species including peroxynitrite (57-58), superoxide (59-60), hypochlorite (61-62) hydrogen peroxide (59) and NO (56, 63), although there is chemical evidence that these anti-oxidant effects are limited by the presence of O2 (64). In addition to scavenging reactive oxygen species H2S has been shown to reduce accumulation of lipid peroxidation (59). H2S downregulates NADPH oxidase expression and activity (65-66), thus reducing superoxide anion production. Additionally, H2S can induce glutathione synthesis and cysteine uptake as well as reducing oxidised glutathione levels (67-70) thus suggesting a role for H2S as an anti-oxidant and cytoprotective agent.
4.2. Role of H2S in endothelial function
The endothelium is a critical regulator of vascular function. It contains the machinery to produce mediators and signaling molecules that regulate vascular function, perfusion of tissues and blood pressure including NO, prostaglandins (PGI2) and endothelium-derived hyperpolarising factor (EDHF). The endothelium also contains the enzymes required to produce gaseous mediators including NO, CO and H2S which are usually formed by enzymatic processes, complying with the criterion that production of gasotransmitters is regulated.
With respect to vasoregulation, the H2S producing enzyme CSE is of particular interest as it is reported to be present in a range of vascular beds and its expression has been clearly identified in vascular smooth muscle cells, in both animal (39) and human (71) studies. It is of significant interest that CSE has recently been reported to be expressed in endothelial cells and contribute to endothelium-dependent vasorelaxation (49, 72). Indeed, L-cysteine elicits vasorelaxation in the rat mesenteric bed (40) and also in isolated mouse aorta where the response was inhibited by both the NOS inhibitor L-NAME and the soluble guanylate cyclase inhibitor, ODQ (73). Additionally we have found that in mouse aorta and mesenteric artery this response is concentration-dependent and inhibited by endothelial removal as well as the CSE inhibitors D,L-propargylglycine (PPG) and β-cyanoalanine (Hart, unpublished observations). New evidence has now been provided to show that endothelial cells also contain the enzymatic machinery to produce H2S via cysteine amino transferase and 3MST and although homogenates of endothelial cells can produce H2S via this mechanism (29) this process has not been demonstrated in any in vitro assay. Other non-enzymatic pathways also exist, however the importance of these for endothelial H2S production is yet to be determined.
Disturbances in H2S levels, CSE activity and expression have been reported in a number of cardiovascular diseases including ischaemia-reperfusion injury (59), chronic obstructive pulmonary disease (74), coronary heart disease (75), hypertension (48, 76), pulmonary hypertension (77), type-1 diabetes (78) and type-2 diabetes (79-80). Generally, lower levels of H2S reflect severity of disease, suggesting that a dysfunction in H2S production or changes in H2S metabolism may be involved in cardiovascular pathology.
In both animal and cellular models of myocardial ischaemia-reperfusion injury there is considerable evidence that H2S elicits cardioprotection (81-84). This area has been well reviewed recently (15). Accumulating evidence shows that H2S preserves myocardial contractile function (85-87), limits infarct size (85-86, 88-90) and reduces arrhythmias (91). In addition, H2S has also been shown to improve coronary microvascular function post myocardial ischemia-reperfusion (87) and inhibit platelet aggregation (92). The protective effects include reduced inflammation (93), increased glutathione production (94), inhibition of ischaemia-induced apoptosis (93, 95-97) preservation of mitochondrial function (85) and protection against Ca2+ overload (43, 98). In addition, exogenous and endogenous H2S have been reported to function as pre-conditioning agents (83, 91, 99) and exogenous H2S as a post-conditioning agent (100).
Vascular remodeling is an active process of structural alteration that involves changes in cell growth, cell death, cell migration, and production or degradation of extracellular matrix. Importantly, H2S inhibits vascular smooth muscle cell proliferation both directly (101-102) and by modulating apoptosis, an effect which is dependent upon endogenous CSE activity and presumably endogenous H2S production (103-104). In addition, CSE expression and activity were decreased after balloon injury in rat carotid arteries and treatment with NaHS significantly reduced neointima formation (105). Interestingly, H2S can inhibit the increased synthesis of type-I collagen observed in spontaneously hypertensive rats. H2S inhibited vascular smooth muscle cell proliferation in vitro and synthesis and secretion of collagen induced by angiotensin II (106). Additionally, H2S can inhibit angiotensin converting enzyme (51) which would add to this effect. On the other hand, in cultured endothelial cells, NaHS stimulated cell growth and enhanced cell adhesion and cell migration via Akt phosphorylation (107), suggesting that H2S may function to promote endothelial cell proliferation whilst inhibiting growth of vascular smooth muscle cells.
Atherosclerosis is a chronic blood vessel disease resulting in thickening of the arterial wall due to a build up of fatty deposits. The multi-factorial pathogenic process involves inflammation, endothelial cell damage, vascular smooth muscle cell migration and lipid deposition resulting in lesion formation. In accord with previous findings that H2S plasma levels are lower in cardiovascular disease states, ApoE-/- mice have been shown to have lower plasma H2S and aortic production of H2S (108). The effects of H2S in the pathogenesis of atherosclerosis have been recently reviewed (109). Hyperhomocysteineamia is a known risk factor for atherosclerosis (110) and mice deficient in CSE develop hyperhomocysteineamia (49), whilst H2S inhibits homocysteine-induced vascular (111) and myocardial (60) damage. H2S can inhibit atherogenic modification of low-density lipoprotein induced by hypochlorite which may be important in early atherogenesis (62). In addition, inhibition of NADPH oxidase activity may also be protective against atherosclerosis development (112) and there is good evidence that H2S modulates the expression of NADPH oxidase (65, 113). In addition to this, H2S inhibits plasma renin activity (50) and angiotensin converting enzyme (51) thereby decreasing angiotensin II production. Angiotensin II is a known activator of NADPH oxidase (114) thus H2S may act as an inhibitor of atherogenesis through the angiotensin II-NADPH oxidase pathway. Calcification of atherosclerotic lesions is another important risk factor that affects the stability of the plaque and H2S has been shown to interfere with the vascular calcification process (115). The mechanism of this effect of H2S requires further investigation. Importantly, treating ApoE-/- mice with NaHS reduced the size of the atherosclerotic plaques (116). In addition, there are detrimental changes in adhesion molecule expression and activity in atherosclerosis, for example, in ApoE-/- mice there were increased plasma levels of the inter-cellular adhesion molecule ICAM-1 as well as increased ICAM-1 in aortic tissue. ICAMs facilitate the migration of inflammatory cells into the lesion. These effects were ameliorated by treatment with NaHS (116). Furthermore, H2S has been reported to modulate inflammation mediated by leukocytes (117). H2S inhibits platelet aggregation in human isolated platelets in a concentration-dependent manner. (92). Thus H2S released from the endothelium could play a role in regulating platelet aggregation in vivo and thereby contribute to cardiovascular homeostasis and may decrease the likelihood of thrombus formation at a lesion site.
There is burgeoning evidence for a role of H2S in the aetiology of diabetes. Plasma levels of H2S are lower in animal models of type-1 diabetes (78-79). In addition, plasma H2S levels were reduced in human patients with type-2 diabetes and in patients that were overweight (80). Importantly there is evidence that synthesis of H2S in aorta declined as endothelial function decreased with the progression of diabetes in non-obese diabetic mice, a model of type-1 diabetes. This occurred due to a decrease in the activity of CSE, despite increases in both CSE and CBS protein and mRNA production (73). Despite lower plasma levels, pancreatic production of H2S was markedly elevated in streptozotocin-induced diabetes, as was CSE activity and mRNA expression but this effect was reversed with insulin treatment (78). Endogenous H2S inhibits insulin release via a KATP channels (118-119) and H2S induces beta-cell apoptosis (120) suggesting a role in diabetes pathogenesis. This is supported by further study which showed that pancreatic H2S production was increased in Zucker diabetic fatty rats, and that treatment with the CSE inhibitor PPG increased serum insulin levels, lowered hyperglycaemia and glycated haemoglobin levels (10). Furthermore, H2S inhibited both basal and stimulated glucose uptake in adipocytes, whilst CSE inhibitors enhanced glucose uptake into adipocytes (11), suggesting that H2S may also act as an insulin resistance regulator.
4.4. Potential therapeutic role of H2S
H2S signaling pathways are implicated in the development and pathology of many cardiovascular diseases. There is now good evidence that plasma H2S levels are inversely correlated with severity of cardiovascular disease, and that excessive H2S production may be a pivotal point in the pathological process. There are various H2S therapy options: H2S gas, H2S donors, activation or upregulation of endogenous H2S generating enzymes. H2S-donating non steroidal anti-inflammatory drugs have been assessed as novel anti-inflammatory agents and it would seem that the anti-oxidant and anti-inflammatory effects of H2S may be useful in therapy for a range of conditions including cardiovascular disease (121). H2S has been shown not only to be an effective pre-conditioning agent in myocardial infarction, but also that it has value as a post-conditioning agent (100), significantly enhancing its potential in the clinic. Finally, H2S inhalation is under investigation for use in conjunction with therapeutic hypothermia. H2S has been shown to protect mitochondrial integrity during the induced hypothermia used to provide organ protection following brain injury or circulatory arrest (122).
Sulfur dioxide is a common atmospheric pollutant that is present in low concentrations in urban air, and at higher levels in industrial areas as it is generated by combustion of fossil fuels (123). A number of epidemiological studies have demonstrated that exposure to SO2 can increase the risk of cardiovascular disease (124-128). When inhaled, SO2 is hydrated to sulfurous acid which then dissociates to form the derivatives bisulfite and sulfite (1:3 M/M at neutral pH) (129). Bisulfite and sulfite are commonly consumed in food, beverages and drugs as sulfiting agents are widely used as preservatives. These SO2 derivatives can then be distributed via the circulation. Biological or toxicological effects of SO2 are thought to be elicited via these derivatives, which are toxic to many organs (130). Interestingly, there is now evidence that SO2 also may qualify as a gasotransmitter (see Table 1), repeating the theme of a "toxic" gas now being seen as an important physiological regulator.
Endogenous SO2 production has not been extensively studied. To date three main pathways for endogenous SO2 production have been reported (see Figure 2); from normal metabolism of sulfur-containing amino acids like L-cysteine via an enzymatic pathway (131), via enzymatic reduction of thiosulfate (132) and from H2S via NADPH oxidase in activated neutrophils (133). Endogenous bisulfite/sulfite is produced during metabolism of sulfur-containing amino acids or drugs (134). It is formed in vivo from the sulfur-containing amino acid L-cysteine (131). L-cysteine is oxidised to L-cysteine sulfinate by cysteine dioxygenase (CDO, EC 1.13.11.20) then L-cysteine sulfinate to β-sulfinylpyruvate by glutamate oxaloacetate transaminase (GOT, EC 2.6.1.1) which decomposes to pyruvate and SO2. (134-136). GOT is reported to be abundant in endothelial cells and additionally shown to be located in vascular smooth muscle cells adjacent to the endothelial layer (137).
SO2 is reported to be endogenously produced in cardiovascular tissues in mammals and is present in plasma (138). Porcine coronary artery rings produce basal levels of SO2, and interestingly the production of these gases is increased 4 fold by the presence of acetylcholine (1�M) and 1.5 fold by stimulation with the endothelium-dependent calcium ionophore, A23187 (1�M) (2). There is evidence that SO2 enhances prostacyclin production as it increases 6-keto-PGF1α levels and cAMP production and that vasorelaxation is reduced by the presence of the cyclo-oxygenase inhibitor indomethacin (139). Such data suggest that SO2 may act as an endothelium-derived relaxing factor.
Production of SO2 is reported in a range of cardiovascular tissues including heart, blood vessels and plasma (138) and specifically from rat pulmonary artery (140) and porcine coronary artery (2). Interestingly, SO2 production was increased in vitro in porcine coronary artery by treatment with either acetylcholine or the calcium ionophore (A213187), suggesting a role for the endothelium in SO2 production (2). It is less clear which of the three pathways (see Figure 2) are important in SO2 generation in vascular tissue. GOT is reported to be abundant in endothelial cells and adjacent vascular smooth muscle cells (137), however the pathway still requires further clarification. The other two pathways (via NADPH oxidase and via thiosulfate reductase) require H2S or thiosulfate as a substrate and their physiological role in endothelial function or vasorelaxation to SO2 remain unknown.
Reports of the vasodilator effects of SO2 are inconsistent. In rat aorta SO2 is reported to cause vasorelaxation that is KATP-dependent (141), Ca2+ channel-dependent (141) or independent of the endothelium, but mediated via prostacyclin (139, 142). Others found that SO2 induced a biphasic vasorelaxation response in rat aorta, the 1st phase being endothelium-dependent and the 2nd endothelium-independent and mediated via cGMP as well as being synergistic with NO (143) or dependent on Ca2+ and K+ channels. (144-145). Further studies showed that blocking endogenous SO2 production with L-aspartate-β-hydroxamate caused a contraction and a shift to the right in the noradrenaline response (141), suggesting a role for SO2 in the basal maintenance of blood vessel tone.
The role of SO2 in the aetiology of cardiovascular disease as not been extensively studied. SO2 causes a decrease in blood pressure in rats (146). Exogenous SO2 is reported to have negative inotropic effects (147) and modulates cardiac Ca2+ (148-149), Na+ channels (150) and K+ channels (151). Infusion of SO2 at reperfusion aggravates the effects of experimental ischemia-reperfusion injury in isolated rat hearts (152). Sulfite content and GOT activity were significantly higher in hearts subjected to ischaemia-reperfusion and correlated negatively with cardiac function. Conversely, inhibiting endogenous SO2 with hydroxamate reduced the deficit in cardiac function and myocardial damage. The mechanism of this effect was associated with increased lipid peroxidation and this is supported by previous work which showed that SO2 causes oxidative damage of a variety of tissues (153), however SO2 did not alter formation of reactive oxygen species, suggesting that sulfur radicals may be involved (152). An additional observation was that SO2 treatment resulted in decreased glutathione (152) which suggests SO2 induced an increased utilisation or decreased production of this important anti-oxidant. Finally, SO2 treatment inhibited pulmonary arterial smooth muscle cell proliferation induced by hypoxia (140) and SO2 exposure has been shown to increase expression of apoptotic processes (154-156) which may have important implications for a variety of disease states. Thus there is preliminary evidence that SO2 is a vasodilator, the mechanism of this action is yet to be confirmed. SO2 appears to be detrimental in ischaemia-reperfusion injury and may have a role in apoptosis and inhibition of vascular cell proliferation. However there is much yet to be determined about the physiological and pathophysiological roles of SO2 in the cardiovascular system.
The endothelium is an important source of gasotransmitters, producing NO, CO, H2S and probably SO2. These mediators are unique in their ability to traverse cellular membranes, but they also have distinct protein targets. There is no doubt that NO and CO are important endothelium-derived mediators. The role of the endothelium in H2S production is still being established, however the evidence for involvement of this gas in the cardiovascular system now exists and the mechanisms involved in these effects are becoming clearer. In particular anti-inflammatory and antioxidant effects of H2S may be useful and potentially exploited for therapeutic benefit in the future. Finally, data is accumulating in support of SO2 as the next new gasotransmitter with important physiological and pathophysiological roles in the cardiovascular system.
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Abbreviations: CBS: cystathione-β-synthase, CSE: cystathionine-γ-lyase, CAT: cysteine aminotransferase, 3MST: 3-mecaptosulfertransferase, SUR: sulphonylurea receptor, ICAM : intra-cellular adhesion molecule, CDO: cysteine dioxygenase, GOT: glutamate oxaloacetate transaminase
Key Words: Hydrogen Sulfide, Sulfur Dioxide, Gasotransmitter, Endothelium, Review
Send correspondence to: Joanne Hart, School of Medical Sciences, RMIT University, Bundoora West, Vic 3083, Tel: 613- 9925-7545, Fax: 613-9925-7063, E-mail:joanne.hart@rmit.edu.au