Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2016 / Article
Special Issue

Hydrogen Sulfide: Biogenesis, Physiology, and Pathology

View this Special Issue

Review Article | Open Access

Volume 2016 |Article ID 8961951 | https://doi.org/10.1155/2016/8961951

Yaqian Huang, Chaoshu Tang, Junbao Du, Hongfang Jin, "Endogenous Sulfur Dioxide: A New Member of Gasotransmitter Family in the Cardiovascular System", Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 8961951, 9 pages, 2016. https://doi.org/10.1155/2016/8961951

Endogenous Sulfur Dioxide: A New Member of Gasotransmitter Family in the Cardiovascular System

Academic Editor: Jin-Song Bian
Received15 Sep 2015
Accepted28 Oct 2015
Published29 Dec 2015


Sulfur dioxide (SO2) was previously regarded as a toxic gas in atmospheric pollutants. But it has been found to be endogenously generated from metabolism of sulfur-containing amino acids in mammals through transamination by aspartate aminotransferase (AAT). SO2 could be produced in cardiovascular tissues catalyzed by its synthase AAT. In recent years, studies revealed that SO2 had physiological effects on the cardiovascular system, including vasorelaxation and cardiac function regulation. In addition, the pathophysiological effects of SO2 were also determined. For example, SO2 ameliorated systemic hypertension and pulmonary hypertension, prevented the development of atherosclerosis, and protected against myocardial ischemia-reperfusion (I/R) injury and isoproterenol-induced myocardial injury. These findings suggested that endogenous SO2 was a novel gasotransmitter in the cardiovascular system and provided a new therapy target for cardiovascular diseases.

1. Introduction

Sulfur dioxide (SO2) was regarded as a toxic gas and environmental pollutant. It is colorless, transparent, odorous, and water-soluble. The harmful effects of SO2 on human, animals, and plants have been extensively investigated [1, 2]. However, SO2 can be endogenously generated from metabolism of the sulfur-containing amino acid L-cysteine in mammals [3]. It has features of low molecular weight, continuous production, and fast diffusion and plays extensive biological action independent of membrane receptors [4, 5]. In neutral fluid or mammal plasma, SO2 is broken down to its derivatives, bisulfite and sulfite (NaHSO3/Na2SO3, 1 : 3 M/M), maintaining organism homeostasis [6]. The sulfite is the physiological form of SO2 in vivo [7, 8]. The reference range for total serum sulfite in healthy human beings was 0–9.85 μmol/L detected by high-performance liquid chromatography with fluorescence detection [9]. Serum sulfite was obviously increased in patients suffering from acute pneumonia and chronic renal failure, as well as pediatric acute lymphoblastic leukemia with bacterial inflammation [1012]. Of note, Balazy et al. found that SO2 could be produced in the porcine coronary arterial rings after incubation with calcium ionophore by gas chromatography-mass spectrometry [13]. Du et al. firstly found that endogenous SO2/aspartate aminotransferase (AAT) pathway existed in the cardiovascular system [14]. SO2 not only has important physiological effects on vascular tone and cardiac function but also exerts pathophysiological effects in the cardiovascular system, including regulation of hypertension, pulmonary hypertension, atherosclerosis, and cardiac ischemia-reperfusion (I/R) injury [1518]. The abovementioned evidence suggests that the endogenous SO2 may be a novel gasotransmitter in mammals, similar to nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). The physiological significance of SO2, particularly its regulatory role in the cardiovascular system, has attracted a great deal of interest in the field [1921].

Therefore, the objective of this review was to elaborate on the generation and metabolism of endogenous SO2 and give a summary of the physiological and pathophysiological effects of SO2 on the cardiovascular system.

2. Generation and Distribution of Endogenous SO2 in the Cardiovascular System

SO2 can be generated from the metabolism of L-cysteine which is converted from methionine via the transmethylation-transsulfuration pathway (Figure 1) [3, 22]. Firstly, L-cysteine is oxidized to form L-cysteine sulfinate by cysteine dioxygenase (CDO), and then the latter is transaminated to form β-sulfinylpyruvate by AAT. The β-sulfinylpyruvate spontaneously decomposes to pyruvate and SO2 (Figure 1) [3]. Additionally, H2S which shares the same substrate L-cysteine with SO2 can be transferred to SO2 in vivo through other pathways. Mitsuhashi et al. reported that H2S could be converted to sulfite or SO2 by NADPH oxidase in activated neutrophils [23]. Besides, H2S can be first oxidized to thiosulfate by sulfide oxidase and then converted to SO2 catalyzed by thiosulfate sulfurtransferase or glutathione-dependent thiosulfate reductase (Figure 1) [6, 24, 25]. SO2 can exist in the gaseous form or be hydrated to sulfite, which is subsequently oxidized to sulfate by sulfite oxidase, and then the sulfate is excreted into the urine by the kidney (Figure 1) [3, 22].

Du et al. first measured endogenous SO2/AAT pathway in the cardiovascular system of Wistar rats and found that SO2 concentration in rat plasma was 15.54 ± 1.68 μmol/L [14]. Li and Meng reported a similar sulfite level of 12.59 ± 9.03μmol/L in rat plasma [26]. The content of SO2 in aortic tissue was highest, up to 5.55 ± 0.35μmol/g protein, followed by pulmonary arteries (3.27 ± 0.21μmol/g protein), mesenteric arteries (2.67 ± 0.17μmol/g protein), tail arteries (2.50 ± 0.20μmol/g protein), and renal arteries (2.23 ± 0.19μmol/g protein), respectively [14]. Moreover, plasma AAT activity was 87 ± 18U/L. Unlike SO2 content, the activity of AAT in the renal arteries was higher than that in other vascular tissues mentioned above [14]. Furthermore, AAT mRNA expression was rich in endothelial cells and in vascular smooth muscle cell (VSMC) beneath the endothelial layer [14].

3. Physiological Effects of SO2 on the Cardiovascular System

3.1. Vasorelaxant Effect of SO2

SO2 derivatives (mixture of sodium bisulfite and sodium sulfite, 1 : 3 M/M in neutral solution) could induce a concentration-dependent relaxation of isolated rat aortic rings, whereas L-aspartate-β-hydroxamate (HDX), an inhibitor of SO2 synthase AAT, caused greater vasoconstriction than that of the control group [14]. And the vasorelaxing effects of SO2 gas and SO2 gas solution were similar [27, 28]. Therefore, SO2 might act as a vasoactive molecule. It had a vital vasodilating function required for maintaining normal vascular tone.

The mechanisms of this physiological vasorelaxation by SO2 were complex. Nicardipine eliminated the vasorelaxing effect induced by SO2 derivatives, indicating that the L-type calcium (L-Ca2+) channel participated in the role of SO2 [14]. Additionally, at low concentration (<450 μmol/L), the vasorelaxing effect of SO2 was related to the big-conductance Ca2+-activated K+ () channel, while at a high concentration (>500 μmol/L) the vasorelaxation induced by SO2 was associated to adenosine triphosphate-sensitive potassium () channel activation and the L-Ca2+ channel [29]. Mechanistically, SO2 and its derivatives induced the and channels activation through increasing the expressions of Kir6.1, Kir6.2, SUR2B, and channel subunits α and β1 in rat aortic rings, while SO2 and its derivatives inhibited the L-type calcium channel through decreasing the expressions of Cav1.2 and Cav1.3 [30]. Besides, SO2 derivatives increased levels of 3′-5′-cyclic adenosine monophosphate (cAMP), prostacyclin (PGI2), adenylyl cyclase (AC) activity, and protein kinase A (PKA) activity in rat aortic rings, indicating that the relaxing effect of SO2 was related to the PGI2-AC-cAMP-PKA signal pathway [31, 32]. Moreover, the endothelial nitric oxide synthase- (eNOS-) nitric oxide- (NO-) 3′-5′-cyclic guanosine monophosphate (cGMP) pathway and channel partially mediated the vasorelaxing effect of SO2 and sodium bisulfite in an endothelium-dependent manner at low concentration (<450 μM), while at high concentration (≥1000 μM) the vasorelaxation induced by SO2 was endothelium independent and relied on the and L-Ca2+ channels [26, 33, 34]. Hence, ion channels, such as L-Ca2+, , and channels, as well as cGMP and cAMP pathways play important roles in the effects of SO2 on vasodilation.

3.2. Negative Inotropic Effect of SO2

In isolated perfused rat heart, gaseous SO2 and its derivatives (NaHSO3/Na2SO3, 1 : 3 M/M, 0–2000 μmol/L) elicited a dose-dependent negative inotropic effect, which affected the heart rate, left ventricular developed pressure (LVDP), and the first derivatives of LVDP (±LV /) [35, 36]. And the gaseous SO2 induced a server negative effect compared to SO2 derivatives. The mechanisms for this inotropic effect are different between high concentration and low concentrations of SO2. At low concentrations, SO2 produced negative inotropic effects through upregulating the activities of protein kinase C (PKC), cyclooxygenase, and cGMP, while, at high concentrations, the inotropic effects induced by SO2 were associated with the activation of channel by increasing the expressions of Kir6.2 and SUR2A and the inhibition of calcium influx via the L-type calcium channel by decreasing the expressions of Cav1.2 and Cav1.3 in rat hearts [36, 37]. Moreover, SO2 could depress L-type calcium channel current in isolated rat cardiomyocytes [38]. These data indicated that SO2 had a negative inotropic effect on myocardial contractility and hemodynamic parameters, which might help to explain some cardiovascular effects induced by SO2.

4. Pathophysiological Effects of SO2 on the Cardiovascular System

4.1. SO2 and Hypertension

Hypertension is a major risk factor for many cardiovascular disorders. However, the pathogenesis of hypertension has not been fully elucidated. Exposure to SO2 (50 ppm, 6 hr/d, 5 d/wk for 31 weeks) was reported to cause a slight but consistent decrease in blood pressure in susceptible to salt-induced hypertension rats [39], implying that SO2 might regulate blood pressure. Moreover, spontaneously hypertensive rats (SHRs) exhibited a significant decrease in the plasma SO2 content and AAT activity in both serum and aorta [15]. And SO2 derivatives administration markedly inhibited the upregulated tail artery pressure of SHRs [15, 40], which suggested that SO2 played a role in the progress of hypertension. Arterial remodeling predominates in severe hypertension [41]. As well, SO2 alleviated the pressure to media, decreased the ratio of media to lumen radius, and reduced the proliferative index of smooth muscle cells in the thoracic aorta of SHRs compared to those of sterile water-treated rats [15]. These findings further verified that the inhibited endogenous SO2/AAT pathway might participate in the development of hypertension. Vasorelaxation dysfunction is the main component of the pathogenesis of hypertension. SO2 could increase vasorelaxation in SHR arteries by enhancing the vasodilating response to NO in isolated aortic rings and promoting NO production of aortic tissues [40]. The interaction between SO2 and NO is involved in the mechanisms by which SO2 regulates hypertension.

The abnormally increased proliferation of VSMCs induces vascular remodeling and accelerates the development of hypertension [42]. Both exogenous SO2 derivatives and endogenous-derived SO2 by AAT overexpression significantly inhibited serum-stimulated VSMC proliferation through preventing cell cycle progression from G1 to S phase and inhibiting DNA synthesis [43]. Further study demonstrated that SO2 elevated cellular cyclic adenosine monophosphate (cAMP) production to activate the PKA signaling, subsequently phosphorylated c-Raf on Ser259 site to block its activation, and then inhibited the extracellular regulated protein kinase (Erk)/mitogen-activated protein kinase (MAPK) signaling transduction, which finally prevented cell cycle progression and led to the suppression of VSMC proliferation [43]. The inhibition of VSMC proliferation might also be involved in SO2-mediated antihypertensive mechanisms.

4.2. SO2 and Pulmonary Hypertension
4.2.1. SO2 and Hypoxic Pulmonary Hypertension

Pulmonary hypertension, characterized by high pressure in pulmonary artery, is a common complication of congenital heart disease (CHD), ultimately inducing right ventricular failure and even death. A prospective cohort study showed that the serum SO2 levels of children were, respectively, (10.6 ± 2.4), (8.9 ± 2.3), (7.3 ± 2.9), and (4.3 ± 2.1) μM, in the control group, CHD without pulmonary hypertension group, CHD with mild pulmonary hypertension group, and CHD with moderate or severe pulmonary hypertension group [44], suggesting that a negative correlation existed between SO2 and pulmonary hypertension. Consistent with this, a downregulated SO2 level and AAT expression in lung tissue, accompanied with significant pulmonary hypertension, pulmonary vascular remodeling, and increased vascular inflammation, were found in rats under hypoxic condition [16, 45]. Most importantly, SO2 derivatives could markedly lower mean pulmonary artery pressure (mPAP) of hypoxic pulmonary hypertensive rats, whereas HDX advanced pulmonary hypertension [16, 45], indicating that decreased SO2/AAT pathway was involved in the development on hypoxic pulmonary hypertension. The hallmark pathological feature of hypoxic pulmonary hypertension is the pulmonary vascular structural remodeling including extracellular matrix accumulation, vascular smooth muscle proliferation, and inflammatory cells infiltrates [46]. SO2 derivatives prevented pulmonary vascular remodeling in hypoxic pulmonary hypertension through promoting collagen I and III degradation, suppressing abnormal collagen deposition in pulmonary vascular walls and through inhibiting pulmonary arterial SMC proliferation by downregulating Raf-1, MEK-1, and phosphorylating ERK under hypoxia [16]. Inflammation is important in the pathogenesis of hypoxic pulmonary hypertension. In addition, SO2 could inhibit pulmonary inflammation by suppressing expressions of nuclear factor-kappa B (NF-κB) and intercellular adhesion molecule-1 (ICAM-1) [16], indicating the inhibitory effects of SO2 on inflammation may also be involved in the mechanism by which SO2 protects against hypoxic pulmonary hypertension.

4.2.2. SO2 and Monocrotaline-Induced Pulmonary Hypertension

Monocrotaline (MCT), a pyrrolizidine alkaloid, increased mPAP and the ratio of right ventricle to left ventricle plus septum, coincident with the elevated SO2 content, AAT activity, and expression in rats [47]. SO2 derivatives injection significantly lowered mPAP and alleviated small and median pulmonary artery structural remodeling, whereas HDX which inhibited the activity of AAT and the production of endogenous SO2 further augmented mPAP, promoted right ventricular hypertrophy, and worsened pulmonary arteries structural remodeling [47]. These findings implied that the upregulation of endogenous SO2/AAT pathway might play a protective role in the development of MCT-induced pulmonary hypertension. The enhancement of oxidative stress is one of the main pathogenesis of MCT-induced pulmonary hypertension [48]. SO2 could upregulate the activities of antioxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in lung tissues and plasma from MCT-induced pulmonary hypertensive rats, whereas HDX decreased the activities of antioxidative enzymes [47]. These data suggested that the promotion of endogenous antioxidative capacities might be responsible for the protective role of SO2 in MCT-induced pulmonary hypertension.

4.2.3. SO2 and High Pulmonary Blood Flow-Induced Pulmonary Hypertension

Severe pulmonary hypertension develops secondary to high pulmonary blood flow in patients with left-to-right shunt congenital heart defects or systemic arteriovenous shunt [49, 50]. However, the underlying mechanisms for flow-induced pulmonary hypertension remain poorly understood. The endogenous SO2/AAT2 pathway in pulmonary tissues was also inhibited in rats with pulmonary hypertension induced by high pulmonary blood flow [51]. SO2 reduced systolic pulmonary arterial pressure and improved pulmonary arterial structural remodeling, exhibiting decreased ratio of muscularized arteries to small pulmonary arteries and increased percentage of nonmuscularized arteries in the development of high pulmonary blood flow-induced pulmonary hypertension [51]. The mechanism was unclear, however. Both SO2 and H2S were derived from the methionine metabolism and they could convert to each other in mammals. Moreover, the endogenous H2S pathway exerted obvious mitigation effect on pulmonary hypertension induced by high pulmonary blood flow and H2S had strong vasodilating effect. Therefore, the researchers investigated the impact of SO2 on the endogenous H2S generating pathway in the pathogenesis of high blood flow-induced pulmonary hypertension. And they found that SO2 derivatives could upregulate the concentration of H2S in lung tissues, as well as the expressions of the key generating enzymes of H2S, including cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3MST) [51]. Furthermore, SO2 increased the protein expression of these H2S producing enzymes probably through upregulating their gene transcription. These data suggested that SO2 alleviated pulmonary hypertension induced by high pulmonary blood flow in association with upregulating the reduced endogenous H2S pathway.

4.3. SO2 and Atherosclerosis

Atherosclerosis, a chronic and progressive pathological process in arteries, is a crucial pathological manifestation of cardiovascular diseases. Vascular inflammation, oxidative stress, VSMC proliferation, endothelial injury, and foam cell accumulation contribute to the formation of atherosclerotic plaque. Environmental toxicological study showed that the chronic exposure to gaseous air pollution such as SO2, NO, and CO might lead to the promotion of atherosclerosis [52, 53]. Growing evidence demonstrated that endogenous NO, CO, and H2S were beneficial in alleviating atherosclerosis [5456]. They exerted significant anti-inflammation effect in the development of atherosclerosis, especially endothelium-derived NO which played a notably protective role in the early stage of atherosclerosis. However, the role of SO2 at physiological concentration in the development of atherosclerosis was unclear. Li et al. found that plasma and aortic SO2 contents were downregulated with the reduced aortic AAT activity in atherosclerosis rats [17], implying that the inhibition of SO2/AAT pathway might be involved in the pathogenesis of atherosclerosis. SO2 derivatives treatment diminished the size of atherosclerotic plaques in the coronary artery, not only by increasing H2S/CSE pathway and the NO/nitric oxide synthase (NOS) pathway, but also by elevating the antioxidative capacities through increasing plasma GSH-Px and SOD activities and decreasing MDA level [17]. Additionally, suppression of VSMC proliferation via cAMP/PKA signaling-mediated Erk/MAPK pathway might also contribute to the antiatherosclerotic effects of SO2 [43].

4.4. SO2 and Myocardial Ischemia Reperfusion

Myocardial ischemia-reperfusion (I/R) injury is an important cause of tissue and cell injury and often leads to heart failure. The main mechanisms involve inflammation, oxidative damage, and intracellular and mitochondrial calcium overload [57]. In rat myocardial I/R models made by ligating the left coronary artery for 30 min and reperfusion for 120 min, AAT1 protein expression was significantly decreased compared to sham operation group [18]. And SO2 derivatives preconditioning for 10 min before ischemia (with a low concentration of sulfur dioxide of 1–10 μmol/kg) significantly decreased myocardial infract size and lowered levels of myocardial enzymes creatine kinase (CK) and lactate dehydrogenase (LDH) in plasma of rats with I/R injury in vivo [18]. SO2 preconditioning also increased cardiac function and attenuated myocardium apoptosis induced by I/R [18]. Ischemic preconditioning-induced endoplasmic reticulum stress (ERS) plays a protective role in the ischemia injury. Glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and phosphorylated eukaryotic initiation of the factor 2α-subunit (p-eIF2α) are the markers of myocardial ERS. SO2 pretreatment induced myocardial GRP78 expression and eIF2α phosphorylation prior to myocardial I/R, while inhibiting expressions of myocardial GRP78, CHOP, and p-eIF2α in rats with myocardial I/R [18]. Dithiothreitol, an ERS activator [58], mimicked the cardioprotective effect of SO2, whereas ERS inhibitor 4-phenylbutyrate abolished the cardioprotection of SO2 preconditioning [18, 59]. The above data suggested that augmentation of ERS by SO2 preconditioning before myocardial I/R contributed to cardioprotection against lethal ischemia. Moreover, SO2 preconditioning significantly elevated the phosphorylation of Akt and PI3K p85 and attenuated the myocardial damage in rats with I/R injury [60]. LY294002, a PI3K inhibitor, prevented the protective function of SO2 preconditioning as well as SO2-induced GRP78 and p-eIF2α expression [18, 60], indicating that PI3K/Akt signaling pathway likely mediated the activation of ERS by SO2 pretreatment in rats subjected to myocardial I/R. In addition, oxidative stress is involved in the pathogenesis of myocardial I/R. SO2 preconditioning with low dose of SO2 (1 and 5 μmol/kg) prior to ischemia could significantly elevate plasma levels of SOD, GSH, and GSH-Px and reduce the MDA level [61], indicating that SO2 preconditioning enhanced the antioxidative capacity in rats with myocardial I/R. MAPK signaling, one of the most important pathways in cell signal transduction, is crucial to myocardial I/R. SO2 preconditioning significantly improved cardiac function and reduced myocardial expression of phosphorylated ERK1/2 protein in isolated rat heart with I/R [62]. Pretreated with PD98059, the ERK1/2 inhibitor abolished the above functions of SO2 [62]. These data indicated that inhibition of ERK1/2 signal pathway activation mediated the cardioprotection of SO2 preconditioning in isolated rat heart subjected to I/R. Taken together, elevation of PI3K/AKT signaling, suppression of ERK-MAPK pathway, augmentation of ERS, enhancement of antioxidative capacity, and attenuation of cardiomyocyte apoptosis might be involved in SO2-mediated cardiac protective mechanisms.

4.5. SO2 and Myocardial Injury

Myocardial injury is a common feature in various cardiac diseases. The underlying mechanisms include hypoxia, overactive oxidative stress, and calcium overload. A previous study found that endogenous SO2/AAT pathway was downregulated in isoproterenol- (ISO-) induced myocardial injury in rats [63]. Administration of SO2 (85 mg/(kg day)) could alleviate cardiac dysfunction and myocardial damage induced by ISO [63]. These data demonstrated that endogenous SO2 might be an important regulator in the pathophysiological process of myocardial injury. The molecular mechanisms underlying the cardioprotective effects of SO2 were still unknown. Oxidative stress was involved in the pathogenesis for ISO-induced myocardial injury. ISO produced oxygen free radicals caused membrane lipid peroxidation, injured the structure of cardiomyocytes, and finally resulted in myocardial damage [64]. But SO2 could increase myocardial antioxidant capacity in rats with myocardial injury by increasing the myocardial activity of SOD and GSH, upregulating the mRNA expression of SOD2 and GSH-Px1, and decreasing products of oxidative stress such as H2O2 and [63]. Oxidative stress could cause ERS in rat cardiomyocytes [65]. And the overactivated ERS would contribute to the development of myocardial injury. SO2 significantly inhibited the excessive activation of ERS, which might be involved in the mechanism by which SO2 derivatives protected against myocardial injury induced by ISO [66]. In addition, the products of oxidative stress cause the cardiomyocyte membrane damage and morphological mitochondrial injury. SO2 also attenuated ISO-induced mitochondrial swelling and deformation, which was important feature in apoptosis [63]. And cardiomyocyte apoptosis is a key pathological change in myocardial injury. Of note, supplementation of SO2 derivatives alleviated ISO-induced myocardial injury partly through reducing cardiomyocyte apoptosis [67]. The antiapoptotic function of SO2 was mediated by promoting bcl-2 expression, suppressing bax expression, enhancing mitochondrial membrane potential, inhibiting mitochondrion MPTP opening, reducing the release of cytochrome c from mitochondrion into cytoplasm, and decreasing the activation of caspase-9 and caspase-3 [67]. Therefore, the bcl-2/cytc/caspase-9/caspase-3 pathway was involved in the ISO-induced myocardial injury in rats. Intracellular calcium homeostasis exerts a fundamental effect on myocardial physiology and pathology. And calcium overload is an important mechanism involved in myocardial injury. SO2 treatment could inhibit the increased intracellular free Ca2+ concentration induced by ISO in H9C2 cells [68], indicating that the protective effect of SO2 in myocardial injury might be related to the calcium homeostasis regulated by SO2 in cardiomyocytes. Moreover, SO2 derivatives could modulate L-type calcium current and voltage-gated potassium channels in rat cardiomyocytes, indicating that ion channels might also be involved in the effect of SO2 on cardiomyocyte injury [69, 70].

5. Interaction among SO2 and Other Gasotransmitters

SO2 and H2S share the same endogenous substrate L-cysteine, and they can transform into each other under some biochemical condition [6, 23, 71]. Moreover, they share similar regulatory roles including vasorelaxation, antioxidative action, and inhibition of inflammation and apoptosis. Chen et al. found that SO2 upregulated the concentration and production of H2S in hypoxic rats. And SO2 increased the expression of CSE and 3MST in pulmonary arteries of hypoxic pulmonary hypertensive rats [72]. In addition, SO2 alleviated pulmonary hypertension and improved the pulmonary vascular pathological injury induced by high pulmonary blood flow in association with upregulating the endogenous H2S pathway [51]. Furthermore, SO2 derivatives have a marked antiatherogenic effect with an increased aortic H2S/CSE pathway in atherosclerotic rats [17]. In rats with myocardial I/R injury, SO2 preconditioning markedly upregulated the myocardial H2S level and CSE expression [61]. The above findings provide some evidence that there is a crosstalk between SO2 and H2S. Moreover, NO also shares a variety of the similar biological effects of H2S and SO2, including vasodilation, antioxidation, and anti-inflammatory actions. Li and Meng found that a low concentration (3 or 5 nM) of a NO donor sodium-nitroprusside enhanced the vasodilating effect of SO2 by nearly sixfold [26], suggesting that SO2 and NO have a synergistic effect on vasodilation. In contrast, the NOS inhibitor L-NAME could abolish the vasorelaxing effect of SO2 derivatives (0.5 and 1 mM) in endothelium-intact rings, indicating that endothelium-dependent vasorelaxation induced by SO2 was partially mediated by a NOS pathway [73]. Additionally, both acute and prolonged SO2 exposure upregulated the eNOS-NO-cGMP pathway, which might be involved in the vasodilation induced by SO2 [34]. Moreover, SO2 increased vasorelaxation in SHRs by enhancing the vasorelaxing response to NO and upregulating NO production in aortic tissues [40]. And SO2 also increased NO/NOS pathway in rats with atherosclerosis [17]. By contrast, SO2 pretreatment reduced the myocardial tissue levels of NO and expression of iNOS in rats with I/R [61]. These data suggest that there is also an interaction between SO2 and NO. Hence, endogenous SO2 participates in crosstalk with H2S and NO and an endogenous gaseous messenger molecule network might exist in mammals. However, there are still many questions to be answered about the interactions among these gases. For example, the exact pertinence among these gases in the various pathways of cardiovascular protection has not been fully explored. It is also not known if a combination of these gases will provide synergistic effects in the therapy of cardiovascular diseases. Therefore, additional studies are needed to further investigate interactions among the gasotransmitter pathways.

6. Conclusions

In summary, SO2 can be generated in the cardiovascular system of mammals and the SO2/AAT pathway participates in many biological functions [22, 74]. Endogenously derived SO2 or SO2 derivatives at physiological concentrations play a crucial role in normal physiological process including regulation of vascular tone and cardiac function. In addition, SO2/AAT pathway has important pathophysiological significance in many cardiovascular diseases, such as hypertension, pulmonary hypertension, atherosclerosis, ischemia-reperfusion injury, and myocardial injury. Just as NO, carbon monoxide (CO), and H2S, SO2 is also an endogenous gaseous signaling molecule in the cardiovascular system [71, 75]. However, the biological mechanisms by which endogenous SO2 regulates different cardiovascular diseases and the further cardiovascular effects of SO2 still need to be deeply investigated.

Clarifying the interactions among SO2 and other endogenous gasotransmitters could improve clinical translation. SO2 could upregulate endogenous level of H2S or NO in several cardiovascular diseases such as atherosclerosis, systemic hypertension, or pulmonary hypertension [17, 40, 51]. These lines of evidence imply a crosstalk among SO2 and other gasotransmitters (NO, CO, and H2S) in the cardiovascular system, which requires further exploration.

An understanding of the cardiovascular protective function of SO2 may lead to a new therapeutic strategy based on the modulation of SO2 production. Thus, the function and signaling pathway relating to AAT in the cardiovascular system are worthy of further investigation. Additionally, the design of SO2-controlled releasing agents under physiological condition is extremely urgent, because the stable and reliable SO2 donors are not only the useful research tools, but also potential therapeutic agents to treat cardiovascular diseases. Nowadays, the majority of cardiovascular studies on SO2 have been performed in rats and mice, which lack clinical evidence. Exploring the role of SO2 in large animal models with similar cardiovascular features as human suffering from cardiovascular diseases would help a transition to clinical trials.


SO2:Sulfur dioxide
AAT:Aspartate aminotransferase
CDO:Cysteine dioxygenase
H2S:Hydrogen sulfide
NO:Nitric oxide
CO:Carbon monoxide
L-Ca2+:L-type calcium
:Big-conductance Ca2+-activated K+
:Adenosine triphosphate-sensitive potassium
cAMP:3′-5′-Cyclic adenosine monophosphate
AC:Adenylyl cyclase
PKA:Protein kinase A
cGMP:3′-5′-Cyclic guanosine monophosphate
LVDP:Left ventricular developed pressure
PKC:Protein kinase C
SHR:Spontaneously hypertensive rats
eNOS:Nitric oxide synthase
VSMCs:Vascular smooth muscle cells
PDGF-BB:Platelet-derived growth factor-BB
Erk 1/2:Extracellular regulated protein kinase 1/2
MAPK:Mitogen-activated protein kinase
CHD:Congenital heart defects
mPAP:Mean pulmonary artery pressure
NF-κB:Nuclear factor-kappa B
ICAM-1:Intercellular adhesion molecule-1
SOD:Superoxide dismutase
GSH-Px:Glutathione peroxidase
CSE:Cystathionine γ-lyase
CBS:Cystathionine β-synthase
3MST:3-Mercaptopyruvate sulfurtransferase
NOS:Nitric oxide synthase
CK:Creatine kinase
LDH:Lactate dehydrogenase
GRP78:Glucose-regulated protein 78
CHOP:C/EBP homologous protein
eIF2α:Eukaryotic initiation of the factor 2α-subunit
p-eIF2α:Phosphorylated eIF2α
ERS:Endoplasmic reticulum stress

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


This work was supported by the National Natural Science Foundation of China (Grants nos. 81400311, 31440052, and 91439110).


  1. A. L. Woerman and D. Mendelowitz, “Perinatal sulfur dioxide exposure alters brainstem parasympathetic control of heart rate,” Cardiovascular Research, vol. 99, no. 1, pp. 16–23, 2013. View at: Publisher Site | Google Scholar
  2. K.-B. Min, J.-Y. Min, S.-I. Cho, and D. Paek, “The relationship between air pollutants and heart-rate variability among community residents in Korea,” Inhalation Toxicology, vol. 20, no. 4, pp. 435–444, 2008. View at: Publisher Site | Google Scholar
  3. T. P. Singer and E. B. Kearney, “Intermediary metabolism of L-cysteinesulfinic acid in animal tissues,” Archives of Biochemistry and Biophysics, vol. 61, no. 2, pp. 397–409, 1956. View at: Publisher Site | Google Scholar
  4. L. Li and P. K. Moore, “An overview of the biological significance of endogenous gases: new roles for old molecules,” Biochemical Society Transactions, vol. 35, no. 5, pp. 1138–1141, 2007. View at: Publisher Site | Google Scholar
  5. D. E. Barañano, C. D. Ferris, and S. H. Snyder, “Atypical neural messengers,” Trends in Neurosciences, vol. 24, no. 2, pp. 99–106, 2001. View at: Publisher Site | Google Scholar
  6. R. Shapiro, “Genetic effects of bisulfite (sulfur dioxide),” Mutation Research, vol. 39, no. 2, pp. 149–175, 1977. View at: Publisher Site | Google Scholar
  7. C. Mottley, T. B. Trice, and R. P. Mason, “Direct detection of the sulfur trioxide radical anion during the horseradish peroxidase-hydrogen peroxide oxidation of sulfite (aqueous sulfur dioxide),” Molecular Pharmacology, vol. 22, no. 3, pp. 732–737, 1982. View at: Google Scholar
  8. G. A. Reed, M. J. Ryan, and K. S. Adams, “Sulfite enhancement of diolepoxide mutagenicity: the role of altered glutathione metabolism,” Carcinogenesis, vol. 11, no. 9, pp. 1635–1639, 1990. View at: Publisher Site | Google Scholar
  9. A. J. Ji, S. R. Savon, and D. W. Jacobsen, “Determination of total serum sulfite by HPLC with fluorescence detection,” Clinical Chemistry, vol. 41, no. 6, part 1, pp. 897–903, 1995. View at: Google Scholar
  10. H. Kajiyama, Y. Nojima, H. Mitsuhashi et al., “Elevated levels of serum sulfite in patients with chronic renal failure,” Journal of the American Society of Nephrology, vol. 11, no. 5, pp. 923–927, 2000. View at: Google Scholar
  11. H. Mitsuhashi, H. Ikeuchi, S. Yamashita et al., “Increased levels of serum sulfite in patients with acute pneumonia,” Shock, vol. 21, no. 2, pp. 99–102, 2004. View at: Google Scholar
  12. W. S. Wu, Y. R. Jia, S. X. Du, H. Tang, Y. L. Sun, and L. M. Sun, “Changes of sulfur dioxide, nuclear factor-κB, and interleukin-8 levels in pediatric acute lymphoblastic leukemia with bacterial inflammation,” Chinese Medical Journal, vol. 127, no. 23, pp. 4110–4113, 2014. View at: Publisher Site | Google Scholar
  13. M. Balazy, I. A. Abu-Yousef, D. N. Harpp, and J. Park, “Identification of carbonyl sulfide and sulfur dioxide in porcine coronary artery by gas chromatography/mass spectrometry, possible relevance to EDHF,” Biochemical and Biophysical Research Communications, vol. 311, no. 3, pp. 728–734, 2003. View at: Publisher Site | Google Scholar
  14. S.-X. Du, H.-F. Jin, D.-F. Bu et al., “Endogenously generated sulfur dioxide and its vasorelaxant effect in rats,” Acta Pharmacologica Sinica, vol. 29, no. 8, pp. 923–930, 2008. View at: Publisher Site | Google Scholar
  15. X. Zhao, H.-F. Jin, C.-S. Tang, and J.-B. Du, “Effects of sulfur dioxide, on the proliferation and apoptosis of aorta smooth muscle cells in hypertension: experiments with rats,” Zhonghua Yi Xue Za Zhi, vol. 88, no. 18, pp. 1279–1283, 2008. View at: Google Scholar
  16. Y. Sun, Y. Tian, M. Prabha et al., “Effects of sulfur dioxide on hypoxic pulmonary vascular structural remodeling,” Laboratory Investigation, vol. 90, no. 1, pp. 68–82, 2010. View at: Publisher Site | Google Scholar
  17. W. Li, C. Tang, H. Jin, and J. Du, “Regulatory effects of sulfur dioxide on the development of atherosclerotic lesions and vascular hydrogen sulfide in atherosclerotic rats,” Atherosclerosis, vol. 215, no. 2, pp. 323–330, 2011. View at: Publisher Site | Google Scholar
  18. X.-B. Wang, X.-M. Huang, T. Ochs et al., “Effect of sulfur dioxide preconditioning on rat myocardial ischemia/reperfusion injury by inducing endoplasmic reticulum stress,” Basic Research in Cardiology, vol. 106, no. 5, pp. 865–878, 2011. View at: Publisher Site | Google Scholar
  19. X. Li, F. W. Bazer, H. Gao et al., “Amino acids and gaseous signaling,” Amino Acids, vol. 37, no. 1, pp. 65–78, 2009. View at: Publisher Site | Google Scholar
  20. Z.-Q. Meng and J.-L. Li, “Progress in sulfur dioxide biology: from toxicology to physiology,” Sheng Li Xue Bao, vol. 63, no. 6, pp. 593–600, 2011. View at: Google Scholar
  21. H. Tian, “Advances in the study on endogenous sulfur dioxide in the cardiovascular system,” Chinese Medical Journal, vol. 127, no. 21, pp. 3803–3807, 2014. View at: Publisher Site | Google Scholar
  22. M. H. Stipanuk, “Metabolism of sulfur-containing amino acids,” Annual Review of Nutrition, vol. 6, pp. 179–209, 1986. View at: Publisher Site | Google Scholar
  23. H. Mitsuhashi, S. Yamashita, H. Ikeuchi et al., “Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils,” Shock, vol. 24, no. 6, pp. 529–534, 2005. View at: Publisher Site | Google Scholar
  24. P. Kamoun, “Endogenous production of hydrogen sulfide in mammals,” Amino Acids, vol. 26, no. 3, pp. 243–254, 2004. View at: Google Scholar
  25. K. Qu, S. W. Lee, J. S. Bian, C.-M. Low, and P. T.-H. Wong, “Hydrogen sulfide: neurochemistry and neurobiology,” Neurochemistry International, vol. 52, no. 1, pp. 155–165, 2008. View at: Publisher Site | Google Scholar
  26. J. Li and Z. Meng, “The role of sulfur dioxide as an endogenous gaseous vasoactive factor in synergy with nitric oxide,” Nitric Oxide, vol. 20, no. 3, pp. 166–174, 2009. View at: Publisher Site | Google Scholar
  27. Z. Meng, J. Li, Q. Zhang et al., “Vasodilator effect of gaseous sulfur dioxide and regulation of its level by Ach in rat vascular tissues,” Inhalation Toxicology, vol. 21, no. 14, pp. 1223–1228, 2009. View at: Publisher Site | Google Scholar
  28. Z. Meng, H. Geng, J. Bai, and G. Yan, “Blood pressure of rats lowered by sulfur dioxide and its derivatives,” Inhalation Toxicology, vol. 15, no. 9, pp. 951–959, 2003. View at: Publisher Site | Google Scholar
  29. Q. Zhang and Z. Meng, “The vasodilator mechanism of sulfur dioxide on isolated aortic rings of rats: involvement of the K+ and Ca2+ channels,” European Journal of Pharmacology, vol. 602, no. 1, pp. 117–123, 2009. View at: Publisher Site | Google Scholar
  30. Q. Zhang, J. Tian, Y. Bai et al., “Effects of gaseous sulfur dioxide and its derivatives on the expression of KATP, BKCa and L-Ca2+ channels in rat aortas in vitro,” European Journal of Pharmacology, vol. 742, pp. 31–41, 2014. View at: Publisher Site | Google Scholar
  31. Z. Meng, Y. Li, and J. Li, “Vasodilatation of sulfur dioxide derivatives and signal transduction,” Archives of Biochemistry and Biophysics, vol. 467, no. 2, pp. 291–296, 2007. View at: Publisher Site | Google Scholar
  32. Z. Meng and H. Zhang, “The vasodilator effect and its mechanism of sulfur dioxide-derivatives on isolated aortic rings of rats,” Inhalation Toxicology, vol. 19, no. 11, pp. 979–986, 2007. View at: Publisher Site | Google Scholar
  33. Z. Meng, Z. Yang, J. Li, and Q. Zhang, “The vasorelaxant effect and its mechanisms of sodium bisulfite as a sulfur dioxide donor,” Chemosphere, vol. 89, no. 5, pp. 579–584, 2012. View at: Publisher Site | Google Scholar
  34. J. Li, R. Li, and Z. Meng, “Sulfur dioxide upregulates the aortic nitric oxide pathway in rats,” European Journal of Pharmacology, vol. 645, no. 1–3, pp. 143–150, 2010. View at: Publisher Site | Google Scholar
  35. S. Q. Zhang, J. B. Du, Y. Tian, B. Geng, C. S. Tang, and X. Y. Tang, “Effects of sulfur dioxide on cardiac function of isolated perfusion heart of rat,” Zhonghua Yi Xue Za Zhi, vol. 88, no. 12, pp. 830–834, 2008. View at: Google Scholar
  36. Q. Zhang and Z. Meng, “The negative inotropic effects of gaseous sulfur dioxide and its derivatives in the isolated perfused rat heart,” Environmental Toxicology, vol. 27, no. 3, pp. 175–184, 2012. View at: Publisher Site | Google Scholar
  37. Q. Zhang, Y. Bai, Z. Yang, J. Tian, and Z. Meng, “Effect of sulfur dioxide inhalation on the expression of KATP and L-Ca2+ channels in rat hearts,” Environmental Toxicology and Pharmacology, vol. 39, no. 3, pp. 1132–1138, 2015. View at: Publisher Site | Google Scholar
  38. R.-Y. Zhang, J.-B. Du, Y. Sun et al., “Sulfur dioxide derivatives depress L-type calcium channel in rat cardiomyocytes,” Clinical and Experimental Pharmacology and Physiology, vol. 38, no. 7, pp. 416–422, 2011. View at: Publisher Site | Google Scholar
  39. R. T. Drew, R. S. Kutzman, D. L. Costa, and J. Iwai, “Effects of sulfur dioxide and ozone on hypertension sensitive and resistant rats,” Fundamental and Applied Toxicology, vol. 3, no. 4, pp. 298–302, 1983. View at: Publisher Site | Google Scholar
  40. W. Lu, Y. Sun, C. Tang et al., “Sulfur dioxide derivatives improve the vasorelaxation in the spontaneously hypertensive rat by enhancing the vasorelaxant response to nitric oxide,” Experimental Biology and Medicine, vol. 237, no. 7, pp. 867–872, 2012. View at: Publisher Site | Google Scholar
  41. H. D. Intengan and E. L. Schiffrin, “Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis,” Hypertension, vol. 38, no. 3, pp. 581–587, 2001. View at: Publisher Site | Google Scholar
  42. Y. C. Fung, “What are the residual stresses doing in our blood vessels?” Annals of Biomedical Engineering, vol. 19, no. 3, pp. 237–249, 1991. View at: Publisher Site | Google Scholar
  43. D. Liu, Y. Huang, D. Bu et al., “Sulfur dioxide inhibits vascular smooth muscle cell proliferation via suppressing the Erk/MAP kinase pathway mediated by cAMP/PKA signaling,” Cell Death & Disease, vol. 5, Article ID e1251, 2014. View at: Publisher Site | Google Scholar
  44. R. Yang, Y. Yang, X. Dong, X. Wu, and Y. Wei, “Correlation between endogenous sulfur dioxide and homocysteine in children with pulmonary arterial hypertension associated with congenital heart disease,” Zhonghua Er Ke Za Zhi, vol. 52, no. 8, pp. 625–629, 2014. View at: Google Scholar
  45. Y. Tian, X.-Y. Tang, H.-F. Jin, C.-S. Tang, and J.-B. Du, “Effect of sulfur dioxide on pulmonary vascular structure of hypoxic pulmonary hypertensive rats,” Chinese Journal of Pediatrics, vol. 46, no. 9, pp. 675–679, 2008. View at: Google Scholar
  46. V. Amsellem, L. Lipskaia, S. Abid et al., “CCR5 as a treatment target in pulmonary arterial hypertension,” Circulation, vol. 130, no. 11, pp. 880–891, 2014. View at: Publisher Site | Google Scholar
  47. H.-F. Jin, S.-X. Du, X. Zhao et al., “Effects of endogenous sulfur dioxide on monocrotaline-induced pulmonary hypertension in rats,” Acta Pharmacologica Sinica, vol. 29, no. 10, pp. 1157–1166, 2008. View at: Publisher Site | Google Scholar
  48. S. M. Aziz, M. Toborek, B. Hennig, E. Endean, and D. W. Lipke, “Polyamine regulatory processes and oxidative stress in monocrotaline-treated pulmonary artery endothelial cells,” Cell Biology International, vol. 21, no. 12, pp. 801–812, 1997. View at: Publisher Site | Google Scholar
  49. J. I. E. Hoffman, A. M. Rudolph, and M. A. Heymann, “Pulmonary vascular disease with congenital heart lesions: pathologic features and causes,” Circulation, vol. 64, no. 5, pp. 873–877, 1981. View at: Publisher Site | Google Scholar
  50. C.-F. Lam, T. E. Peterson, A. J. Croatt, K. A. Nath, and Z. S. Katusic, “Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 289, no. 6, pp. H2334–H2341, 2005. View at: Publisher Site | Google Scholar
  51. L. Luo, D. Liu, C. Tang et al., “Sulfur dioxide upregulates the inhibited endogenous hydrogen sulfide pathway in rats with pulmonary hypertension induced by high pulmonary blood flow,” Biochemical and Biophysical Research Communications, vol. 433, no. 4, pp. 519–525, 2013. View at: Publisher Site | Google Scholar
  52. I. Brüske, R. Hampel, Z. Baumgärtner et al., “Ambient air pollution and lipoprotein-associated phospholipase A2 in survivors of myocardial infarction,” Environmental Health Perspectives, vol. 119, no. 7, pp. 921–926, 2011. View at: Publisher Site | Google Scholar
  53. V. Lenters, C. S. Uiterwaal, R. Beelen et al., “Long-term exposure to air pollution and vascular damage in young adults,” Epidemiology, vol. 21, no. 4, pp. 512–520, 2010. View at: Publisher Site | Google Scholar
  54. D. Liu, Z. He, L. Wu, and Y. Fang, “Effects of induction/inhibition of endogenous heme oxygenase-1 on lipid metabolism, endothelial function, and atherosclerosis in rabbits on a high fat diet,” Journal of Pharmacological Sciences, vol. 118, no. 1, pp. 14–24, 2012. View at: Publisher Site | Google Scholar
  55. Y. Wang, X. Zhao, H. Jin et al., “Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 2, pp. 173–179, 2009. View at: Publisher Site | Google Scholar
  56. T. P. Vacek, S. Rahman, S. Yu, D. Neamtu, S. Givimani, and S. C. Tyagi, “Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms,” Vascular Health and Risk Management, vol. 11, pp. 173–183, 2015. View at: Publisher Site | Google Scholar
  57. Y. Shen, Z. Shen, S. Luo, W. Guo, and Y. Z. Zhu, “The cardioprotective effects of hydrogen sulfide in heart diseases: from molecular mechanisms to therapeutic potential,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 925167, 13 pages, 2015. View at: Publisher Site | Google Scholar
  58. H. S. Kim, K.-A. Kong, H. Chung, S. Park, and M. H. Kim, “ER stress induces the expression of Jpk, which inhibits cell cycle progression in F9 teratocarcinoma cell,” Annals of the New York Academy of Sciences, vol. 1095, pp. 76–81, 2007. View at: Publisher Site | Google Scholar
  59. S.-E. Choi, Y.-J. Lee, H.-J. Jang et al., “A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucose-stimulated insulin secretion (GSIS),” Archives of Biochemistry and Biophysics, vol. 475, no. 2, pp. 109–114, 2008. View at: Publisher Site | Google Scholar
  60. M.-M. Zhao, J.-Y. Yang, X.-B. Wang, C.-S. Tang, J.-B. Du, and H.-F. Jin, “The PI3K/Akt pathway mediates the protection of SO2 preconditioning against myocardial ischemia/reperfusion injury in rats,” Acta Pharmacologica Sinica, vol. 34, no. 4, pp. 501–506, 2013. View at: Publisher Site | Google Scholar
  61. H. F. Jin, Y. Wang, X. B. Wang, Y. Sun, C. S. Tang, and J. B. Du, “Sulfur dioxide preconditioning increases antioxidative capacity in rat with myocardial ischemia reperfusion (I/R) injury,” Nitric Oxide—Biology and Chemistry, vol. 32, pp. 56–61, 2013. View at: Publisher Site | Google Scholar
  62. P. Huang, Y. Sun, J. Yang et al., “The ERK1/2 signaling pathway is involved in sulfur dioxide preconditioning-induced protection against cardiac dysfunction in isolated perfused rat heart subjected to myocardial ischemia/reperfusion,” International Journal of Molecular Sciences, vol. 14, no. 11, pp. 22190–22201, 2013. View at: Publisher Site | Google Scholar
  63. Y. Liang, D. Liu, T. Ochs et al., “Endogenous sulfur dioxide protects against isoproterenol-induced myocardial injury and increases myocardial antioxidant capacity in rats,” Laboratory Investigation, vol. 91, no. 1, pp. 12–23, 2011. View at: Publisher Site | Google Scholar
  64. A. A. Noronha-Dutra, E. M. Steen-Dutra, and N. Woolf, “Epinephrine-induced cytotoxicity of rat plasma. Its effects on isolated cardiac myocytes,” Laboratory Investigation, vol. 59, no. 6, pp. 817–823, 1988. View at: Google Scholar
  65. C. W. Younce and P. E. Kolattukudy, “MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP,” Biochemical Journal, vol. 426, no. 1, pp. 43–53, 2010. View at: Publisher Site | Google Scholar
  66. S. Chen, J. Du, Y. Liang et al., “Sulfur dioxide inhibits excessively activated endoplasmic reticulum stress in rats with myocardial injury,” Heart and Vessels, vol. 27, no. 5, pp. 505–516, 2012. View at: Publisher Site | Google Scholar
  67. H. Jin, A. D. Liu, L. Holmberg et al., “The role of sulfur dioxide in the regulation of mitochondrion-related cardiomyocyte apoptosis in rats with isopropylarterenol-induced myocardial injury,” International Journal of Molecular Sciences, vol. 14, no. 5, pp. 10465–10482, 2013. View at: Publisher Site | Google Scholar
  68. S. Chen, J. Du, Y. Liang, R. Zhang, C. Tang, and H. Jin, “Sulfur dioxide restores calcium homeostasis disturbance in rat with isoproterenol-induced myocardial injury,” Histology and Histopathology, vol. 27, no. 9, pp. 1219–1226, 2012. View at: Google Scholar
  69. A. Nie and Z. Meng, “Modulation of L-type calcium current in rat cardiac myocytes by sulfur dioxide derivatives,” Food and Chemical Toxicology, vol. 44, no. 3, pp. 355–363, 2006. View at: Publisher Site | Google Scholar
  70. A. Nie and Z. Meng, “Sulfur dioxide derivative modulation of potassium channels in rat ventricular myocytes,” Archives of Biochemistry and Biophysics, vol. 442, no. 2, pp. 187–195, 2005. View at: Publisher Site | Google Scholar
  71. X.-B. Wang, H.-F. Jin, C.-S. Tang, and J.-B. Du, “The biological effect of endogenous sulfur dioxide in the cardiovascular system,” European Journal of Pharmacology, vol. 670, no. 1, pp. 1–6, 2011. View at: Publisher Site | Google Scholar
  72. S.-Y. Chen, H.-F. Jin, Y. Sun, Y. Tian, C.-S. Tang, and J.-B. Du, “Impact of sulfur dioxide on hydrogen sulfide/cystathionine-γ-lyase and hydrogen sulfide/mercaptopyruvate sulfurtransferase pathways in the pathogenesis of hypoxic pulmonary hypertension in rats,” Zhonghua Er Ke Za Zhi, vol. 49, no. 12, pp. 890–894, 2011. View at: Google Scholar
  73. Y. K. Wang, A. J. Ren, X. Q. Yang et al., “Sulfur dioxide relaxes rat aorta by endothelium-dependent and -independent mechanisms,” Physiological Research, vol. 58, no. 4, pp. 521–527, 2009. View at: Google Scholar
  74. H.-J. Ma, X.-L. Huang, Y. Liu, and Y.-M. Fan, “Sulfur dioxide attenuates LPS-induced acute lung injury via enhancing polymorphonuclear neutrophil apoptosis,” Acta Pharmacologica Sinica, vol. 33, no. 8, pp. 983–990, 2012. View at: Publisher Site | Google Scholar
  75. J. L. Hart, “Role of sulfur-containing gaseous substances in the cardiovascular system,” Frontiers in Bioscience (Elite Edition), vol. 3, no. 2, pp. 736–749, 2011. View at: Publisher Site | Google Scholar

Copyright © 2016 Yaqian Huang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.