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

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.National Natural Science Foundation of China [81400311, 31440052, 91439110]SCI(E)[email protected]

Hydrogen Sulfide Inhibits L-Type Calcium Currents Depending upon the Protein Sulfhydryl State in Rat Cardiomyocytes

Hydrogen sulfide (H2S) is a novel gasotransmitter that inhibits L-type calcium currents (I Ca, L). However, the underlying molecular mechanisms are unclear. In particular, the targeting site in the L-type calcium channel where H2S functions remains unknown. The study was designed to investigate if the sulfhydryl group could be the possible targeting site in the L-type calcium channel in rat cardiomyocytes. Cardiac function was measured in isolated perfused rat hearts. The L-type calcium currents were recorded by using a whole cell voltage clamp technique on the isolated cardiomyocytes. The L-type calcium channel containing free sulfhydryl groups in H9C2 cells were measured by using Western blot. The results showed that sodium hydrosulfide (NaHS, an H2S donor) produced a negative inotropic effect on cardiac function, which could be partly inhibited by the oxidant sulfhydryl modifier diamide (DM). H2S donor inhibited the peak amplitude of I Ca, L in a concentration-dependent manner. However, dithiothreitol (DTT), a reducing sulfhydryl modifier markedly reversed the H2S donor-induced inhibition of I Ca, L in cardiomyocytes. In contrast, in the presence of DM, H2S donor could not alter cardiac function and L type calcium currents. After the isolated rat heart or the cardiomyocytes were treated with DTT, NaHS could markedly alter cardiac function and L-type calcium currents in cardiomyocytes. Furthermore, NaHS could decrease the functional free sulfhydryl group in the L-type Ca2+ channel, which could be reversed by thiol reductant, either DTT or reduced glutathione. Therefore, our results suggest that H2S might inhibit L-type calcium currents depending on the sulfhydryl group in rat cardiomyocytes

Role of Endogenous Sulfur Dioxide in Regulating Vascular Structural Remodeling in Hypertension

Sulfur dioxide (SO2), an emerging gasotransmitter, was discovered to be endogenously generated in the cardiovascular system. Recently, the physiological effects of endogenous SO2 were confirmed. Vascular structural remodeling (VSR), an important pathological change in many cardiovascular diseases, plays a crucial role in the pathogenesis of the diseases. Here, the authors reviewed the research progress of endogenous SO2 in regulating VSR by searching the relevant data from PubMed and Medline. In spontaneously hypertensive rats (SHRs) and pulmonary hypertensive rats, SO2/aspartate aminotransferase (AAT) pathway was significantly altered. SO2 inhibited vascular smooth muscle cell (VSMC) proliferation, promoted apoptosis, inhibited the synthesis of extracellular collagen but promoted its degradation, and enhanced antioxidative capacity, thereby playing a significant role in attenuating VSR. However, the detailed mechanisms needed to be further explored. Further studies in this field would be important for the better understanding of the pathogenesis of systemic hypertension and pulmonary hypertension. Also, clinical trials are needed to demonstrate if SO2 would be a potential therapeutic target in cardiovascular diseases

Hydrogen Sulfide Maintains Mesenchymal Stem Cell Function and Bone Homeostasis via Regulation of Ca2+ Channel Sulfhydration

Gaseous signaling molecules such as hydrogen sulfide (H2S) are produced endogenously and mediate effects through diverse mechanisms. H2S is one such gasotrasmitter which regulates multiple signaling pathways in mammalian cells, and abnormal H2S metabolism has been linked to defects in bone homeostasis. Here, we demonstrate that bone marrow mesenchymal stem cells (BMMSCs) produce H2S to regulate their self-renewal and osteogenic differentiation, and H2S deficiency results in defects in BMMSC differentiation. H2S deficiency causes aberrant intracellular Ca2+ influx, due to reduced sulfhydration of cysteine residues on multiple Ca2+ TRP channels. This decreased Ca2+ flux downregulates PKC/Erk-mediated Wnt/β-catenin signaling which controls osteogenic differentiation of BMMSCs. Consistently, H2S-deficient mice display an osteoporotic phenotype, which can be rescued by small molecules which release H2S. These results demonstrate H2S regulates BMMSCs, and restoring H2S levels via non-toxic donors may provide treatments for diseases such as osteoporosis which can arise from H2S deficiencies

Plasma Homocysteine Level in Children With Postural Tachycardia Syndrome

The study was designed to evaluate the changes of plasma homocysteine (Hcy) level in children with postural tachycardia syndrome (POTS) and explore its significance. A total of 65 subjects were recruited in our study, of whom 35 children were in the POTS group and 30 healthy children were in the control group. Plasma Hcy levels were determined in all subjects. The relationship between the plasma Hcy level and the symptom score was analyzed in the 35 POTS patients. The relationship between the plasma Hcy level and the change in heart rate from the supine to upright position (ΔHR) and between the plasma Hcy level and the rate of increase in heart rate from the supine to upright position (ΔHR/sHR × 100%) were analyzed in all subjects. The plasma Hcy levels were significantly higher in the children with POTS than those in the control group (9.78 [7.68, 15.31] μmol/L vs. 7.79 [7.46, 9.63] μmol/L, P < 0.05). The plasma Hcy levels were positively correlated with symptom scores in the POTS patients (n = 35, r = 0.522, P < 0.01). The plasma Hcy levels were also positively correlated with ΔHR (n = 65, r = 0.332, P < 0.01) and ΔHR/sHR × 100% (n = 65, r = 0.341, P < 0.01) in all the subjects. In conclusion, the plasma Hcy levels were elevated in the children with POTS positively correlated with the severity of POTS, suggesting that Hcy might be involved in the pathogenesis of POTS

Wet and Dry Atmospheric Depositions of Inorganic Nitrogen during Plant Growing Season in the Coastal Zone of Yellow River Delta

The ecological problems caused by dry and wet deposition of atmospheric nitrogen have been widespread concern in the world. In this study, wet and dry atmospheric depositions were monitored in plant growing season in the coastal zone of the Yellow River Delta (YRD) using automatic sampling equipment. The results showed that SO42- and Na+ were the predominant anion and cation, respectively, in both wet and dry atmospheric depositions. The total atmospheric nitrogen deposition was ~2264.24 mg m−2, in which dry atmospheric nitrogen deposition was about 32.02%. The highest values of dry and wet atmospheric nitrogen deposition appeared in May and August, respectively. In the studied area, NO3-–N was the main nitrogen form in dry deposition, while the predominant nitrogen in wet atmospheric deposition was NH4+–N with ~56.51% of total wet atmospheric nitrogen deposition. The average monthly attribution rate of atmospheric deposition of NO3-–N and NH4+–N was ~31.38% and ~20.50% for the contents of NO3-–N and NH4+–N in 0–10 cm soil layer, respectively, suggested that the atmospheric nitrogen was one of main sources for soil nitrogen in coastal zone of the YRD

Ион-парная ВЭЖХ производных пиримидина и пурина

ПИРИМИДИНЫГЕТЕРОЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ ОДНОКОЛЬЦЕВЫЕПУРИНЫГЕТЕРОЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ ДВУХКОЛЬЦЕВЫЕХРОМАТОГРАФИЯ ЖИДКОСТНАЯ ВЫСОКОГО ДАВЛЕНИЯХРОМАТОГРАФИЯ ИОНООБМЕННАЯДНКРНКПРОТИВООПУХОЛЕВЫЕ СРЕДСТВАПРОТИВОВИРУСНЫЕ СРЕДСТВ

Sulfur Dioxide Activates Cl-/HCO3- Exchanger via Sulphenylating AE2 to Reduce Intracellular pH in Vascular Smooth Muscle Cells

Sulfur dioxide (SO2) is a colorless and irritating gas. Recent studies indicate that SO2 acts as the gas signal molecule and inhibits vascular smooth muscle cell (VSMC) proliferation. Cell proliferation depends on intracellular pH (pHi). Transmembrane cystein mutation of Na+- independent Cl-/HCO3- exchanger (anion exchanger, AE) affects pHi. However, whether SO2 inhibits VSMC proliferation by reducing pHi is still unknown. Here, we investigated whether SO2 reduced pHi to inhibit the proliferation of VSMCs and explore its molecular mechanisms. Within a range of 50–200 μM, SO2 was found to lower the pHi in VSMCs. Concurrently, NH4Cl pre-perfusion showed that SO2 significantly activated AE, whereas the AE inhibitor 4,4′-diisothiocyanatostilbene- 2,20-disulfonic acid (DIDS) significantly attenuated the effect of SO2 on pHi in VSMCs. While 200 μM SO2 sulphenylated AE2, while dithiothreitol (DTT) blocked the sulphenylation of AE2 and subsequent AE activation by SO2, thereby restoring the pHi in VSMCs. Furthermore, DIDS pretreatment eliminated SO2-induced inhibition of PDGF-BB-stimulated VSMC proliferation. We report for the first time that SO2 inhibits VSMC proliferation in part by direct activation of the AE via posttranslational sulphenylation and induction of intracellular acidification

Value of Immediate Heart Rate Alteration From Supine to Upright in Differential Diagnosis Between Vasovagal Syncope and Postural Tachycardia Syndrome in Children

Objectives: To explore the predictive value of immediate heart rate alteration from supine to upright in the differential diagnosis between vasovagal syncope (VVS) and postural tachycardia syndrome (POTS) in children.Materials and Methods: A total of 76 pediatric outpatients or inpatients who visited the Peking University First Hospital from July 2016 to November 2017 were recruited in the study. Among them, 52 patients were diagnosed with VVS and 24 patients were diagnosed with POTS. The differential diagnostic value of acceleration index (AI) and 30/15 ratio was evaluated by the receiver operating characteristic (ROC) curve. An external validation test was performed in another 46 patients.Results: Compared with the cases in the VVS group, patients in the POTS group had a significantly increased AI but a decreased 30/15 ratio (33.495 ± 8.472 vs. 23.440 ± 8.693, p < 0.001; 0.962 ± 0.067 vs. 1.025 ± 0.084, p = 0.002; respectively). The ROC curves showed that AI and 30/15 ratio were useful for differentiating POTS from VVS. A cut-off value of AI set at 28.180 yielded a sensitivity of 79.2% and a specificity of 73.1%. A cut-off value of 30/15 ratio set at 1.025 yielded a sensitivity of 87.5% and a specificity of 61.5%. A combined use of these two indices improved the sensitivity to 95.8% when either AI or 30/15 was used, and specificity to 80.8% with the use of both AI and 30/15 at the same diagnosis. The external validation test showed that the positive and negative predictive values of the AI and 30/15 ratio were 77.3 and 79.2%, and 72.0 and 81.0%, respectively. The positive predictive value increased to 87.5% when both the AI and 30/15 ratio cut-off values were used together.Conclusions: The AI and 30/15 ratio, which are easy to perform and non-invasive, have proper sensitivity and specificity to differentiate patients with POTS from those with VVS. The combination of these two indices significantly improves the predictive value

Sulfur dioxide inhibits mast cell degranulation by sulphenylation of galectin-9 at cysteine 74

ObjectivesMast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO2) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO2 controlled MC degranulation.MethodsHMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO2 content was detected by in situ fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO2. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO2 on mast cell activation in vivo. Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO2 and support the significance of SO2/Gal-9 signal axis in the regulation of MC degranulation.ResultsDegranulation was increased in AAT1-knockdowned MCs, and SO2 supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO2 contributed to IgE-mediated degranulation in vitro. Besides, SO2 inhibited IgE-mediated and hypoxia-driven MC degranulation in vivo. Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO2 sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74th cysteine of Gal-9 protein was required in the SO2-inhibited MC degranulation under both physiological and pathophysiological conditions.ConclusionThese findings elucidated that SO2 inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases