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Zhang F.,Peking University | Li X.,Peking University | Stella C.,University of San Diego | Chen L.,Peking University | And 5 more authors.
Journal of Pediatrics | Year: 2012

Objective: To explore the predictive value of plasma hydrogen sulfide (H 2S) in differentiating between vasovagal syncope (VVS) and postural orthostatic tachycardia syndrome (POTS) in children. Study design: Patients were divided between the POTS group (n = 60) and VVS group (n = 17) by using either the head-up test or head-up tilt test. Twenty-eight healthy children were selected for the control group. Plasma concentrations of H 2S were determined for children in all groups (POTS, VVS, and control). Results: Plasma levels of H 2S were significantly higher in children with VVS (95.3 ± 3.8 μmol/L) and POTS (100.9 ± 2.1 μmol/L) than in children in the control group (82.6 ± 6.5 μmol/L). Compared with the VVS group, the POTS group had plasma levels of H 2S that were significantly increased. The receiver operating characteristic curve for the predictive value of H 2S differentiation of VVS from POTS showed a H 2S plasma level of 98 μmol/L as the cutoff value for high probability of distinction. Such a level produced both high sensitivity (90%) and specificity (80%) rates of correctly discriminating between patients with VVS and patients with POTS. Conclusion: H 2S plasma level has both high sensitivity and specificity rates to predict the probability of correctly differentiating between patients with VVS and patients with POTS. Copyright © 2012 Mosby Inc. All rights reserved.

Zhang F.,Peking University | Li X.,Peking University | Ochs T.,Northwestern University | Chen L.,Peking University | And 5 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: This study was designed to explore the predictive value of the midregional fragment of pro-adrenomedullin (MR-proADM) in assessing the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). Background: Midodrine hydrochloride is an important therapeutic option for children with POTS. However, there has not been any method to predict response to the drug. The MR-proADM is produced in equimolar amounts to adrenomedullin (ADM), and directly reflects levels of the rapidly degraded active peptide, ADM. Methods: Fifty-seven children with POTS were designated as the POTS group. Twenty healthy children served as the control group. The children in the POTS group received midodrine hydrochloride treatment. The plasma concentration of MR-proADM was measured, using a sandwich immunoluminometric assay. A receiver-operating characteristic curve was used to explore the predictive value of MR-proADM. Results: Plasma levels of MR-proADM were significantly higher in children with POTS (75.0 [62.5 to 96.0] pg/ml) than in the control group (58.5 [50.3 to 69.0] pg/ml). Plasma levels of MR-proADM in responders to midodrine hydrochloride was significantly higher than that of nonresponders (76.0 [66.0 to 91.0] pg/ml vs. 59.0 [54.0 to 65.5] pg/ml, p < 0.01]. A receiver-operating characteristic curve on the predictive value of MR-proADM showed that the area under the curve was 0.879 with a 95% confidence interval of 0.761 to 0.997. Using a cutoff value for MR-proADM of 61.5 pg/ml produced both high sensitivity (100%) and specificity (71.6%) in predicting the efficacy of midodrine hydrochloride therapy for treating POTS. Conclusions: MR-proADM can help guide midodrine hydrochloride therapy in the management of POTS in children. © 2012 American College of Cardiology Foundation.

Luo L.,Peking University | Chen S.,University of California at San Diego | Jin H.,Peking University | Tang C.,Peking University | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

While sulfur dioxide (SO 2) has been previously known for its toxicological effects, it is now known to be produced endogenously in mammals from sulfur-containing amino acid l-cysteine. l-cysteine is catalyzed by cysteine dioxygenase (CDO) to l-cysteinesulfinate, which converts to β-sulfinylpyruvate through transamination by aspartate aminotransferase (AAT), and finally spontaneously decomposes to pyruvate and SO 2. The present study explored endogenous SO 2 production, and AAT and CDO distribution in different rat tissue. SO 2 content was highest in stomach, followed by tissues in the right ventricle, left ventricle, cerebral gray matter, pancreas, lung, cerebral white matter, renal medulla, spleen, renal cortex and liver. AAT activity and AAT1 mRNA expression were highest in the left ventricle, while AAT1 protein expression was highest in the right ventricle. AAT2 and CDO mRNA expressions were both highest in liver tissue. AAT2 protein expression was highest in the renal medulla, but CDO protein expression was highest in liver tissue. In all tissues, AAT1 and AAT2 were mainly distributed in the cytoplasm rather than the nucleus. These observed differences among tissues endogenously generating SO 2 and associated enzymes are important in implicating the discovery of SO 2 as a novel endogenous signaling molecule. © 2011 Elsevier Inc.

Jin H.F.,Peking University | Wang Y.,Peking University | Wang X.B.,Peking University | Sun Y.,Peking University | And 3 more authors.
Nitric Oxide - Biology and Chemistry | Year: 2013

Background The study was designed to explore if sulfur dioxide (SO 2) preconditioning increased antioxidative capacity in rat with myocardial ischemia reperfusion (I/R) injury. Methods The myocardial I/R model was made by left coronary artery ligation for 30 min and reperfusion for 120 min in rats. Myocardial infarct size and plasma lactate dehydrogenase (LDH) and creatine kinase (CK) activities, plasma superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and glutathione (GSH) changes were detected for the rats. The contents of myocardial hydrogen sulfide (H2S) and nitric oxide (NO) were measured. Myocardial protein expressions of SOD1, SOD2, cystathionine γ-lyase (CSE) and iNOS were tested using Western blot. Results Myocardial infarction developed and plasma CK and LDH activities were significantly increased in I/R group compared with those in control group, but SO2 preconditioning significantly reduced myocardial infarct size, and plasma CK and LDH activities. SO2 preconditioning successfully increased plasma SOD, GSH and GSH-Px levels and myocardial SOD1 protein expression, but decreased MDA level in rats of I/R group. Compared with controls, the myocardial H2S level and CSE expression were decreased after I/R, but myocardial NO level and iNOS expression were increased. With the treatment of SO2, myocardial H2S level and CSE expression were increased, but myocardial NO level and iNOS expression were decreased compared with those in I/R group. Conclusions SO 2 preconditioning could significantly reduce I/R-induced myocardial injury in vivo in association with increased myocardial antioxidative capacity, upregulated myocardial H2S/CSE pathway but downregulated NO/iNOS pathway. © 2013 Elsevier Inc. All rights reserved.

Wang X.-B.,Peking University | Jin H.-F.,Peking University | Tang C.-S.,Key Laboratory of Molecular Cardiology | Tang C.-S.,Peking University | Du J.-B.,Peking University
Clinical and Experimental Pharmacology and Physiology | Year: 2010

1. The sulphur-containing gases hydrogen sulphide and sulphur dioxide can be generated endogenously in mammalian tissues and exert significant biological effects in the cardiovascular system. Hydrogen sulphide is considered to be the third novel gasotransmitter in addition to nitric oxide and carbon monoxide. The present review describes the effects of hydrogen sulphide on the cardiovascular system and its possible mechanisms under physiological conditions. We also discuss the pathophysiological effects of hydrogen sulphide on cardiovascular diseases. The therapeutic potential of hydrogen sulphide is summarized. 2. We recently discovered that sulphur dioxide, another endogenous sulphur-containing gas, has important physiological and pathophysiological roles in the cardiovascular system. To some extent, the effect of sulphur dioxide is similar to that of the other gasotransmitters nitric oxide, carbon monoxide and hydrogen sulphide. Sulphur dioxide may also be a novel gas mediator in the cardiovascular system. © 2010 Blackwell Publishing Asia Pty Ltd.

Wang X.-B.,Peking University | Huang X.-M.,Peking University | Ochs T.,University of Illinois at Chicago | Li X.-Y.,Peking University | And 4 more authors.
Basic Research in Cardiology | Year: 2011

Sulfur dioxide has recently been found to be produced endogenously in the cardiovascular system and have important positive biological effects. However, it is unknown whether sulfur dioxide preconditioning has a protective effect on rat myocardial ischemia/reperfusion (I/ R) injury and whether this process involves endoplasmic reticulum stress (ERS). In this study, we showed that preconditioning with sulfur dioxide 10 min before ischemia (with a low concentration of sulfur dioxide of 1-10 lmol/kg) could reduce myocardial infarct size and plasma activities of lactate dehydrogenase and creatine kinase in rats with I/R in vivo. Sulfur dioxide preconditioning also reduced myocardium apoptosis induced by I/R. In addition, sulfur dioxide preconditioning increased cardiac function in vitro. Sulfur dioxide preconditioning induced expression of myocardial glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic initiation of the factor 2α-subunit (p-eIF2α) prior to myocardial I/R but suppressed expression of myocardial GRP78, C/EBP homologous protein, and p-eIF2α during myocardial I/R, in association with improved myocardial injury in vivo and in vitro. Pretreatment with dithiothreitol, an ERS stimulator mimicked the above cardioprotective effect. However, pretreatment with the ERS inhibitor 4-phenylbutyrate reversed the cardioprotection provided by sulfur dioxide preconditioning. These data indicated that sulfur dioxide preconditioning reduced I/R-induced myocardial injury in vivo and in vitro, and that augmenting ERS by sulfur dioxide preconditioning prior to I/R contributed to protection against myocardial I/R injury. © 2011 Springer-Verlag.

Sun Y.,Peking University | Tang C.-S.,Peking University | Tang C.-S.,Key Laboratory of Molecular Cardiology | Jin H.-F.,Peking University | And 2 more authors.
Acta Pharmacologica Sinica | Year: 2011

Aim:To compare the vasorelaxing effects of hydrogen sulfide (H2 S) on isolated aortic and pulmonary artery rings and to determine their action mechanisms.Methods:H2 S-induced vasorelaxation of isolated rat aortic versus pulmonary artery rings under 95% O2 and 5% CO2 was analyzed. The expression of cystathinonine gamma-lyase (CSE), cystathionine beta synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3MST), SUR2B and Kir6.1 was examined.Results:NaHS caused vasorelaxation of rat aortic and pulmonary artery rings in a dose-dependent manner. NaHS dilated aortic rings to a greater extent (16.4%, 38.4%, 64.1%, 84.3%, and 95.9% at concentrations of 50, 100, 200, 500, and 1000 mol/L, respectively) than pulmonary artery rings (10.1%, 22.2%, 50.6%, 73.6%, and 84.6% at concentrations of 50, 100, 200, 500 and 1000 μmol/L, respectively). The EC50 of the vasorelaxant effect for aortic rings was 152.17 μmol/L, whereas the EC50 for pulmonary artery rings was 233.65 μmol/L. The vasorelaxing effect of H 2 S was markedly blocked b y cellular and mitochondrial membrane K ATP channel blockers in aortic rings (P < 0.01). In contrast, only the cellular membrane K ATP channel blocker inhibited H2 S-induced vasorelaxation in pulmonary artery rings. SUR2B mRNA and protein expression was higher in aortic rings than in pulmonary artery rings. Cystathinonine gamma-lyase (CSE) but not cystathionine beta synthase (CBS) expression in aortic rings was higher than in pulmonary artery rings. 3-Mercapto pyruvate sulfurtransferase (3MST) mRNA was lower in aortic rings than in pulmonary artery rings.Conclusion:The vasorelaxing effect of H2 S on isolated aortic rings was more pronounced than the effect on pulmonary artery rings at specific concentrations, which might be associated with increased expression of the KATP channel subunit SUR2B. © 2011 CPS and SIMM All rights reserved.

Zhao M.-M.,Peking University | Yang J.-Y.,Peking University | Wang X.-B.,Peking University | Tang C.-S.,Key Laboratory of Molecular Cardiology | And 4 more authors.
Acta Pharmacologica Sinica | Year: 2013

Aim: To explore the mechanisms underlying the protection by SO 2 preconditioning against rat myocardial ischemia/reperfusion (I/R) injury. Methods: Male Wistar rats underwent 30-min left coronary artery ligation followed by 120-min reperfusion. An SO 2 donor (1 μmol/kg) was intravenously injected 10 min before the ischemia, while LY294002 (0.3 mg/kg) was intravenously injected 30 min before the ischemia. Plasma activities of LDH and CK were measured with an automatic enzyme analyzer. Myocardial infarct size was detected using Evans-TTC method. The activities of caspase-3 and -9 in myocardium were assayed using a commercial kit, and the levels of p-Akt, Akt, PI3K and p-PI3K were examined with Western blotting. Results: Pretreatment with SO 2 significantly reduced the myocardial infarct size and plasma LDH and CK activities, as well as myocardial caspase-3 and -9 activities in the rats. Furthermore, the pretreatment significantly increased the expression levels of myocardial p-Akt and p-PI3K p85. Administration of the PI3K inhibitor LY294002 blocked all the effects induced by SO 2 pretreatment.Conclusion:The results suggest that the PI3K/Akt pathway mediates the protective effects of SO 2 preconditioning against myocardial I/R injury in rats. © 2013 CPS and SIMM All rights reserved.

Chen S.,Peking University | Zheng S.,Beijing Jishuitan Hospital | Liu Z.,Beijing Jishuitan Hospital | Tang C.,Peking University | And 5 more authors.
Laboratory Investigation | Year: 2015

The role of endogenous sulfur dioxide (SO2), an efficient gasotransmitter maintaining homeostasis, in the development of acute lung injury (ALI) remains unidentified. We aimed to investigate the role of endogenous SO2 in the pathogenesis of ALI. An oleic acid (OA)-induced ALI rat model was established. Endogenous SO2 levels, lung injury, oxidative stress markers and apoptosis were examined. OA-induced ALI rats showed a markedly downregulated endogenous SO2/aspartate aminotransferase 1 (AAT1)/AAT2 pathway and severe lung injury. Chemical colorimetry assays demonstrated upregulated reactive oxygen species generation and downregulated antioxidant capacity in OA-induced ALI rats. However, SO2 increased endogenous SO2 levels, protected against oxidative stress and alleviated ALI. Moreover, compared with OA-treated cells, in human alveolar epithelial cells SO2 downregulated O2-and OH-generation. In contrast, L-aspartic acid-β-hydroxamate (HDX, Sigma-Aldrich Corporation), an inhibitor of endogenous SO2 generating enzyme, promoted free radical generation, upregulated poly (ADP-ribose) polymerase expression, activated caspase-3, as well as promoted cell apoptosis. Importantly, apoptosis could be inhibited by the free radical scavengers glutathione (GSH) and N-acetyl-L-cysteine (NAC). The results suggest that SO2/AAT1/AAT2 pathway might protect against the development of OA-induced ALI by inhibiting oxidative stress. © 2015 USCAP, Inc All rights reserved.

Wang L.,Xi'an Jiaotong University | Wang L.,Key Laboratory of Molecular Cardiology | Gao S.,Xi'an Jiaotong University | Xu W.,Xi'an Jiaotong University | And 6 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2014

Aims. The chronic inflammation of atherosclerosis is regulated by Th1, while allergic asthma is controlled by Th2. The direct relationship between atherosclerosis and asthma is contradictory. The aim of this study was to investigate the role of allergic asthma in atherosclerotic plaque formation and the change of CD4+ T cells subsets. Methods and results. Six-week C57BL/6J or apoE-/- mice were sensitized on day 0, 7 and 14, then exposed to aerosolized 1% Ovalbumin (OVA) or PBS 30min/day, 3 times/week for 8 or 16weeks from day 14 onward. The results showed that allergic asthma mice models were successfully established and the accelerated atherosclerosis induced by allergic asthma accompanied with increased Th2 and Th17 cells but not Th1 cells in spleen. Moreover, the expression and production of Th2 and Th17 biomarkers including IL-4 and IL-17A were significantly elevated in asthmatic apoE-/- mice. After 8-week treated with the neutralizing antibody of IL-4 or IL-17A, the lesion area in the aortic root of asthmatic apoE-/- mice was markedly decreased, and more dramatical result was observed after the combined treatment with IL-4 and IL-17A mAbs. The expression of IgE and FcεRIα in the aortic root of apoE-/- mice was markedly increased but was significantly reduced after 8-week treatment with IL-4 mAb. Conclusion. Allergic asthma accelerates atherosclerosis by modulating the balance of Teff/Treg cells in apoE-/- mice, which is associated with increased Th2 and Th17 cells but not Th1 cells. © 2014 Elsevier Ltd.

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