BACKGROUND Ferroptosis can induce low retention and engraftment after mesenchymal stem cell(MSC)delivery,which is considered a major challenge to the effectiveness of MSC-based pulmonary arterial hypertension(PAH)ther...BACKGROUND Ferroptosis can induce low retention and engraftment after mesenchymal stem cell(MSC)delivery,which is considered a major challenge to the effectiveness of MSC-based pulmonary arterial hypertension(PAH)therapy.Interestingly,the cystathionineγ-lyase(CSE)/hydrogen sulfide(H_(2)S)pathway may contribute to mediating ferroptosis.However,the influence of the CSE/H_(2)S pathway on ferroptosis in human umbilical cord MSCs(HUCMSCs)remains unclear.AIM To clarify whether the effect of HUCMSCs on vascular remodelling in PAH mice is affected by CSE/H_(2)S pathway-mediated ferroptosis,and to investigate the functions of the CSE/H_(2)S pathway in ferroptosis in HUCMSCs and the underlying mechanisms.METHODS Erastin and ferrostatin-1(Fer-1)were used to induce and inhibit ferroptosis,respectively.HUCMSCs were transfected with a vector to overexpress or inhibit expression of CSE.A PAH mouse model was established using 4-wk-old male BALB/c nude mice under hypoxic conditions,and pulmonary pressure and vascular remodelling were measured.The survival of HUCMSCs after delivery was observed by in vivo bioluminescence imaging.Cell viability,iron accumulation,reactive oxygen species production,cystine uptake,and lipid peroxidation in HUCMSCs were tested.Ferroptosis-related proteins and S-sulfhydrated Kelchlike ECH-associating protein 1(Keap1)were detected by western blot analysis.RESULTS In vivo,CSE overexpression improved cell survival after erastin-treated HUCMSC delivery in mice with hypoxiainduced PAH.In vitro,CSE overexpression improved H_(2)S production and ferroptosis-related indexes,such as cell viability,iron level,reactive oxygen species production,cystine uptake,lipid peroxidation,mitochondrial membrane density,and ferroptosis-related protein expression,in erastin-treated HUCMSCs.In contrast,in vivo,CSE inhibition decreased cell survival after Fer-1-treated HUCMSC delivery and aggravated vascular remodelling in PAH mice.In vitro,CSE inhibition decreased H_(2)S levels and restored ferroptosis in Fer-1-treated HUCMSCs.Interestingly,upregulation of the CSE/H_(2)S pathway induced Keap1 S-sulfhydration,which contributed to the inhibition of ferroptosis.CONCLUSION Regulation of the CSE/H_(2)S pathway in HUCMSCs contributes to the inhibition of ferroptosis and improves the suppressive effect on vascular remodelling in mice with hypoxia-induced PAH.Moreover,the protective effect of the CSE/H_(2)S pathway against ferroptosis in HUCMSCs is mediated via S-sulfhydrated Keap1/nuclear factor erythroid 2-related factor 2 signalling.The present study may provide a novel therapeutic avenue for improving the protective capacity of transplanted MSCs in PAH.展开更多
Background Hydrogen sulfide （H2S） plays an important role in the smooth muscle cell relaxation and thereby participates in the development of hypertension. Cystathionine γ-lyase is the key enzyme in the endogenous ...Background Hydrogen sulfide （H2S） plays an important role in the smooth muscle cell relaxation and thereby participates in the development of hypertension. Cystathionine γ-lyase is the key enzyme in the endogenous production of H2S. Up to now, the reports on the relationship between the polymorphisms of cystathionine γ-lyase gene （CTH） and essential hypertension （EH） are limited. This study was designed to assess their underlying relationship. Methods A total of 503 hypertensive patients and 490 age-, gender- and area-matched normotensive controls were enrolled in this study. Based on the FASTSNP, a web server to identify putative functional single nucleotide polymorphisms （SNPs） of genes, we selected two SNPs, rs482843 and rs1021737, in the CTH gene for genotyping. Genotyping was performed by the polymerase chain reaction and restriction fragment length polymorphism method （PCR-RFLP）. The frequencies of the alleles and genotypes between cases and controls were compared by the chi-square test. The program Haplo.stats was used to investigate the relationship between the haplotypes and EH. Results These two SNPs were in Hardy-Weinberg Equilibrium in both cases and controls. The genotype distribution and allele frequencies of them did not significantly differ between cases and controls （all P〉0.05）. In the stepwise logistic regression analysis we failed to observe their association with hypertension. In addition, none of the four estimated haplotypes or diplotypes significantly increased or decreased the risk of hypertension before or after adjustment for several known risk factors. Conclusions The present study suggests that the SNPs rs482843 and rs1021737 of the CTH gene were not associated with essential hypertension in the Northern Chinese Han population. However, replications in other populations and further functional studies are still necessary to clarify the role of the CTH gene in the pathogenesis of EH.展开更多
目的探讨是否可通过使用钙敏感受体(CaSR)激动剂增强胱硫醚-γ-裂解酶(CSE)的表达促使内源性硫化氢(H_2S)的含量增加,从而抑制肺动脉平滑肌细胞(PASMC)的增殖、迁移。方法以人肺动脉平滑肌细胞(HPASMC)为研究对象,将样本设置为空白对照...目的探讨是否可通过使用钙敏感受体(CaSR)激动剂增强胱硫醚-γ-裂解酶(CSE)的表达促使内源性硫化氢(H_2S)的含量增加,从而抑制肺动脉平滑肌细胞(PASMC)的增殖、迁移。方法以人肺动脉平滑肌细胞(HPASMC)为研究对象,将样本设置为空白对照组(使用PBS液干预)、GdCl_3组(使用CaSR激动剂GdCl_3干预)、NPS2390组(使用CaSR抑制剂NPS2390干预),在样本中加药孵育后,检测比较各组细胞增殖、迁移情况和细胞中Ca SR、CSE、H_2S的水平。结果三组细胞增殖、迁移情况和细胞中CaSR、CSE、H_2S的水平比较差异有统计学意义(P<0.05)。GdCl_3组细胞CaSR、CSE的表达和H2S的含量高于对照组,MTT实验吸光度(OD值)低于对照组,细胞迁移数少于对照组,差异有统计学意义(P<0.05);NPS2390组细胞CaSR的表达和H2S的水平均低于对照组,MTT实验吸光度(OD值)高于对照组,细胞迁移数多于对照组,差异有统计学意义(P<0.05)。结论 Ca SR激动剂可通过增强CSE的表达增加H_2S的含量,进而抑制PASMC的增殖及迁移。展开更多
Hydrogen sulfide(H2S)is a gasotransmitter that acts as an antioxidant and exhibits a wide variety of cytoprotective and physiological functions in age-associated diseases.One of the major causes of age-related disease...Hydrogen sulfide(H2S)is a gasotransmitter that acts as an antioxidant and exhibits a wide variety of cytoprotective and physiological functions in age-associated diseases.One of the major causes of age-related diseases is oxidative stress.In recent years,the importance of H2S has become clear,although its antioxidant function has not yet been fully explored.The enzymes cystathionineβ-synthase,cystathionineγ-lya-se,and 3-mercaptopyruvate sulfurtransferase are involved in the enzymatic production of H2S.Previously,H2S was considered a neuromodulator,given its role in long-term hippocampal potentiation,but it is now also recognized as an antioxidant in age-related neurodegeneration.Due to aerobic metabolism,the central nervous system is vulnerable to oxidative stress in brain aging,resulting in age-associated degenerative diseases.H2S exerts its antioxidant effect by limiting free radical reactions through the activation of antioxidant enzymes,including superoxide dismutase,catalase,and glutathione peroxidase,which protect against the effects of aging by regulating apoptosis-related genes,including p53,Bax,and Bcl-2.This review explores the implications and mechanisms of H2S as an antioxidant in age-associated neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,and Down syndrome.展开更多
AIM: To investigate the association between endogenous hydrogen sulfide (H<sub>2</sub>S) and portal hypertension as well as its effect on vascular smooth muscle cells.
This study aimed to observe changes in the hydrogen sulfide（H_2S） system in the blood and liver tissue of rats with hepatic cirrhosis at different stages by studying the effect of H_2S on the course of hyperdynamic ...This study aimed to observe changes in the hydrogen sulfide（H_2S） system in the blood and liver tissue of rats with hepatic cirrhosis at different stages by studying the effect of H_2S on the course of hyperdynamic circulation in rats with hepatic cirrhosis. H_2S concentration in the blood from the portal vein and inferior vena cava of hepatic cirrhosis rat model induced with carbon tetrachloride was detected on the 15 th, 30 th, and 52 nd day. The expression of cystathionine β-synthase（CBS） and cystathionine γ-lyase（CSE） protein, and CBS and CSE mRNA in the liver was detected by immunohistochemistry and reverse transcriptase polymerase chain reaction（RT-PCR）, respectively. The results indicated that H_2S concentration in the blood from the portal vein and inferior vena cava of rats with hepatic cirrhosis was significantly lower than that in the control group. H_2S was gradually decreased with the development of the disease and significantly lower in the blood from portal vein than in the blood of inferior vena cava at the mid-stage and the late stage groups. The expression levels of CBS and CSE protein, and CBS and CSE mR NA in the livers with hepatic cirrhosis at different stages were all higher than those in the control group, and the expression gradually increased with the development of the disease. The expression of CBS was lower than CSE in the same stages. The results indicated that the CSE mRNA was expressed predominantly in the cirrhosis groups as compared with CBS mRNA. Among experimental rats, the H_2S system has an important effect on the occurrence and development of hyperdynamic circulation in rats with hepatic cirrhosis. This finding adds to the literature by demonstrating that H_2S protects vascular remodelling in the liver, and that CSE is indispensable in this process.展开更多
Background It has been reported that endogenous or exogenous hydrogen sulfide （H2S） exerts physiological effects in the vertebrate cardiovascular system. We have also demonstrated that H2S acts as an important regul...Background It has been reported that endogenous or exogenous hydrogen sulfide （H2S） exerts physiological effects in the vertebrate cardiovascular system. We have also demonstrated that H2S acts as an important regulator of electrophysiological properties in guinea pig papillary muscles and on pacemaker cells in sinoatrial nodes of rabbits. This study was to observe the electrophysiological effects of H2S on human atrial fibers. Methods Human atrial samples were collected during cardiac surgery. Parameters of action potential in human atrial specialized fibers were recorded using a standard intracellular microetectrode technique. Results NariS （H2S donor） （50, 100 and 200 pmol/L） decreased the amplitude of action potential （APA）, maximal rate of depolarization （Vmax）, velocity of diastolic （phase 4） depolarization （VDD） and rate of pacemaker firing （RPF）, and shortened the duration of 90% repolarization （APD90） in a concentration-dependent manner. ATP-sensitive K＋ （KATP） channel blocker glibenclamide （Gli, 20 μmol/L） partially blocked the effects of NariS （100 μmol/L） on human atrial fiber cells. The L-type Ca2＋ channel agonist Bay K8644 （0.5 μmol/L） also partially blocked the effects of NariS （100 μmol/L）. An inhibitor of cystathionine y-lyase （CSE）, DL-propargylglycine （PPG, 200 μmol/L）, increased APA, Vmax, VDD and RPF, and prolonged APDg0. Conclusions H2S exerts a negative chronotropic action and accelerates the repolarization of human atrial specialized fibers, possibly as a result of increases in potassium efflux through the opening of KATP channels and a concomitant decrease in calcium influx. Endogenous H2S may be generated by CSE and act as an important regulator of electrophysiological properties in human atrial fibers.展开更多
基金the Natural Science Foundation of Shandong Province of China,No.ZR2021QH179 and ZR2020MH014.
文摘BACKGROUND Ferroptosis can induce low retention and engraftment after mesenchymal stem cell(MSC)delivery,which is considered a major challenge to the effectiveness of MSC-based pulmonary arterial hypertension(PAH)therapy.Interestingly,the cystathionineγ-lyase(CSE)/hydrogen sulfide(H_(2)S)pathway may contribute to mediating ferroptosis.However,the influence of the CSE/H_(2)S pathway on ferroptosis in human umbilical cord MSCs(HUCMSCs)remains unclear.AIM To clarify whether the effect of HUCMSCs on vascular remodelling in PAH mice is affected by CSE/H_(2)S pathway-mediated ferroptosis,and to investigate the functions of the CSE/H_(2)S pathway in ferroptosis in HUCMSCs and the underlying mechanisms.METHODS Erastin and ferrostatin-1(Fer-1)were used to induce and inhibit ferroptosis,respectively.HUCMSCs were transfected with a vector to overexpress or inhibit expression of CSE.A PAH mouse model was established using 4-wk-old male BALB/c nude mice under hypoxic conditions,and pulmonary pressure and vascular remodelling were measured.The survival of HUCMSCs after delivery was observed by in vivo bioluminescence imaging.Cell viability,iron accumulation,reactive oxygen species production,cystine uptake,and lipid peroxidation in HUCMSCs were tested.Ferroptosis-related proteins and S-sulfhydrated Kelchlike ECH-associating protein 1(Keap1)were detected by western blot analysis.RESULTS In vivo,CSE overexpression improved cell survival after erastin-treated HUCMSC delivery in mice with hypoxiainduced PAH.In vitro,CSE overexpression improved H_(2)S production and ferroptosis-related indexes,such as cell viability,iron level,reactive oxygen species production,cystine uptake,lipid peroxidation,mitochondrial membrane density,and ferroptosis-related protein expression,in erastin-treated HUCMSCs.In contrast,in vivo,CSE inhibition decreased cell survival after Fer-1-treated HUCMSC delivery and aggravated vascular remodelling in PAH mice.In vitro,CSE inhibition decreased H_(2)S levels and restored ferroptosis in Fer-1-treated HUCMSCs.Interestingly,upregulation of the CSE/H_(2)S pathway induced Keap1 S-sulfhydration,which contributed to the inhibition of ferroptosis.CONCLUSION Regulation of the CSE/H_(2)S pathway in HUCMSCs contributes to the inhibition of ferroptosis and improves the suppressive effect on vascular remodelling in mice with hypoxia-induced PAH.Moreover,the protective effect of the CSE/H_(2)S pathway against ferroptosis in HUCMSCs is mediated via S-sulfhydrated Keap1/nuclear factor erythroid 2-related factor 2 signalling.The present study may provide a novel therapeutic avenue for improving the protective capacity of transplanted MSCs in PAH.
基金This work was supported by the grants of the National Basic Research Program of China （No. 2006CB503805） and the Beijing Natural Science Foundation （No. 7061006）.
文摘Background Hydrogen sulfide （H2S） plays an important role in the smooth muscle cell relaxation and thereby participates in the development of hypertension. Cystathionine γ-lyase is the key enzyme in the endogenous production of H2S. Up to now, the reports on the relationship between the polymorphisms of cystathionine γ-lyase gene （CTH） and essential hypertension （EH） are limited. This study was designed to assess their underlying relationship. Methods A total of 503 hypertensive patients and 490 age-, gender- and area-matched normotensive controls were enrolled in this study. Based on the FASTSNP, a web server to identify putative functional single nucleotide polymorphisms （SNPs） of genes, we selected two SNPs, rs482843 and rs1021737, in the CTH gene for genotyping. Genotyping was performed by the polymerase chain reaction and restriction fragment length polymorphism method （PCR-RFLP）. The frequencies of the alleles and genotypes between cases and controls were compared by the chi-square test. The program Haplo.stats was used to investigate the relationship between the haplotypes and EH. Results These two SNPs were in Hardy-Weinberg Equilibrium in both cases and controls. The genotype distribution and allele frequencies of them did not significantly differ between cases and controls （all P〉0.05）. In the stepwise logistic regression analysis we failed to observe their association with hypertension. In addition, none of the four estimated haplotypes or diplotypes significantly increased or decreased the risk of hypertension before or after adjustment for several known risk factors. Conclusions The present study suggests that the SNPs rs482843 and rs1021737 of the CTH gene were not associated with essential hypertension in the Northern Chinese Han population. However, replications in other populations and further functional studies are still necessary to clarify the role of the CTH gene in the pathogenesis of EH.
文摘目的探讨是否可通过使用钙敏感受体(CaSR)激动剂增强胱硫醚-γ-裂解酶(CSE)的表达促使内源性硫化氢(H_2S)的含量增加,从而抑制肺动脉平滑肌细胞(PASMC)的增殖、迁移。方法以人肺动脉平滑肌细胞(HPASMC)为研究对象,将样本设置为空白对照组(使用PBS液干预)、GdCl_3组(使用CaSR激动剂GdCl_3干预)、NPS2390组(使用CaSR抑制剂NPS2390干预),在样本中加药孵育后,检测比较各组细胞增殖、迁移情况和细胞中Ca SR、CSE、H_2S的水平。结果三组细胞增殖、迁移情况和细胞中CaSR、CSE、H_2S的水平比较差异有统计学意义(P<0.05)。GdCl_3组细胞CaSR、CSE的表达和H2S的含量高于对照组,MTT实验吸光度(OD值)低于对照组,细胞迁移数少于对照组,差异有统计学意义(P<0.05);NPS2390组细胞CaSR的表达和H2S的水平均低于对照组,MTT实验吸光度(OD值)高于对照组,细胞迁移数多于对照组,差异有统计学意义(P<0.05)。结论 Ca SR激动剂可通过增强CSE的表达增加H_2S的含量,进而抑制PASMC的增殖及迁移。
基金supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning, No. 2018R1A2B6001123 (to NYJ), No. 2018R1D1A1B07040282 (to JJ)
文摘Hydrogen sulfide(H2S)is a gasotransmitter that acts as an antioxidant and exhibits a wide variety of cytoprotective and physiological functions in age-associated diseases.One of the major causes of age-related diseases is oxidative stress.In recent years,the importance of H2S has become clear,although its antioxidant function has not yet been fully explored.The enzymes cystathionineβ-synthase,cystathionineγ-lya-se,and 3-mercaptopyruvate sulfurtransferase are involved in the enzymatic production of H2S.Previously,H2S was considered a neuromodulator,given its role in long-term hippocampal potentiation,but it is now also recognized as an antioxidant in age-related neurodegeneration.Due to aerobic metabolism,the central nervous system is vulnerable to oxidative stress in brain aging,resulting in age-associated degenerative diseases.H2S exerts its antioxidant effect by limiting free radical reactions through the activation of antioxidant enzymes,including superoxide dismutase,catalase,and glutathione peroxidase,which protect against the effects of aging by regulating apoptosis-related genes,including p53,Bax,and Bcl-2.This review explores the implications and mechanisms of H2S as an antioxidant in age-associated neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,and Down syndrome.
基金Supported by Specialized Research Fund for the Doctoral Program of Higher Education of China,No.20120142120048Natural Science Foundation of Hubei Province,China,No.2012FFB02308
文摘AIM: To investigate the association between endogenous hydrogen sulfide (H<sub>2</sub>S) and portal hypertension as well as its effect on vascular smooth muscle cells.
基金supported by grants from the National Natural Science Foundation of China(No.30850004 and No.81170402)
文摘This study aimed to observe changes in the hydrogen sulfide（H_2S） system in the blood and liver tissue of rats with hepatic cirrhosis at different stages by studying the effect of H_2S on the course of hyperdynamic circulation in rats with hepatic cirrhosis. H_2S concentration in the blood from the portal vein and inferior vena cava of hepatic cirrhosis rat model induced with carbon tetrachloride was detected on the 15 th, 30 th, and 52 nd day. The expression of cystathionine β-synthase（CBS） and cystathionine γ-lyase（CSE） protein, and CBS and CSE mRNA in the liver was detected by immunohistochemistry and reverse transcriptase polymerase chain reaction（RT-PCR）, respectively. The results indicated that H_2S concentration in the blood from the portal vein and inferior vena cava of rats with hepatic cirrhosis was significantly lower than that in the control group. H_2S was gradually decreased with the development of the disease and significantly lower in the blood from portal vein than in the blood of inferior vena cava at the mid-stage and the late stage groups. The expression levels of CBS and CSE protein, and CBS and CSE mR NA in the livers with hepatic cirrhosis at different stages were all higher than those in the control group, and the expression gradually increased with the development of the disease. The expression of CBS was lower than CSE in the same stages. The results indicated that the CSE mRNA was expressed predominantly in the cirrhosis groups as compared with CBS mRNA. Among experimental rats, the H_2S system has an important effect on the occurrence and development of hyperdynamic circulation in rats with hepatic cirrhosis. This finding adds to the literature by demonstrating that H_2S protects vascular remodelling in the liver, and that CSE is indispensable in this process.
基金This work was supported by the grants from Program for New Century Excellent Talents in University （No. NCET-07-0252） and Hebei Province Funds for Distinguished Young Scientists （No. 2010000471） and Natural Science Foundation of Hebei Province of China （No. C2007000821）.
文摘Background It has been reported that endogenous or exogenous hydrogen sulfide （H2S） exerts physiological effects in the vertebrate cardiovascular system. We have also demonstrated that H2S acts as an important regulator of electrophysiological properties in guinea pig papillary muscles and on pacemaker cells in sinoatrial nodes of rabbits. This study was to observe the electrophysiological effects of H2S on human atrial fibers. Methods Human atrial samples were collected during cardiac surgery. Parameters of action potential in human atrial specialized fibers were recorded using a standard intracellular microetectrode technique. Results NariS （H2S donor） （50, 100 and 200 pmol/L） decreased the amplitude of action potential （APA）, maximal rate of depolarization （Vmax）, velocity of diastolic （phase 4） depolarization （VDD） and rate of pacemaker firing （RPF）, and shortened the duration of 90% repolarization （APD90） in a concentration-dependent manner. ATP-sensitive K＋ （KATP） channel blocker glibenclamide （Gli, 20 μmol/L） partially blocked the effects of NariS （100 μmol/L） on human atrial fiber cells. The L-type Ca2＋ channel agonist Bay K8644 （0.5 μmol/L） also partially blocked the effects of NariS （100 μmol/L）. An inhibitor of cystathionine y-lyase （CSE）, DL-propargylglycine （PPG, 200 μmol/L）, increased APA, Vmax, VDD and RPF, and prolonged APDg0. Conclusions H2S exerts a negative chronotropic action and accelerates the repolarization of human atrial specialized fibers, possibly as a result of increases in potassium efflux through the opening of KATP channels and a concomitant decrease in calcium influx. Endogenous H2S may be generated by CSE and act as an important regulator of electrophysiological properties in human atrial fibers.
