亚砷酸钠及保护剂对血管内皮细胞效应中microRNAs的作用研究
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摘要
地方性砷中毒(Endemic Arsenism，地砷病)是一种生物地球化学性疾病，据不完全统计,全世界数亿人暴露于高砷环境。研究证明，周围血管是砷毒作用的主要靶器官，对于砷化物引起血管内皮细胞损伤和凋亡的分子机制，目前既不完全清楚，且没有行之有效的防治措施，因此本研究以亚砷酸钠（NaAsO2）作用于体外培养的人脐静脉内皮细胞为模型观察血管损伤效应，及保护剂对其保护效应两方面进行系统研究。
我们发现miRNAs参与了亚砷酸钠（NaAsO2）诱导的血管内皮细胞HUVECs的损伤和凋亡。miRNAs芯片技术分析在NaAsO2作用于HUVECs细胞时，细胞内miRNAs表达谱的改变情况，这部分结果得到实时定量RT-PCR的进一步证实。接着，我们应用DAVID等生物信息资源分析了miRNAs中具有参与蛋白磷酸化、mRNA剪接、细胞凋亡等生物学功能的靶蛋白，并通过Western blot的方法发现这些靶蛋白的表达发生了改变。通过使用生物信息学软件Targetscan, miRandaand PicTar等预测细胞抗凋亡蛋白Mcl-1mRNA的调控miRNAs，我们发现其与Mcl-1mRNA的3’ UTR区具有特异性结合位点，miR-29b可靶向调控Mcl-1mRNA的表达，提示miR-29b参与了凋亡相关基因转录后表达的调控。
在人肝细胞中砷化物通过产生过多的活性氧ROS诱导线粒体依赖性细胞凋亡[1]，可能是其诱导肝损伤的重要机制。我们也发现，亚砷酸钠（NaAsO2）可诱导HUVECs内ROS水平发生改变，诱导血管内皮细胞的损伤和凋亡，证明其主要是在地砷病血管损伤凋亡中发挥介导作用。
保护剂人参皂苷Rb1能起到保护内皮细胞的功效，其经典的作用机制在于能提高损伤细胞内抗氧化酶超氧化物歧化酶SOD2的活性，从而降低细胞内活性氧ROS的含量，避免线粒体受氧化损伤，从而修复细胞损伤及避免细胞死亡。叶酸和维生素B12也具有降低细胞内活性氧ROS的含量的抗氧化功效，且能确保重要物质的合成代谢，帮助机体及时进行损伤修复。在本实验中我们发现，对于亚砷酸钠引起的HUVECs的损伤及凋亡，三种保护剂具有修复和抑制效应，能降低细胞内活性氧ROS的含量，明显降低亚砷酸钠（NaAsO2）诱导的细胞凋亡。同时在保护剂的作用下，miRNA29b的表达下调，其靶蛋白抗凋亡蛋白Mcl-1表达上调，二者呈负相关。我们推测其保护机制可能是通过下调miRNA29b的表达，从而上调了其靶蛋白抗凋亡蛋白Mcl-1的表达，而抑制细胞凋亡的。
通过研究我们发现在亚砷酸钠诱导的血管内皮细胞损伤和凋亡中miRNAs介导了凋亡的过程，而且证实叶酸、维生素B12和人参皂苷对损伤的血管内皮细胞具有保护效应，且发现其分子机制与miRNAs有关。理论上，为亚砷酸钠诱导的血管损伤和凋亡的分子机制提供新的视角；临床应用上，为地砷病防治的临床药物研究和开发开辟新道路。
Endemic arsenic poisoning is a biogeochemical diseases. It leads to skinpigmentation and palm Billiton hyperplasia keratosis, and even threatens to the livesof patients. Endemic arsenic poisoning was caused by Arsenide mainly and vasc ularinjury is the primary pathological damage. For lack of clear understanding andeffective prevention of this, the arsenide generates vascular endothelial cell injury andapoptosis. Sodium arsenite and human umbilical vein endothelial cells are widelyused in research in vitro model. In this study, we discuss the injury and pro-apoptoticof vascular endothelial cells coused by arsenite, protective effects of protective agentand relative molecular mechanisms.
Epidemiological studies have shown there is a clear correlation betweenenvironment of chronic arsenic exposure and peripheral vascular disease. Vascularendothelial cells are directly target cells of toxic substances such as arseniccompounds, which play a very critical role in repairing of damaged vessels andmaintaining the integrity of vessels. Consequently, it is crucial to study the relativemolecular mechanisms and prevention measures of vascular endothelial cell injury byarsenide.
Injury and apoptosis of vascular endothelial cell caused the loss of its originalshape, function and the integrity of vessels, which initiates peripheral vascular disease.In our research, we cultured human umbilical vein endothelial cells exposed to arseniccompounds to explore the molecular mechanisms of cell injury and apoptosis invascular endothelial injury model. Little is known about this.
Cell injury is a response of persistent stimulation in vivo and vitro, which makes cellinjury in metabolic, morphological, functional and structural changes. Mild injury isreversible, but severe cases leads to irreversible damage and even apoptosis or necrosis.When cells happen to irrevers metabolism, structure and dysfunction, it will lead to celldeath. Cell death is divided into two basic types of necrosis and apoptosis. Ourexperiment focuses on the new aspect of its molecular mechanism and pro-apoptotic effects of the arsenide toxic on vascular endothelial cells, and studying how to reduce celldamage and block the process of apoptosis. Thus, we provide the basis for the preventionand treatment of peripheral vascular disease caused by arsenic compounds.
Apoptosis, programmed cell death, is involved in important physiological functionsof embryonic development and homeostasis. However, insufficient or excessive apoptosiscould cause certain diseases. It was suggested that apoptotic process can be regulated bythe intracellular redox statement. Intracellular redox is involved in the physiologicalprocesses of cellular oxidative phosphorylation. Excessive reactive oxygen radicals ROSin mitochondria leads to cellular oxidative damage and apoptosis.
Small RNA (microRNAs, miRNAs) are a class of small single-stranded RNA,18-25nt, highly conserved itself, encoding no proteins, interact with its target mRNA bybases complementary pairing principle. With complete or incomplete pairing, miRNAcould achieve the effect of its target mRNA’s degradation or inhibit its translation andplay the role in the post-transcriptional level to regulate gene expression.
MiRNAs have been widely used to explain and study development diseases todetermine the prognosis and outcome of the disease from a new perspective aspect, whichare involved in the prevention and diagnosis of diseases as well. The technology ofmicro RNA array has become an important scientific method. miRNAs have significantchanged in the injury and apoptotic process of the study of NaAsO2on HUVECs. It isvaluable to explore molecular mechanisms of vascular endothelial cells injury by arsenide.There is few reports that mir-29b relates with apoptosis targeted anti-apoptotic proteinMcl-1, which can regulate the expression of Mcl-1.
The ginsenoside Rb1has a variety of biological activity as one of the main activeingredients in ginseng. It conducives to the normalization of body functions, and hasthe efficacy to inhibit tumor cell, anti-aging, anti-free radical damage also.Ginsenoside Rb1has been reported to increase the activity of antioxidant enzymeSOD2, especially for endothelial cell damage in the cardiovasc ular system, having abetter fix. Numerous studies have demonstrated that ginsenoside Rb1play aprotective efficacy of endothelial cells. Its mechanism of action is improving theactivity of the antioxidant enzyme, superoxide dismutase SOD2, in damage cells,thereby clearing the excess of intracellular reactive oxygen species ROS, reducing itscontent, avoiding mitochondrial oxidative damage, and protecting the cell free ininjury and death. Ginsenoside has been studied mainly in animal models, but there islittle research in cell damage model. There is no report for the protective effects and mechanisms of vascular endothelial injury and repair by arsenide injury.
Folic acid and vitamin B12are involved in the synthesis and metabolism of lifeimportant substances as indispensable vitamin in the body. They both have powerfμlantioxidant efficacy of anti-injury. It was confirmed by Sangita Ma jumdar that vitaminB12and folic acid have anti-apoptotic effects in arsenide-induced liver cytotoxic in rats.Ginsenoside Rb1, folic acid together with vitamin B12can resist damaging in sodiumarsenite induced HUVECs cell damage and apoptosis. As well, the study on the relatedexpression of mir-29b and anti-apoptotic protein Mcl-1has not been reported.
In our research, we have conducted molecular mechanisms of the effects on humanumbilical vein endothelial cells of cell injury, apoptosis by sodium arsenite in vitro.
We studied and analyzed the interaction of transcription factor SP1with SOD2promoter region and the relationship with the SOD2gene transcription using dualfluorescent reporter gene technology. In order to clarify the miRNAs in the role ofapoptosis in endothelial cell injury induced by sodium arsenite, miRNAs biochiptechnology was used to analyze miRNAs expression profiles changed after sodiumarsenite poisoning HUVECs cells, and then we used biological information softwares ofTargetscan, miRanda and P icTar to predict regulatory factors of anti-apoptotic proteinMcl-1among the changed miRNAs in endothelial cells induced by sodium arsenite, andconfirmed the most related miRNA with the anti-apoptotic protein Mcl-1. To find theeffective protective drugs and measures for providing new ideas of the prevention ofdiseases caused by arsenic poisoning, we studied protection effects and mechanisms ofginsenoside Rb1, folic ac id, vitamin B12alone and combined in the confrontation sodiumarsenite-induced cell damage and apoptosis on HUVECs.
This experiment provides a reliable theoretical and experimental basis, and lays thefoundation for the clinical treatment and drug development for pathogenesis of arsenicdiseases.Part ⅠHUVECs happened to apoptosis induced by NaAsO2.
Objective: To study the mechanism of injuries on HUVECs by arsenite.
Methods: We observed the proliferation of cells treated with arsenite. We examedthe ability of cell migration in vitro scratch assay. In addition, we checked the levelsof intracellular ROS by flow cytometry with a cell based ROS assay. Apoptotic cellswere detected by flow cytometry with Annexin V-FITC and PI double staining, byHoechst staining and TUNEL assay. Results: Cell injury and apoptosis were occurred.Cell migration ability was destroyed. The group of20μM NaAsO2displayed more obviously at the generation of ROS and cell apoptosis The apoptotic cells weresignificantly increased in a dose-dependent manner following arsenite treatments for24hours by NaAsO2. Conclusion: HUVECs were injuried by NaAsO2, and NaAsO2induced its apoptosis, which is the experimental evidence of vascular lesion byNaAsO2.PartⅡ miRNAs expression profiles was changed in HUVECs induced by NaAsO2.The mechenism of apoptosis is upregulated miR-29b and downregulated Mcl-1.
Objective：To analyze the miRNAs expression profiles in HUVECs induced byNaAsO2, to find apoptosis-related protein and regulated miRNAs. Methods:Wedetected miRNAs expression profiles in HUVECs induced by NaAsO2through themiRNA array technology and verified by qRT-PCR. miRNAs target genes wereanalyzed by DAVID software. Forecasting regulative miRNAs of Mcl-1mRNA bysoftwares of TargetScan, miRanda and PicTar. Resμlts:85miRNAs were increased,52miRNAs were reduced and verified by qRT-PCR. We found that mir-29b isassociated with apoptosis, and it has the area-specific binding sites with Mcl-1mRNA3'UTR. Conclusion: miRNAs expression profiles were changed. miRN As targetproteins were involved in protein phosphorylation and mRNA splicing. Highexpression of mir-29b targeting suppressed the mRNA expression of Mcl-1.
Part Ⅲ Rb1, folic acid and VB12we re used to antiapoptosis of HUVECstreated by NaAsO2.
Objective: To explore protective effects of Rb1, folic acid and vitamin B12inHUVECs induced by NaAsO2. Methods: We observed cell survival and migrationability with treatment of protectant by CCK-8and scratch methods in HUVEC cells.Also, treated the cells with protectant, we determined intracellular ROS by flowcytometry. Then cell apoptosis was detected by Annexin V-FITC and PI doublestaining, Hoechst staining and TUNEL assay respectively.
Results: Three protective drugs have the effects of inhibiting apoptosis, andleading to change the expression of miR-29b and Mcl-1. Conclusion: The combinedapplication of three drugs inhibited the apoptosis of HUVECs induced by NaAsO2more effectively than drug used respectively.
我们发现miRNAs参与了亚砷酸钠（NaAsO2）诱导的血管内皮细胞HUVECs的损伤和凋亡。miRNAs芯片技术分析在NaAsO2作用于HUVECs细胞时，细胞内miRNAs表达谱的改变情况，这部分结果得到实时定量RT-PCR的进一步证实。接着，我们应用DAVID等生物信息资源分析了miRNAs中具有参与蛋白磷酸化、mRNA剪接、细胞凋亡等生物学功能的靶蛋白，并通过Western blot的方法发现这些靶蛋白的表达发生了改变。通过使用生物信息学软件Targetscan, miRandaand PicTar等预测细胞抗凋亡蛋白Mcl-1mRNA的调控miRNAs，我们发现其与Mcl-1mRNA的3’ UTR区具有特异性结合位点，miR-29b可靶向调控Mcl-1mRNA的表达，提示miR-29b参与了凋亡相关基因转录后表达的调控。
在人肝细胞中砷化物通过产生过多的活性氧ROS诱导线粒体依赖性细胞凋亡[1]，可能是其诱导肝损伤的重要机制。我们也发现，亚砷酸钠（NaAsO2）可诱导HUVECs内ROS水平发生改变，诱导血管内皮细胞的损伤和凋亡，证明其主要是在地砷病血管损伤凋亡中发挥介导作用。
保护剂人参皂苷Rb1能起到保护内皮细胞的功效，其经典的作用机制在于能提高损伤细胞内抗氧化酶超氧化物歧化酶SOD2的活性，从而降低细胞内活性氧ROS的含量，避免线粒体受氧化损伤，从而修复细胞损伤及避免细胞死亡。叶酸和维生素B12也具有降低细胞内活性氧ROS的含量的抗氧化功效，且能确保重要物质的合成代谢，帮助机体及时进行损伤修复。在本实验中我们发现，对于亚砷酸钠引起的HUVECs的损伤及凋亡，三种保护剂具有修复和抑制效应，能降低细胞内活性氧ROS的含量，明显降低亚砷酸钠（NaAsO2）诱导的细胞凋亡。同时在保护剂的作用下，miRNA29b的表达下调，其靶蛋白抗凋亡蛋白Mcl-1表达上调，二者呈负相关。我们推测其保护机制可能是通过下调miRNA29b的表达，从而上调了其靶蛋白抗凋亡蛋白Mcl-1的表达，而抑制细胞凋亡的。
通过研究我们发现在亚砷酸钠诱导的血管内皮细胞损伤和凋亡中miRNAs介导了凋亡的过程，而且证实叶酸、维生素B12和人参皂苷对损伤的血管内皮细胞具有保护效应，且发现其分子机制与miRNAs有关。理论上，为亚砷酸钠诱导的血管损伤和凋亡的分子机制提供新的视角；临床应用上，为地砷病防治的临床药物研究和开发开辟新道路。
Endemic arsenic poisoning is a biogeochemical diseases. It leads to skinpigmentation and palm Billiton hyperplasia keratosis, and even threatens to the livesof patients. Endemic arsenic poisoning was caused by Arsenide mainly and vasc ularinjury is the primary pathological damage. For lack of clear understanding andeffective prevention of this, the arsenide generates vascular endothelial cell injury andapoptosis. Sodium arsenite and human umbilical vein endothelial cells are widelyused in research in vitro model. In this study, we discuss the injury and pro-apoptoticof vascular endothelial cells coused by arsenite, protective effects of protective agentand relative molecular mechanisms.
Epidemiological studies have shown there is a clear correlation betweenenvironment of chronic arsenic exposure and peripheral vascular disease. Vascularendothelial cells are directly target cells of toxic substances such as arseniccompounds, which play a very critical role in repairing of damaged vessels andmaintaining the integrity of vessels. Consequently, it is crucial to study the relativemolecular mechanisms and prevention measures of vascular endothelial cell injury byarsenide.
Injury and apoptosis of vascular endothelial cell caused the loss of its originalshape, function and the integrity of vessels, which initiates peripheral vascular disease.In our research, we cultured human umbilical vein endothelial cells exposed to arseniccompounds to explore the molecular mechanisms of cell injury and apoptosis invascular endothelial injury model. Little is known about this.
Cell injury is a response of persistent stimulation in vivo and vitro, which makes cellinjury in metabolic, morphological, functional and structural changes. Mild injury isreversible, but severe cases leads to irreversible damage and even apoptosis or necrosis.When cells happen to irrevers metabolism, structure and dysfunction, it will lead to celldeath. Cell death is divided into two basic types of necrosis and apoptosis. Ourexperiment focuses on the new aspect of its molecular mechanism and pro-apoptotic effects of the arsenide toxic on vascular endothelial cells, and studying how to reduce celldamage and block the process of apoptosis. Thus, we provide the basis for the preventionand treatment of peripheral vascular disease caused by arsenic compounds.
Apoptosis, programmed cell death, is involved in important physiological functionsof embryonic development and homeostasis. However, insufficient or excessive apoptosiscould cause certain diseases. It was suggested that apoptotic process can be regulated bythe intracellular redox statement. Intracellular redox is involved in the physiologicalprocesses of cellular oxidative phosphorylation. Excessive reactive oxygen radicals ROSin mitochondria leads to cellular oxidative damage and apoptosis.
Small RNA (microRNAs, miRNAs) are a class of small single-stranded RNA,18-25nt, highly conserved itself, encoding no proteins, interact with its target mRNA bybases complementary pairing principle. With complete or incomplete pairing, miRNAcould achieve the effect of its target mRNA’s degradation or inhibit its translation andplay the role in the post-transcriptional level to regulate gene expression.
MiRNAs have been widely used to explain and study development diseases todetermine the prognosis and outcome of the disease from a new perspective aspect, whichare involved in the prevention and diagnosis of diseases as well. The technology ofmicro RNA array has become an important scientific method. miRNAs have significantchanged in the injury and apoptotic process of the study of NaAsO2on HUVECs. It isvaluable to explore molecular mechanisms of vascular endothelial cells injury by arsenide.There is few reports that mir-29b relates with apoptosis targeted anti-apoptotic proteinMcl-1, which can regulate the expression of Mcl-1.
The ginsenoside Rb1has a variety of biological activity as one of the main activeingredients in ginseng. It conducives to the normalization of body functions, and hasthe efficacy to inhibit tumor cell, anti-aging, anti-free radical damage also.Ginsenoside Rb1has been reported to increase the activity of antioxidant enzymeSOD2, especially for endothelial cell damage in the cardiovasc ular system, having abetter fix. Numerous studies have demonstrated that ginsenoside Rb1play aprotective efficacy of endothelial cells. Its mechanism of action is improving theactivity of the antioxidant enzyme, superoxide dismutase SOD2, in damage cells,thereby clearing the excess of intracellular reactive oxygen species ROS, reducing itscontent, avoiding mitochondrial oxidative damage, and protecting the cell free ininjury and death. Ginsenoside has been studied mainly in animal models, but there islittle research in cell damage model. There is no report for the protective effects and mechanisms of vascular endothelial injury and repair by arsenide injury.
Folic acid and vitamin B12are involved in the synthesis and metabolism of lifeimportant substances as indispensable vitamin in the body. They both have powerfμlantioxidant efficacy of anti-injury. It was confirmed by Sangita Ma jumdar that vitaminB12and folic acid have anti-apoptotic effects in arsenide-induced liver cytotoxic in rats.Ginsenoside Rb1, folic acid together with vitamin B12can resist damaging in sodiumarsenite induced HUVECs cell damage and apoptosis. As well, the study on the relatedexpression of mir-29b and anti-apoptotic protein Mcl-1has not been reported.
In our research, we have conducted molecular mechanisms of the effects on humanumbilical vein endothelial cells of cell injury, apoptosis by sodium arsenite in vitro.
We studied and analyzed the interaction of transcription factor SP1with SOD2promoter region and the relationship with the SOD2gene transcription using dualfluorescent reporter gene technology. In order to clarify the miRNAs in the role ofapoptosis in endothelial cell injury induced by sodium arsenite, miRNAs biochiptechnology was used to analyze miRNAs expression profiles changed after sodiumarsenite poisoning HUVECs cells, and then we used biological information softwares ofTargetscan, miRanda and P icTar to predict regulatory factors of anti-apoptotic proteinMcl-1among the changed miRNAs in endothelial cells induced by sodium arsenite, andconfirmed the most related miRNA with the anti-apoptotic protein Mcl-1. To find theeffective protective drugs and measures for providing new ideas of the prevention ofdiseases caused by arsenic poisoning, we studied protection effects and mechanisms ofginsenoside Rb1, folic ac id, vitamin B12alone and combined in the confrontation sodiumarsenite-induced cell damage and apoptosis on HUVECs.
This experiment provides a reliable theoretical and experimental basis, and lays thefoundation for the clinical treatment and drug development for pathogenesis of arsenicdiseases.Part ⅠHUVECs happened to apoptosis induced by NaAsO2.
Objective: To study the mechanism of injuries on HUVECs by arsenite.
Methods: We observed the proliferation of cells treated with arsenite. We examedthe ability of cell migration in vitro scratch assay. In addition, we checked the levelsof intracellular ROS by flow cytometry with a cell based ROS assay. Apoptotic cellswere detected by flow cytometry with Annexin V-FITC and PI double staining, byHoechst staining and TUNEL assay. Results: Cell injury and apoptosis were occurred.Cell migration ability was destroyed. The group of20μM NaAsO2displayed more obviously at the generation of ROS and cell apoptosis The apoptotic cells weresignificantly increased in a dose-dependent manner following arsenite treatments for24hours by NaAsO2. Conclusion: HUVECs were injuried by NaAsO2, and NaAsO2induced its apoptosis, which is the experimental evidence of vascular lesion byNaAsO2.PartⅡ miRNAs expression profiles was changed in HUVECs induced by NaAsO2.The mechenism of apoptosis is upregulated miR-29b and downregulated Mcl-1.
Objective：To analyze the miRNAs expression profiles in HUVECs induced byNaAsO2, to find apoptosis-related protein and regulated miRNAs. Methods:Wedetected miRNAs expression profiles in HUVECs induced by NaAsO2through themiRNA array technology and verified by qRT-PCR. miRNAs target genes wereanalyzed by DAVID software. Forecasting regulative miRNAs of Mcl-1mRNA bysoftwares of TargetScan, miRanda and PicTar. Resμlts:85miRNAs were increased,52miRNAs were reduced and verified by qRT-PCR. We found that mir-29b isassociated with apoptosis, and it has the area-specific binding sites with Mcl-1mRNA3'UTR. Conclusion: miRNAs expression profiles were changed. miRN As targetproteins were involved in protein phosphorylation and mRNA splicing. Highexpression of mir-29b targeting suppressed the mRNA expression of Mcl-1.
Part Ⅲ Rb1, folic acid and VB12we re used to antiapoptosis of HUVECstreated by NaAsO2.
Objective: To explore protective effects of Rb1, folic acid and vitamin B12inHUVECs induced by NaAsO2. Methods: We observed cell survival and migrationability with treatment of protectant by CCK-8and scratch methods in HUVEC cells.Also, treated the cells with protectant, we determined intracellular ROS by flowcytometry. Then cell apoptosis was detected by Annexin V-FITC and PI doublestaining, Hoechst staining and TUNEL assay respectively.
Results: Three protective drugs have the effects of inhibiting apoptosis, andleading to change the expression of miR-29b and Mcl-1. Conclusion: The combinedapplication of three drugs inhibited the apoptosis of HUVECs induced by NaAsO2more effectively than drug used respectively.
引文
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