摘要
第一部分外源性活性氮供体GSNO对内皮细胞损伤及机制研究
阿尔茨海默病(Alzheimer's disease,AD)的病变过程中可伴有活性氮(reactivenitrogen species,RNS)大量生成,但RNS对内皮细胞的损伤机制至今仍未阐明。本研究选择外源性RNS供体S-亚硝酰谷胱甘肽(S-nitrosoglutathione,GSNO)直接作用于内皮细胞的模型,试图揭示RNS和内皮细胞损伤之间内在的病理生理关联性。研究采用在培养的EA.hy926内皮细胞株(下简称内皮细胞)体系中加入GSNO(0.5 mM),通过DAPI染色和PI流式细胞术检测到内皮细胞呈浓度和时间依赖性凋亡。结果显示,细胞内活性氧(reactive oxygen species,ROS)增加的同时伴随线粒体膜电位(△Ψm)降低。尤为重要的发现是该损伤过程中,过氧亚硝酸阴离子形成和线粒体促凋亡蛋白丝氨酸蛋白酶(Omi/HtrA2)和细胞色素C(Cytochrome C,Cyt C)从线粒体释放至胞浆中,启动了凋亡终端蛋白caspase 3的活化,而在这一过程中未检测到死亡受体途径相关蛋白变化,表明GSNO可通过ROS-线粒体信号途径诱导细胞凋亡。在该体系中加入NADPH氧化酶抑制剂apocynin,ROS清除剂TEMPOL和Omi/HtrA2抑制剂ucf-101,均能显著抑制caspase3的活化发挥抗GSNO诱导凋亡的作用。上述结果进一步证实了外源性GSNO可引起内皮细胞线粒体依赖性损伤,该过程中ROS过表达及线粒体促凋亡蛋白Omi/HtrA2移位,在RNS诱导的内皮细胞凋亡中起着至关重要的作用,药物调控这些相关途径有望发挥显著的抗内皮细胞损伤效应。
第二部分Aβ肽源性RNS致内皮细胞损伤及人参皂苷Rg1保护机制研究
β淀粉样(beta-amyloid,Aβ)肽在脑实质和脑微血管上沉积是AD的主要病理特征,但Aβ肽介导的神经元和内皮细胞损伤机制仍不清楚。鉴于本文第一部分研究结果表明,GNSO具有致内皮细胞凋亡作用。本部分研究首先探讨Aβ_(25-35)肽损伤内皮细胞模型是否有RNS产生及其损伤特征。并在此基础上,评价了人参皂苷Rg1的保护机制。选择25μM的Aβ肽作用于内皮细胞,引起细胞存活率减少,乳酸脱氢酶释放和显著的细胞凋亡特征,同时伴随细胞内NO过表达和氧化亚硝基阴离子(Peroxynitrite anion,ONOO~-)大量生成,和蛋白酪氨酸硝基化。而加入人参皂苷Rg1预处理可显著减轻Aβ肽所引起的上述细胞毒性,显著减少Aβ肽诱导的NO过表达和蛋白酪氨酸硝基化。并可部分逆转Aβ肽导致的线粒体△Ψm降低,Bcl-2/Bax下调,Cyt C释放及caspase 3激活,提示人参皂苷Rg1预处理具有抗Aβ肽导致的内皮细胞线粒体依赖性凋亡作用。此外,Aβ肽尚能在激活p38-MAPK的同时抑制ERK的磷酸化,并激活NF-κB核转录及I-κB的磷酸化,这些效应均能不同程度地被人参皂苷Rg1逆转。另鉴于人参皂苷Rg1的核心结构与甾体类似,为论证保护作用机制是否涉及相关受体,本研究尚通过甾体激素受体拮抗剂和ERK抑制剂对抗,结果表明两者均能部分减弱Rg1的保护效应。上述试验结果提示,Aβ肽致内皮细胞损伤与RNS所致的蛋白硝基化和凋亡有关,糖皮质激素受体激活和ERK减少可能涉及人参皂苷Rg1的上述抗凋亡作用,同时通过其抗氧化效应,阻断下游级联反应而发挥保护作用。
总结:
1.体外实验体系中过量活性氮供体GSNO作用于内皮细胞,可引起ROS的过量生成伴随NO/过氧化亚硝基阴离子信号途径的激活,诱导线粒体依赖性凋亡。
2.Aβ肽介导的内皮细胞损伤与RNS的生成关系密切,人参皂苷Rg1主要通过其抗氧化、抗线粒体依赖性凋亡和抑制蛋白酪氨酸硝基化作用发挥内皮细胞保护效应。
Chapter1 The mechanisms of ectogenesis RNS donor S-nitrosoglutathione (GSNO)-induced damage in human endothelial cells
The course of Alzheimer's disease accompanied by a large generation of RNS,but the mechanisms of RNS-induced endothelial cell injury has not been clarified. Furthermore,the pathophysiological relevance of S-nitrosoglutathione(GSNO)-induced endothelial cell injury remains unclear.The main objective of this study was to elucidate the molecular mechanisms of GSNO-induced oxidative stress in endothelial cells.Morphological evaluation through DAPI staining and propidium iodide(PI) flow cytometry was used to detect apoptosis.In cultured EA.hy926 endothelial cells, exposure to GSNO led to a time- and dose-dependent apoptotic cascade.When intracellular reactive oxygen species(ROS) production was monitored in GSNO-treated cells by diaminofluorescein-FM,we observed elevated ROS levels and a concomitant loss in mitochondrial membrane potential,indicating that GSNO-induced death signaling is mediated through a ROS-mitochondrial pathway.Importantly,we found that peroxynitrite formation and omi/HtrA2 release from mitochondria were involved in this phenomenon,whereas changes of death-receptor dependent signaling were not detected in the same context.The inhibition of NADPH oxidase activation and omi/HtrA2 by a pharmacological approach provided significant protection against caspase 3 activation as well as GSNO-induced cell death,confirming that GSNO triggers the death cascade in endothelial cells in a mitochondria-dependent manner. Taken together,ROS overproduction and loss of mitochondrial omi/HtrA2 play a pivotal role in reactive nitrogen species-induced cell death,and the modulation of these pathways can be of significant therapeutic benefit.
Chapter2 The effect of RNS in Aβ-mediated damage to EA.hy926 endothelial cells and the protective mechanisms of ginsenoside Rg1
The deposition of beta-amyloid(Aβ) in the brain parenchyma and cerebrovasculature has been characterized in Alzheimer's disease(AD),but the precise mechanisms of Aβ-mediated neuronal and endothelial insult remains unclear.In the present study,we attempted to evaluate the potential mechanisms of Aβ-mediated insult in endothelial cells as well as protective effect of Ginsenocide Rg1.In cultured EA.hy926 endothelial cells,Aβ_(25-35)(25μM) treatment induced cell toxicity, characterized by decreased cell viability,lactate dehydrogenase(LDH) release,and significant apoptotic characteristics,which is associated with both the overproduction of intracellular ROS and loss of mitochondrial membrane potential.By contrast, cytotoxicity of Aβ_(25-35) was significantly reversed by pre-incubation of Rgl in endothelial cells.Furthermore,Rgl prevented Aβ_(25-35)-induced nitric oxide overproduction and protein tyrosine nitration in same context.Immunoblotting results revealed that upregulation of iNOS and nitrotyrosine,Bcl-2/Bax downregulation, Cytochrome C release and activation of caspase 3 in Aβ_(25-35)-treated cells were partially blocked by Rg1.Additionally,Aβ25-35 triggered the activation of p38-MAPK and inhibited the phosphorylation of ERK,and these effect were effectively suppressed by Rg1 treatment,whereas glucocorticoid receptor antagonist RU 486 and MEK inhibitor U0126 both weakened the protective effect of Rg1.Taken together,our results suggest that Rgl protects EA.hy926 endothelial cells against Aβ_(25-35)-induced apoptotic cascade through suppressing peroxynitrite formation and anti-oxidative mechanisms.
Summary:
1.We demonstrate that excessive ROS generation and peroxynitrite formation resulting from GSNO treatment accounts for initiation of GSNO/NO-induced endothelial injury in vitro.
2.Our results indicate that NO-mediated intrinsic pathway signaling constitutes a critical component of apoptotic signaling in Aβ-mediated endothelial cell death.Rg1 is a potential endothelial protective compound against Aβ_(25-35) insult which was exerted by suppressing protein tyrosine nitration and anti-oxidative mechanisms.
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