肝细胞生长因子对神经元缺氧/复氧损伤的影响及其分子机制研究

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英文题名：Effects of HGF on Neurons Subjected to Hypoxia/Reoxygenation and the Molecular Mechanisms Mediated the Effects 作者：贺芳 论文级别：博士 学科专业名称：生理学 中文关键词：肝细胞生长因子 ; 神经元 ; 缺氧/复氧 ; 细胞外信号调节激酶 ; 基因芯片 英文关键词：hepatocyte growth factor ; neuron ; hypoxia / reoxygenation ; extracellular signal-regulated kinase ; gene array 学位年度：2007 导师：邬力祥 学科代码：071003 学位授予单位：中南大学 论文提交日期：2007-11-01

摘要

目的:研究肝细胞生长因子(hepatocyte growth factor,HGF)对大脑皮层神经元缺氧/复氧损伤的影响,并探讨其可能的分子机制。
     方法:取原代培养的Sprague-Dawley大鼠大脑皮层神经元细胞,以LDH漏出率作为细胞损伤指标、MTT比色法检测细胞活力、流式细胞术分析细胞凋亡率,研究缺氧、低(无)糖、缺氧/复氧对神经元的影响,建立体外缺氧/复氧损伤模型。在此基础上,通过LDH漏出率的测定、MTT比色法、流式细胞术、Hoechst 33258染色法、RT-PCR、Western blotting的方法研究HGF对皮层神经元缺氧/复氧损伤的影响及其与MEK/ERK1/2、PI-3K/Akt信号传导途径,凋亡相关分子Bcl-2、Bcl-xL和Bax的关系。利用基因芯片技术研究HGF对缺氧/复氧损伤神经元缺氧信号通路的影响。用实时定量PCR的方法进一步验证这些差异表达基因中的6个(Mybl2、Cygb、Birc5、Cdc42、IL1β、NOS2),并通过Western blotting检测HGF对缺氧/复氧损伤神经元Cygb和NOS2蛋白表达水平的影响。
     结果:
     1.缺氧、低(无)糖及缺氧/复氧对神经元的影响
     (1)MTT比色实验的结果显示,缺氧1h,神经元细胞活力即降低,而LDH漏出率从缺氧4h开始增高,且随缺氧时间的延长,细胞活力呈降低的趋势,LDH漏出率呈增高的趋势。
     (2)低糖(葡萄糖浓度为2.5 mmol/L)、无糖处理均诱导神经元损伤,且无糖组的损伤较低糖组更为严重。
     (3)缺氧条件下培养,各组对缺氧耐受性由高到低排列依次为正常糖组＞低糖组＞无糖组。
     (4)神经元缺氧/复氧与单独缺氧比较,细胞活力降低,LDH漏出率和细胞凋亡率均增高,且随复氧时间的延长(0～24h),细胞活力呈下降趋势,LDH漏出率及细胞凋亡率呈上升趋势。
     2.HGF对神经元缺氧/复氧损伤的影响
     (1)用RT-PCR、Western blotting的方法,在体外培养10d的大脑皮层神经元和生后10d大鼠的大脑皮层组织均检测到c-MetmRNA和c-Met蛋白的表达。
     (2)HGF对缺氧8h/复氧12h(H_8/R_(12))损伤神经元的影响:HGF降低LDH漏出率的效应从20 ng/ml开始出现,在60ng/ml达最高峰;增强细胞活力和抗凋亡效应均从10 ng/ml开始出现,也是在60ng/ml达最高峰。此外,在缺氧处理前12h、缺氧处理前1h、缺氧即刻及复氧即刻加入终浓度为60ng/ml的HGF,均使H_8R_(12)损伤神经元LDH漏出率降低,细胞活力增高,细胞凋亡率降低。其中缺氧处理前1h加入HGF在上述4个时间点中,增强细胞活力的效应为最强。c-Met抑制剂SU11274(5μmol/L)明显阻断了HGF的神经保护作用。
     (3)HGF对氧糖剥夺2h/再灌注24h(OGD_2R_(24))损伤神经元的影响:HGF增强细胞活力,降低LDH漏出率和细胞凋亡率的效应均从20 ng/ml开始出现,在80ng/ml达最高峰。此外,在缺氧处理前12h、缺氧处理前2h、缺氧即刻及复氧即刻4个时间点加入终浓度为80ng/ml的HGF,均使细胞活力增高,细胞凋亡率降低。在复氧即刻加入HGF,对OGD_2R_(24)损伤神经元的LDH漏出率无明显影响,其余三个时间点的LDH漏出率均降低。缺氧处理前2h加入HGF,在上述4个时间点中降低LDH漏出率和增强细胞活力的效应均为最大。c=Met抑制剂SU11274(5μmol/L)显著抑制了HGF介导的神经保护效应。
     3.HGF对缺氧/复氧神经元的保护作用与ERK1/2、PI-3K/Akt通路及凋亡相关分子的关系
     (1)Western blotting的结果显示,HGF激活大脑皮层神经元MEK/ERK1/2与PI3-K/Akt信号通路。
     (2)MTT比色实验、流式细胞术和Hoechst 33258染色的结果显示,用MEK的抑制剂,U0126(500nmol/L)明显阻断了HGF对H_8/R_(12)损伤神经元的促细胞存活和抗凋亡效应。PI3-K的抑制剂,LY294002(LY,10μmol/L)预处理抑制了HGF介导的神经保护作用。使用上述浓度的两种抑制剂(不加HGF)对常氧条件下培养及H_8R_(12)处理神经元的细胞活力和凋亡率均无明显影响。
     (3)RT-PCR和Western blotting的结果显示,H_8/R_(12)损伤后,皮层神经元Bcl-2、Bcl-xL的mRNA和蛋白表达水平明显下调,BaxmRNA的表达显著上调,而Bax蛋白的表达无明显变化。用HGF(60ng/ml)预处理明显上调了缺氧/复氧损伤神经元Bcl-2、Bcl-xL的mRNA和蛋白表达水平,但对Bax mRNA和蛋白的表达无显著影响。
     4.HGF对缺氧/复氧神经元缺氧信号通路的影响
     (1)对缺氧信号通路基因芯片显示的差异表达基因进行功能分类,涉及代谢、信号传导、细胞生长、转录、细胞骨架、凋亡等方面。
     (2)实时定量PCR的结果显示,神经元H_8/R_(12)损伤后Mybl2mRNA、Cygb mRNA、Birc5 mRNA表达下调,Cdc42 mRNA、Nos2mRNA、IL1βmRNA表达上调;HGF(60 ng/ml)预处理能明显抑制H_8/R_(12)损伤神经元Mybl2 mRNA、Cygb mRNA、Birc5 mRNA水平的降低,以及Cdc42 mRNA、NOS2 mRNA、IL1βmRNA水平的增高。
     (3)Western blotting的结果显示,H_8/R_(12)损伤后,神经元Cygb蛋白表达水平明显降低,NOS 2蛋白表达显著增高,HGF预处理能明显上调H_8/R_(12)损伤神经元Cygb蛋白的表达,下调NOS2蛋白表达水平。
     结论:
     1.缺氧、低(无)糖可引起皮层神经元损伤,且与持续时间密切相关,皮层神经元对缺氧、低(无)糖十分敏感。
     2.低(无)糖能加重缺氧导致的皮层神经元损伤,呈一定的时效依赖性,无糖对缺氧的耐受性低于正常糖和低糖。
     3.缺氧后复氧可加重缺氧引起的皮层神经元损伤和细胞凋亡,呈一定的时效依赖关系。
     4.c-Met受体存在于大脑皮层组织和体外培养的大脑皮层神经元。
     5.HGF对体外培养的皮层神经元缺氧/复氧损伤具有直接的保护作用,并呈一定的量效和时效关系。
     6.MEK/ERK1/2通路的激活在HGF对皮层神经元缺氧/复氧损伤的保护效应中起重要作用,PI3-K/Akt通路也参与了这一效应。
     7.Bcl-2和Bcl-xL可能参与了HGF对皮层神经元缺氧/复氧损伤的保护作用。
     8.初步明确皮层神经元缺氧/复氧损伤后,缺氧信号通路相关基因的变化规律。
     9.初步明确HGF对缺氧/复氧损伤皮层神经元缺氧信号通路相关基因的影响规律。
     10.HGF对缺氧/复氧损伤皮层神经元保护作用可能与抑制Mybl2、Cygb、Birc5的表达降低和Cdc42、NOS2、IL1β的表达增高有关。
Objective:To investigate the effects of hepatocyte growth factor (HGF)on cerebral cortical neurons subjected to hypoxia/reoxygenation (H/R)and explore the molecular mechanisms mediated the effects.
     Methods:Primary cultured cerebral cortical neurons were prepared from Sprague-Dawley rats.Cell injury was evaluated by lactate dehydrogenase(LDH)release rate,cell viability was assessed by MTT assay and percentage of apoptotic cells was analyzed by Flow Cytometry The effects of hypoxia,low(no)glucose and hypoxia / reoxygenation on cultured cerebral cortical neurons were observed to establish a hypoxia/reoxygenation model in vitro.We studied the effects of HGF on cortical neurons by the model.The relationship between the influence of HGF on neurons exposed to H/R with MEK/ERK1/2 pathway,PI-3K/Akt pathway and apoptosis-related molecules(Bcl-2,Bcl-xL,Bax)was evaluated by MTT assay,Flow Cytometry,Hoechst 33258 staining,semiquantitative RT-PCR and Western blotting analysis.Then,we observed the alteration of HGF on the expression,of hypoxia signaling pathway by gene array technology.Real-time quantitative PCR assay was conducted to examine the level of Myb12 mRNA,Cygb mRNA,Birc5 mRNA,Cdc42 rnRNA,IL1βmRNA,NOS2 mRNA which had been affected by HGF.Western blotting analysis was performed to detect the expression of Cygb protein and NOS2 protein.
     Results:
     1.Effects of hypoxia,low glucose,glucose-free and hypoxia /reoxygenation on cortical neurons
     (1)MTT assay showed that the cell viability was decreased 1 h after hypoxia,and the LDH release rate was increased 4 h after hypoxia.As the treatment time went on,the cell viability was on the decline and the LDH release rate was on the rise.
     (2)Either low glucose(2.5mmol/L)or glucose-free induced cell injury.Compared with low glucose group,the cell viability of glucose-free group was lower and the LDH release rate was higher.
     (3)The tolerance to hypoxia in various group followed this rule: normal glucose＞low glucose＞glucose-free.
     (4)Hypoxia/reoxygenation decreased the cell viability,increased the LDH release rate and the apoptotic rate of cortical neurons exposed to hypoxia.Along with the duration of reoxygenation(0～24h),the cell viability was on the decline,the LDH release rate and the apoptotic rate were on the rise.
     2.Effects of HGF on cortical neurons subjected to hypoxia /reoxygenation
     (1)c-Met mRNA and c-Met protein were present in both the cultured cortical neurons at 10 days in vitro(DIV10)and the cerebral cortical tissue from post-natal day 10 rat detected by RT-PCR and Western blotting analysis.
     (2)Effects of HGF on cortical neurons subjected to hypoxia 8 h/reoxygenation 12 h(H_8/R_(12)):The,decrease of LDH release rate by HGF was observed at 20 ng/ml,and the maximum effect was at 60ng/ml; The increase of cell viability and the anti-apoptotic effect by HGF were observed at 10 ng/ml,and the maximum effect was at 60ng/ml. Furthermore,administration of HGF(60ng/ml)at 12 h before hypoxia,1 h before hypoxia,the same time of hypoxia or the same time of reoxygenation decreased the LDH release,rate,increased the cell viability and decreased the apoptotic rate.And the most potent effect of HGF mediated cell survival was observed,at 1 h before hypoxia.Application of c-Met inhibitor SUl1274(5μmol/L)significantly abolished the HGF mediated protection in cortical neurons subjected,to H_8/R_(12).
     (3)Effects of HGF on cortical neurons exposed to oxygen-glucose deprivation 2 h/reperfusion 24 h(OGD_2/R_(24)):The decrease of LDH release rate,the increase of cell viability and the decrease of apoptotic rate by HGF were observed at 20 ng/ml,and the maximum effect was at 80ng/ml.Moreover,administration of HGF(80ng/ml)at 12 h before hypoxia,2 h before hypoxia,the same time of hypoxia or the same time of reoxygenation increased the cell viability and decreased the apoptotic rate.Treatment with HGF(80ng/ml)at the same time of reoxygenation had no significant effect on the LDH release rate.The most potent effect of HGF mediated cell survival and decrease of LDH release rate were observed at 2 h before hypoxia.Treatment with c-Met inhibitor SU11274 (5μmol/L)remarkably eliminated the neuroprotection by HGF.
     3.Relationship between the influence of HGF on neurons exposed to hypoxia/reoxygenation with MEK/ERK1/2 pathway, PI-3K/Akt pathway and apoptosis-related molecules
     (1)As detected by Western blotting analysis,HGF activated both MEK/ERK1/2 and PI3-K/Akt pathways in cerebral cortical neurons.
     (2)The presence of U0126(500 nmol/L),a potent inhibitor of MEK, significantly eliminated HGF mediated cell survival and anti-apoptotic effects on neurons subjected to H_8R_(12).Inhibition of Akt activation with LY294002(10μmol/L)reduced the HGF mediated cell survival and anti-apoptotic effects.Neither inhibitor at the concentration used in this work,in the absence of HGF,significantly altered cell viability and the amount of apoptosis in cultures not exposed to H_8/R_(12)or H_8/R_(12)-treated culttires.
     (3)As determined by semi-quantitative RT-PCR and Western blotting analysis,the level of Bcl-2 mRNA,Bcl-xL mRNA,Bcl-2 protein and Bcl-xL protein in cortical neurons exposed to H_8/R_(12)were significantly decreased.The expression of Bax mRNA in cortical neurons exposed to H_8/R_(12)was remarkably increased,whereas no detectable change in Bax protein was observed.Pre-treatment with HGF(60 ng/ml) remarkably attenuated H_8/R_(12)induced decrease in the level of Bcl-2 mRNA,Bcl-xL mRNA,Bcl-2 protein and Bcl-xL protein.The expression of Bax mRNA and-Bax protein in cortical neurons exposed to H_8/R_(12)was not affected by the application of HGF(60 ng/ml).
     4.Influence of HGF on the expression of hypoxia signaling pathway in cortical neurons subjected to hypoxia/reoxygenation
     (1)Functional clustering analysis of the genes affected by HGF indicated that these genes were involved in metabolism,signal transduction,cell growth,transcription,cytoskeleton,apoptosis and so on.
     (2)As assessed by real-time quantitative PCR assay,H_8/R_(12)treatment decreased the level of Myb12 mRNA,Cygb mRNA,Birc5 mRNA,and increased the expression of Cdc42 mRNA,NOS2 mRNA,I11b mRNA in cortical neurons;Pre-treatment with HGF(60 ng/ml)remarkably inhibited H_8/R_(12)induced decrease in the level of Myb12 mRNA,Cygb mRNA, Birc5 mRNA and increase in the expression of Cdc42 mRNA,NOS2 mRNA,I11b mRNA.
     (3)As detected by Western blotting analysis,the level of Cygb protein in corticat neurons exposed to H_8/R_(12)was significantly decreased,and the expression of NOS2 protein was remarkably increased.HGF(60 ng/ml) significantly attenuated H_8/R_(12)induced decrease in the level of Cygb protein and increase of the expression of NOS2 protein.
     Conclusions:
     1.Hypoxia or low(no)glucose can induce injury in cortical neurons, which is closely related to sustained time,and the cortical neurons are very sensitive to hypoxia or low(no)glucose.
     2.Low glucose or glucose-free can aggravate the injury in cortical neurons resulting from hypoxia in a time-dependent manner,and the tolerance to hypoxia under glucose-free condition is lower than normal or low glucose.
     3.Hypoxia/reoxygenation can aggravate hypoxia induced injury and apoptosis of cortical neurons in a time-dependent manner.
     4.c-Met receptor is expressed in both the cerebral cortical tissue and the cultured cortical neurons.
     5.HGF has a direct protection on cultured cerebral cortical neurons subjected to hypoxia/reoxygenation in a dose-and time-dependent manner.
     6.The neuroprotection of HGF depend on ERK1/2 pathway,and,to a lesser extent,PI-3K/Akt pathway.
     7.Bcl-2 and Bcl-xL appear to be involved in the neuroprotection of HGF.
     8.The hypoxia signaling pathway related genes,which are influnced by hypoxia/reoxygenation are achieved.
     9.The hypoxia signaling pathway related genes in cortical neurons exposed to H/R,which are affected by HGF are clarified.
     10.The protection of HGF on cortical neurons subjected to H/R may be related to inhibition of decrease of the level of Myb12、Cygb、Birc5 and the increase of the expression of Cdc42、NOS2、IL1β.

引文

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