线粒体氧化应激信号通路参与缺糖缺氧诱导内皮细胞凋亡调控机制研究
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摘要
背景:
以脑血管内皮损伤为病变基础的缺血性脑中风,随着我国社会老龄化进展,发病率和死亡率不断攀升,是严重危害我国人民生命健康的重大疾病。脑血管内皮细胞氧化应激损伤是缺血性脑中风发生发展中的重要病理现象。近年来越来越多的研究显示线粒体在介导细胞凋亡的过程中发挥了极为重要的作用,位于线粒体内外膜间隙凋亡相关分子释放是线粒体介导的凋亡过程中的关键事件,可以引起细胞结构和功能的广泛损害。我们前期研究结果发现缺血性脑中风在发生发展过程中,钙离子、钙调素依存的一氧化氮合酶(Nitric oxide synthase,NOSs)被激活,伴有合成大量一氧化氮(Nitric oxide,NO)生成,NO在体内可与超氧阴离子(Superoxide,O_2~-)快速结合生成过氧亚硝基阴离子(peroxynitrite,ONOO~-),参与脑血管内皮损伤、血脑屏障破坏及细胞凋亡过程。另外,脑血管内皮细胞内存在高密度的线粒体来维持正常的生理活动,线粒体呼吸功能下降是各种脑系疾病的早期现象;神经系统疾病发生发展中线粒体内外膜间隙的凋亡相关分子释放与调控处于线粒体氧化应激损伤的关键部位,已经受到生物医学研究领域的极大关注,但关于酪氨酸蛋白硝基化与线粒体氧化应激损伤的内在关联性研究尚未阐明。根据文献报道,Omi/HtrA2(oocyte maturation inhibitor/the high temperature requirement factor A2)是一种线粒体丝氨酸蛋白水解酶,当细胞受到刺激发生应激反应时线粒体膜通透性增加,并与X连锁凋亡抑制蛋白(X-linked inhibitor ofapoptosis protein,XIAP)等相互作用,继发激活caspase原,最终导致细胞死亡。XIAP的脑保护作用可能与其能够直接与启动性caspase(caspase-9)和效应性caspase(caspase-3、caspase-7)结合并抑制其活性有关。此外,PED/pea-15(phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes)的生物功能的多样性和翻译后调控及对Omi/HtrA2介导的下游细胞凋亡级联反应的制衡作用也被关注。
目的:
通过构建缺糖缺氧(Oxygen-Glucose Deprivation,OGD)内皮细胞损伤模型,探索内皮损伤病理状态下ONOO-介导的酪氨酸硝基化与线粒体氧化应激损伤信号转导的内在关联性及线粒体Omi/HtrA2-PED/pea-15的平衡紊乱对下游细胞XIAP-caspases凋亡级联反应的调控机制,并利用基因芯片技术对氧化应激损伤后的多基因表达变化进行探索性研究,为脑缺血疾病的预防及治疗提供理论性研究依据。
方法:
在OGD条件下,分别处理内皮细胞1 h,3 h,6 h,12 h和24 h,然后通过MTT法分别检测细胞存活分数;通过光镜,透射电镜,JC-1(5,5',6,6'-tetrachloro-1,1',3,3'tetraethylbenzimidazolylcarbocyanine iodide)染色等方法观察经OGD处理不同时间后内皮细胞表型变化;通过流式细胞仪定量测定线粒体膜电位变化;在分子生物学机制方面,通过Western-blot法法及免疫定位染色法检测相关蛋白表达。
OGD处理6 h前,分别加入ONOO~-的清除剂尿酸(Uric acid,UA),Omi/HtrA2的特异性阻断剂ucf-101,观察细胞的存活分数的改变情况;通过Western-blot法检测相关蛋白表达;在检测凋亡率方面,通过Annexin V/PI染料进行流式定量检测。在研究内皮细胞多基因表达变化方面,采用基因芯片技术进行检测。
结果:
光镜、电镜、JC-1结果分别显示经OGD处理后,血管内皮细胞逐渐拉长,变细,细胞间隙变大,细胞核由规则的圆形变成不规则的多边形,并出现染色质边聚现象,线粒体出现肿胀、变形,线粒体膜电位下降明显;Western-blot结果显示内皮细胞经OGD诱导3 h后,细胞质Omi/HtrA2显著显著增加,并且至少在24 h内尤为显著,线粒体Omi/HtrA2随着OGD诱导时间延长而减少。内皮细胞内的XIAP自OGD诱导3 h后显著下调。pro-caspase3和pro-caspase9,PED/pea15蛋白在OGD诱导后随之减少。同时,MMP-9在OGD处理较短时间内(3 h)被激活。免疫定位染色结果显示OGD诱导6 h后线粒体内Omi/HtrA2荧光强度明显减弱。
加入ucf-101后,细胞存活分数与OGD 6 h组相比略有提高,但无显著性差异。加入UA后,细胞存活分数显著提高并且两药合用后效果最为明显;Western-blot结果显示,当加入UA及两药合用后,细胞质Omi/HtrA2、cleaved-caspase 3及硝基化酪氨酸蛋白下调明显,而XIAP、PED/pea15、、pro-caspase-3则出现了显著的上调。间质金属酶(GelatinaseB,MMP-9)和nitrotyrosine蛋白表达也随着UA的加入出现显著的下调趋势。
基因芯片结果显示以caspase家族为代表的多种基因分别出现了上调及下调趋势。
结论:
以上结果提示在缺糖缺氧条件下,诱导了内皮细胞以线粒体依赖的内皮细胞凋亡程序的发生。Omi/HtrA2由线粒体向胞浆外释放增多,胞浆Omi/HtrA2与PED/pea15结合及水解酶作用后将会加速抗凋亡蛋白PED/pea15的降解。随着体内Omi/HtrA2- PED/pea15的稳态失衡,将进一步触发Omi/HtrA2介导的下游内皮细胞凋亡事件,包括抑制XIAP的表达,进而导致capase-9活化,并使下游caspase-3活化。同时,我们观察到缺糖缺氧条件下伴有ONOO~-的过度产生,ONOO~-的特异性抑制剂UA有效阻断了Omi/HtrA2-PED/pea15的稳态失衡及Omi/HtrA2介导的下游内皮细胞凋亡过程。此外,Omi/HtrA2处于凋亡过程的下游事件,因此单纯抑制Omi/HtrA2活性并不能有效逆转凋亡。我们的研究提示,ONOO~-诱导的氧化应激损伤处于其上游环节并占主导地位,ONOO~-通过硝基化反应导致线粒体膜电位的改变,并与粒体内部的Omi/HtrA2发生硝基化反应,进一步在Omi/HtrA2-PED/pea15的稳态失衡起调控作用。鉴于在内皮细胞缺糖缺氧损伤环节中,多因素参与线粒体氧化应激损伤过程,相关诱导机制将结合基因芯片分析结果进行进一步深入研究。
Backgroud:
Stroke or "brain attack" refers to an acute onset of cerebrovascular accident with long-lasting neurological deficits.The brain functions entirely depend on the continuous blood supply of oxygen and glucose.Notably,mitochondrial oxidative stress plays a criticle role in the development of ischemic stroke.We previously reported that an abnormal elevation of intracellular Ca~(2+) triggers activation of various Ca~(2+)-dependent enzymes,accompanying with nitric oxide(NO) and its other reactive species during neurovascular injury.NO along with superoxide radical forms a highly reactive peroxynitrite radical(ONOO~-) leads to membrane lipid peroxidation,protein nitration, as well as endothelial injury.However,little is known about cross-talk between ONOO~-and mitochondrial oxidative stress signaling in endothelial cell death.Therefore,we asked whether cross-talk of ONOO~-/Omi/HtrA2 signaling involve in endothelial cell injury.
Aim:The present study aims to investigate the mechanisms involved in oxygen-glucose deprivation(OGD)-induced endothelial cell death.We first address the morphological changes of endothelial cells following OGD.Secondly,we examine the temporal changes of Omi/HtrA2-PED/pea-15 pathway after OGD by Western blot and immunohistochemical studies.We also determine the protective effect of uric acid (ONOO~- inhibitor) and Ucf-101(Omi/HtrA2 inhibitor) on OGD-induced endothelial cell death.
Methods and results:Human umbilical vein cell line EA.hy926 cell(EA strain) were used in the study,which were subject to OGD for 1 h,3 h,6 h,12 h and 24 h, respectively.The morphological changes of endothelial cells were observed by the light microscope,transmission electron microscopy,as well as JC -1 staining.Moreover, Western-blot and immunohistochemical staining were used to detect the changes in protein levels.Immunoblotting of cytosolic extracts of endothelial cells revealed that Omi/HtrA2 significantly increased 3 h after OGD induction and remained elevated at least until 24 h.By contrast,XIAP(X-linked inhibitor of apoptosis protein) in endothelial cells was observed down-regulated significantly since 3 h after OGD induction. Additionally,we also found that PED/pea15 in endothelial cells was observed down-regulated significantly 6 h after OGD induction.Consistently,the pro-caspase3 and pro-caspase8 protein levels also concomitantly decreased following OGD treatment, as did activation of gelatinase B(MMP-9).Ucf-101treatment effectively inhibited the Omi/HtrA2 release from Mitochondria to the cytosol,moderately reduced ischemia-induced XIAP degradation,whereas did not decrease the overexpression of cleaved-caspase3.Meanwhile,we observed that UA treatment significantly reduced OGD-induced cell death,along with significantly enhanced XIAP and PED/pea 15 expression in same context.
By gene-chip analysis,a total of 1184 genes were differentially expressed in the 6 h after OGD induction compared to the normal ECs,Including 636 up-regulated genes and 548 down-regulated genes.These gene play important roles in the ECs apoptosis, cell cycle regulation,signal transduction and transcription.
Conclusions:our results provide evidence that ONOO--mediated oxidatice stress associated with changes in mitochondrial Omi/HtrA2-XIAP-caspases and Omi/HtrA2-PED/pea15 signaling,which accounts for endothelial cell death.Targeting ONOO~- or Omi/HtrA2-PED/pea15 signaling might be a potential therapeutic strategy against neurovascular unit damage in cerebral ischemia.
以脑血管内皮损伤为病变基础的缺血性脑中风,随着我国社会老龄化进展,发病率和死亡率不断攀升,是严重危害我国人民生命健康的重大疾病。脑血管内皮细胞氧化应激损伤是缺血性脑中风发生发展中的重要病理现象。近年来越来越多的研究显示线粒体在介导细胞凋亡的过程中发挥了极为重要的作用,位于线粒体内外膜间隙凋亡相关分子释放是线粒体介导的凋亡过程中的关键事件,可以引起细胞结构和功能的广泛损害。我们前期研究结果发现缺血性脑中风在发生发展过程中,钙离子、钙调素依存的一氧化氮合酶(Nitric oxide synthase,NOSs)被激活,伴有合成大量一氧化氮(Nitric oxide,NO)生成,NO在体内可与超氧阴离子(Superoxide,O_2~-)快速结合生成过氧亚硝基阴离子(peroxynitrite,ONOO~-),参与脑血管内皮损伤、血脑屏障破坏及细胞凋亡过程。另外,脑血管内皮细胞内存在高密度的线粒体来维持正常的生理活动,线粒体呼吸功能下降是各种脑系疾病的早期现象;神经系统疾病发生发展中线粒体内外膜间隙的凋亡相关分子释放与调控处于线粒体氧化应激损伤的关键部位,已经受到生物医学研究领域的极大关注,但关于酪氨酸蛋白硝基化与线粒体氧化应激损伤的内在关联性研究尚未阐明。根据文献报道,Omi/HtrA2(oocyte maturation inhibitor/the high temperature requirement factor A2)是一种线粒体丝氨酸蛋白水解酶,当细胞受到刺激发生应激反应时线粒体膜通透性增加,并与X连锁凋亡抑制蛋白(X-linked inhibitor ofapoptosis protein,XIAP)等相互作用,继发激活caspase原,最终导致细胞死亡。XIAP的脑保护作用可能与其能够直接与启动性caspase(caspase-9)和效应性caspase(caspase-3、caspase-7)结合并抑制其活性有关。此外,PED/pea-15(phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes)的生物功能的多样性和翻译后调控及对Omi/HtrA2介导的下游细胞凋亡级联反应的制衡作用也被关注。
目的:
通过构建缺糖缺氧(Oxygen-Glucose Deprivation,OGD)内皮细胞损伤模型,探索内皮损伤病理状态下ONOO-介导的酪氨酸硝基化与线粒体氧化应激损伤信号转导的内在关联性及线粒体Omi/HtrA2-PED/pea-15的平衡紊乱对下游细胞XIAP-caspases凋亡级联反应的调控机制,并利用基因芯片技术对氧化应激损伤后的多基因表达变化进行探索性研究,为脑缺血疾病的预防及治疗提供理论性研究依据。
方法:
在OGD条件下,分别处理内皮细胞1 h,3 h,6 h,12 h和24 h,然后通过MTT法分别检测细胞存活分数;通过光镜,透射电镜,JC-1(5,5',6,6'-tetrachloro-1,1',3,3'tetraethylbenzimidazolylcarbocyanine iodide)染色等方法观察经OGD处理不同时间后内皮细胞表型变化;通过流式细胞仪定量测定线粒体膜电位变化;在分子生物学机制方面,通过Western-blot法法及免疫定位染色法检测相关蛋白表达。
OGD处理6 h前,分别加入ONOO~-的清除剂尿酸(Uric acid,UA),Omi/HtrA2的特异性阻断剂ucf-101,观察细胞的存活分数的改变情况;通过Western-blot法检测相关蛋白表达;在检测凋亡率方面,通过Annexin V/PI染料进行流式定量检测。在研究内皮细胞多基因表达变化方面,采用基因芯片技术进行检测。
结果:
光镜、电镜、JC-1结果分别显示经OGD处理后,血管内皮细胞逐渐拉长,变细,细胞间隙变大,细胞核由规则的圆形变成不规则的多边形,并出现染色质边聚现象,线粒体出现肿胀、变形,线粒体膜电位下降明显;Western-blot结果显示内皮细胞经OGD诱导3 h后,细胞质Omi/HtrA2显著显著增加,并且至少在24 h内尤为显著,线粒体Omi/HtrA2随着OGD诱导时间延长而减少。内皮细胞内的XIAP自OGD诱导3 h后显著下调。pro-caspase3和pro-caspase9,PED/pea15蛋白在OGD诱导后随之减少。同时,MMP-9在OGD处理较短时间内(3 h)被激活。免疫定位染色结果显示OGD诱导6 h后线粒体内Omi/HtrA2荧光强度明显减弱。
加入ucf-101后,细胞存活分数与OGD 6 h组相比略有提高,但无显著性差异。加入UA后,细胞存活分数显著提高并且两药合用后效果最为明显;Western-blot结果显示,当加入UA及两药合用后,细胞质Omi/HtrA2、cleaved-caspase 3及硝基化酪氨酸蛋白下调明显,而XIAP、PED/pea15、、pro-caspase-3则出现了显著的上调。间质金属酶(GelatinaseB,MMP-9)和nitrotyrosine蛋白表达也随着UA的加入出现显著的下调趋势。
基因芯片结果显示以caspase家族为代表的多种基因分别出现了上调及下调趋势。
结论:
以上结果提示在缺糖缺氧条件下,诱导了内皮细胞以线粒体依赖的内皮细胞凋亡程序的发生。Omi/HtrA2由线粒体向胞浆外释放增多,胞浆Omi/HtrA2与PED/pea15结合及水解酶作用后将会加速抗凋亡蛋白PED/pea15的降解。随着体内Omi/HtrA2- PED/pea15的稳态失衡,将进一步触发Omi/HtrA2介导的下游内皮细胞凋亡事件,包括抑制XIAP的表达,进而导致capase-9活化,并使下游caspase-3活化。同时,我们观察到缺糖缺氧条件下伴有ONOO~-的过度产生,ONOO~-的特异性抑制剂UA有效阻断了Omi/HtrA2-PED/pea15的稳态失衡及Omi/HtrA2介导的下游内皮细胞凋亡过程。此外,Omi/HtrA2处于凋亡过程的下游事件,因此单纯抑制Omi/HtrA2活性并不能有效逆转凋亡。我们的研究提示,ONOO~-诱导的氧化应激损伤处于其上游环节并占主导地位,ONOO~-通过硝基化反应导致线粒体膜电位的改变,并与粒体内部的Omi/HtrA2发生硝基化反应,进一步在Omi/HtrA2-PED/pea15的稳态失衡起调控作用。鉴于在内皮细胞缺糖缺氧损伤环节中,多因素参与线粒体氧化应激损伤过程,相关诱导机制将结合基因芯片分析结果进行进一步深入研究。
Backgroud:
Stroke or "brain attack" refers to an acute onset of cerebrovascular accident with long-lasting neurological deficits.The brain functions entirely depend on the continuous blood supply of oxygen and glucose.Notably,mitochondrial oxidative stress plays a criticle role in the development of ischemic stroke.We previously reported that an abnormal elevation of intracellular Ca~(2+) triggers activation of various Ca~(2+)-dependent enzymes,accompanying with nitric oxide(NO) and its other reactive species during neurovascular injury.NO along with superoxide radical forms a highly reactive peroxynitrite radical(ONOO~-) leads to membrane lipid peroxidation,protein nitration, as well as endothelial injury.However,little is known about cross-talk between ONOO~-and mitochondrial oxidative stress signaling in endothelial cell death.Therefore,we asked whether cross-talk of ONOO~-/Omi/HtrA2 signaling involve in endothelial cell injury.
Aim:The present study aims to investigate the mechanisms involved in oxygen-glucose deprivation(OGD)-induced endothelial cell death.We first address the morphological changes of endothelial cells following OGD.Secondly,we examine the temporal changes of Omi/HtrA2-PED/pea-15 pathway after OGD by Western blot and immunohistochemical studies.We also determine the protective effect of uric acid (ONOO~- inhibitor) and Ucf-101(Omi/HtrA2 inhibitor) on OGD-induced endothelial cell death.
Methods and results:Human umbilical vein cell line EA.hy926 cell(EA strain) were used in the study,which were subject to OGD for 1 h,3 h,6 h,12 h and 24 h, respectively.The morphological changes of endothelial cells were observed by the light microscope,transmission electron microscopy,as well as JC -1 staining.Moreover, Western-blot and immunohistochemical staining were used to detect the changes in protein levels.Immunoblotting of cytosolic extracts of endothelial cells revealed that Omi/HtrA2 significantly increased 3 h after OGD induction and remained elevated at least until 24 h.By contrast,XIAP(X-linked inhibitor of apoptosis protein) in endothelial cells was observed down-regulated significantly since 3 h after OGD induction. Additionally,we also found that PED/pea15 in endothelial cells was observed down-regulated significantly 6 h after OGD induction.Consistently,the pro-caspase3 and pro-caspase8 protein levels also concomitantly decreased following OGD treatment, as did activation of gelatinase B(MMP-9).Ucf-101treatment effectively inhibited the Omi/HtrA2 release from Mitochondria to the cytosol,moderately reduced ischemia-induced XIAP degradation,whereas did not decrease the overexpression of cleaved-caspase3.Meanwhile,we observed that UA treatment significantly reduced OGD-induced cell death,along with significantly enhanced XIAP and PED/pea 15 expression in same context.
By gene-chip analysis,a total of 1184 genes were differentially expressed in the 6 h after OGD induction compared to the normal ECs,Including 636 up-regulated genes and 548 down-regulated genes.These gene play important roles in the ECs apoptosis, cell cycle regulation,signal transduction and transcription.
Conclusions:our results provide evidence that ONOO--mediated oxidatice stress associated with changes in mitochondrial Omi/HtrA2-XIAP-caspases and Omi/HtrA2-PED/pea15 signaling,which accounts for endothelial cell death.Targeting ONOO~- or Omi/HtrA2-PED/pea15 signaling might be a potential therapeutic strategy against neurovascular unit damage in cerebral ischemia.
引文
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7) Trencia A,Fiory F,Maitan MA,et al.Omi/HtrA2 Promotes Cell Death by Binding and Degrading the Anti-apoptotic Protein ped/pea-15.J Bio Chem.2004;279(45):46566-72.
8) Hart F,Fukunaga K.Beta-amyloid accumulation in neurovascular units following brain embolism.J Pharmacol Sci.2009;111(2):101-9.
9) Han F, Lu YM, Hasegawa H,et al. Inhibition of dystrophin breakdown and endothelial nitric oxide synthaseuncoupling accounts for cytoprotection by 3-[2-[4-(3-Chloro-2-methylphenyl)-1 -piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidaz olylmethyl)-1H-indazole Dihydrochloride 3.5 Hydrate (DY-9760e) in leftventricular hypertrophied mice. J Pharmacol Exp Ther. 2010;332(2):421-8.
10) Cilenti L, Lee Y, Hess S, et al. Characterization of a novel andspecific inhibitor for the pro-apoptotic protease Omi/HtrA2.J Bio Chem. 2003;278(13):11489-94.
11) Rawal A, Muddeshwar A, Biswas S. Effect of Rubia cordifolia, Fagonia cretica linn, and Tinospora cordifolia on free radical generation and lipid peroxidation during oxygen-glucose deprivation in rat hippocampal slices. Biochem Bioph Res Co. 2004;4:11.
12) Bolton C , Wood EG,Scott GS,et al. A Comparative Evaluation of the Response to Peroxynitrite by a Brain Endothelial Cell Line and Control of the Effects by Drug Targeting. Cell Mol Neurobiol. 2009;29(5):707-17.
13) Gersch C,Palii SP, Kim KM,et al. Inactivation of Nitric Oxide by Uric Acid. Nucleosides Nucleotides Nucleic Acids. 2008;27(8):967-78.
14) Dickhout JG,Hossain GS,Pozza LM, et al. Peroxynitrite Causes Endoplasmic Reticulum Stress and Apoptosis in Human Vascular Endothelium Implications in Atherogenesis.Arterioscler Thromb Vasc biol. 2005;25(12):2623-9.
15) Banasiak KJ,Xia Y, Haddad GG. Mechanisms underlying hypoxia-induced neuronal apoptosis. Prog Neurobiol. 2000;62(3):215-49.
16) Walford GA, Moussignac RL,Scribner AW, et al. Hypoxia Potentiates Nitric Oxide-mediated Apoptosis in Endothelial Cells via Peroxynitrite-induced Activation of Mitochondria-dependent and -independent Pathways. J Bio Chem. 2004;279(6):4425-32.
17) Rami A, Bechmann I, Stehle JH. Exploiting endogenous anti-apoptotic proteins for novel therapeutic strategies in cerebral ischemia. Prog Neurobiol. 2008 ;85(3):273-96.
18) An P, Xue YX. Effects of preconditioning on tight junction and cell adhesion of cerebral endothelial cells.Brain Res.. 2009;1272:81-8.
19) Stoica BA,Movsesyan VA, Knoblach SM,et al. Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol. Cell. Neurosci. 2005;29(3):355-71.
20) Liu HR,Gao E, Hu AH, et al. Role of Omi/HtrA2 in Apoptotic Cell Death After Myocardial Ischemia and Reperfusion.Circulation. 2005;111(1):90-6.
21) Mitochondrial Control of Apoptosis. Cell sig. 2003-2007.
22) Bou(?)s D, Hospers GA, Meijer C,,etal.Endothelium in vitro:A review of human vascular endothelial cell lines for blood vessel-ralated research. Angiogensis. 2001;4(2):91-102.
23) Cilenti L, Lee Y, Hess S, et al.Characterization of a Novel and Specific Inhibitor for the Pro-apoptotic Protease Omi/HtrA2. JBio Chem. 2003;278(13):l 1489-94.
24) Goffredo D, Rigamonti D, Zuccato C, et al. Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntingdon's Disease. Pharmacol Res. 2005;52(2):140-50.
25) Klupsch K, Downward J.The protease inhibitor Ucf-101 induces cellular responses independently of its known target,HtrA2/Omi. Cell Death Differ. 2006;13(12):2157-9.
26) Fan YF, Lu CZ, Xie J, et al. Apoptosis inhibition in ischemic brain by intraperitoneal PTD-BIR3-RING (XIAP). Neurochem Int.2006;48(1):50-9.
27) Yu Z,Liu J,Guo S,et al.Neuroglobin-overexpression alters hypoxic response gene experssion in primary neuron culture following oxygen glucose deprivation.Neuroscience.2009;162(2):396-403.
28)王晓棵,王瑾,吕小萍;线粒体丝氨酸蛋白酶Omi/HtrA2与细胞凋亡。生理科学进展,2006,37(3):285-288;
29)刘聪,周晟,阮秋蓉;线粒体促凋亡因子Omi/HtrA2在乳腺癌中的表达及意义。中国组织化学与细胞化学杂志,2005,14(4):434-437;
30)张颖,李树清;线粒体-缺血神经元凋亡信号转导途径。中国微循环,2007(5):343-345;
31)刘乔飞,冯超,隆艳艳;缺氧诱导因子-1与脑缺血缺氧性损伤研究进展。亚太传统医药,2008(4):23-27;
32)张力明;短暂脑缺血发作的诊断与治疗新进展.。中国实用神经疾病杂志,2008(11):137-138;
33)李子广;C-jun氨基末端激酶与脑缺血性损伤。中国现代医药杂志,2008(10):118-120;
34)李桂香,董林森,王运良;全脑缺血后脑损伤的机制。中国实用神经疾病杂志,2008(11):126-129;
35)柳挺,尹金鹏;脑缺血损伤的病理生理机制。包头医学,2008(32):216-218;
36)[李培添;短暂性脑缺血发作新进展。健康大视野·医学分册,2006:45;
1.彭争荣 肖平田 郭华 刘清红.早期高压氧对脑缺血再灌注损伤大鼠神经细胞凋亡及学习记忆的影响[J].中南大学学报:医学版,2009,34(6):468-475.
2.罗春霞 桂莉 张映琦 张艳玲 迟路湘 李露斯 陈康宁.局灶性脑缺血大鼠模型皮层运动诱发电位的研究[J].医学研究生学报,2009,22(9):900-903.
3.董玮 王益光 刘晓霞 芈如珊.神经生长因子对大鼠脑缺血再灌注损伤的保护作用及机制[J].山东医药,2009,49(35):47-48.
4.苏凯.浅谈短暂性脑缺血的中西医防治[J].中华现代中医学杂志,2009,5(5):288-289.
5.高永强 杨巧莲 王伟.大鼠局灶性脑缺血模型制备及取脑方法实验研究[J].包头医学院学报,2009,25(4):6-9.
6.黄宏艳 肖晓山.脑缺血损伤病理及脑细胞凋亡的干预[J].现代医院,2009,9(10):8-11.
7.余芬 袁秀珠.慢性脑缺血大鼠海马中APE、PCNA的表达与神经细胞凋亡[J].山东医药,2009,49(33):1-4.
8.刘敏 郇英 吕涌涛 陈兴旺 赵修敏 苗莉莉.短暂性脑缺血发作患者颈动脉狭窄与认知功能障碍的相关性[J].山东医药,2009,49(33):46-47.
9.刘持善 孙颖 王明雁 郑乃智.短暂性脑缺血发作与脑梗死的相关因素分析[J].山东医药,2009,49(33):50-51.
10.王毅刚 王允 孙晓晶 张探 秦伟 谷淑玲.大鼠线栓法局灶性脑缺血再灌注损伤模型改进的实验研究[J].徐州医学院学报,2009,29(9):568-570.
11.苗明三 马霄 史晶晶.药物提高脑缺血耐受探讨[J].时珍国医国药,2009,20(9):2288-2289.
12.孟冰 闵冬雨 谷淑玲.5种中药对脑缺血缺氧损伤的保护作用[J].徐州医学院学报,2009,29(9):615-617.
13.王继生 周成林 邱宗荫 夏永鹏 李惠芝.大鼠局灶性脑缺血脑组织的比较蛋白质组学研究[J].中国药理学通报,2009,25(8):1077-1080.
14.鲁国 宿少华 曲立新 张振岭 壬秀芳.脑缺血对AD模型大鼠脑组织Aβ1-40表达的影响[J].山东医药,2009,49(31):35-36.
15.王晓哲 白波 张秋玲.脑缺血后脑血流量的变化[J].泰山医学院学报,2009,30(5):391-394.
16.魏永(综述) 梁日生 杨卫忠(审校).围手术期颅内动脉瘤与脑缺血的研究进展[J].中国现代医生,2009(25):21-23.
17.杨德兵 张利宏 马存根.大鼠大脑中动脉缺血再灌注模型的改良[J].中国民族民间医药杂志,2009,18(16):27-28.
18.徐双云 徐家丽 沈怀云 周瑞 孔平.缺氧缺血性脑病新生儿血浆中血管内皮生长因子动态变化的临床意义[J].蚌埠医学院学报,2009,34(8):669-671.
19.李军 娄季宇 杨霄鹏.雌激素对大鼠脑缺血再灌注损伤脑组织NF-κB、iNoS表达和细胞凋亡的影响[J].中国实用神经疾病杂志,2009,12(18):15-16.
20.范红斌 邱丽颖 李英.脑缺血再灌注时心肾损伤的形态学变化及代谢特征[J].中国老年学杂志,2009,29(16):2039-2041.
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22.杨冀萍 刘怀军 刘瑞春 李荚.Caspase-3,-9,-12及c-jun在VEGF介导的神经保护作用中的调控机制[J].脑与神经疾病杂志,2009,17(2):114-117.
23.潘晓峰 陈国华 邵卫.短暂性脑缺血发作患者DSA影像学特征分析[J].内科急危重症杂志,2009(4):186-187.
24.王德任 张世洪 刘鸣.短暂性脑缺血发作后早期卒中风险预测模型的评价[J].内科急危重症杂志,2009(4):182-185.
25.倪立新 吕学海 袁建新.短暂性脑缺血发作与颅内-外血管狭窄的关系[J].河北医药,2009(15):1907-1909.
26.马小亚 王美纳 王玉虎 梁维薇.舒络抗脑缺血与降压作用研究[J].医药导报,2009,28(8):993-995.
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28.王改梅 刘喆 曾超.过氧化物酶体增殖物激活受体-γ脑缺血抗炎神经保护作用机制与中药研究新思路[J].中国中医药信息杂志,2009,16(8):92-94.
29.张世娟 卢洁 张苗.颈内动脉狭窄性短暂性脑缺血发作的磁共振波谱研究[J].卒中与神经疾病,2009(4):206-209.
30.杜斌 邱丽颖 李英 范红斌 程建青.增龄对大鼠局灶性脑缺血/再灌注损伤的影响[J].中国老年学杂志,2009,29(15):1930-1932.
31.李志亮.三种药物联合治疗短暂脑缺血发作24例临床分析[J].实用心脑肺血管病杂志,2009,17(7):587-588.
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33.燕虹.短暂性脑缺血发作对后继脑梗死影响的研究[J].中西医结合心脑血管病杂志,2009,7(8):988-990.
34.李小刚.短暂性脑缺血发作的重新定义和病理生理学的探讨[J].中国卒中杂志,2009(6):490-494.
35.毕齐 王力锋 宋哲.短暂性脑缺血发作研究的历史、现状与未来[J].中国卒中杂志,2009(6):448-453.
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38.杨磊 胡文立.短暂性脑缺血发作与卒中、心血管疾病和外周动脉疾病之间的关系[J].中国卒中杂志,2009(6):495-499.
39.张全贵 张宁男楠 李德欣.短暂性脑缺血发作进展至脑梗死的研究[J].中国医学创新,2009,6(20):159-160.
40.陈艳秋.日常习性与脑血管疾病[J].健康人生,2009(4):48-48.
41.李春颖 曲娴 李东盈.反复脑缺血再灌注对小鼠学习记忆和脑内氧化损伤的影响[J].北华大学学报:自然科学版,2009,10(4):322-326.
42.王乃东 谭兰.脑缺血与阿尔茨海默病关系的研究现状[J].山东医药,2009,49(21):107-108.
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44.赵凤霞.短暂性脑缺血发作研究进展[J].医学理论与实践,2009,22(7):780-781,783.
45.叶宗果 严浩成 潘红英.中风口服液对老龄大鼠急性脑缺血实验研究[J].广东科技,2009(12):77-78.
46.张伟 陈晓君 姜岩.试论短暂性脑缺血发作和脑梗死诊断评价系统[J].中国医药指南:学术版,2009,7(11):186-188.
47.王金娥.短暂性脑缺血发作的临床观察[J].中西医结合心脑血管病杂志,2009,7(6):748-749.
48.郭森 朱江 赵淑敏(审校).针刺治疗实验性脑缺血研究进展[J].承德医学院学报,2009,26(2):193-195.
49.徐晓燕 王浩 张峰 高允生 朱玉云.苦参水提物对低氧模型小鼠的保护作用[J].泰山医学院学报,2009(2):-.
50.潘洪平 莫祥兰 杨嘉珍 李高.葛根素对脑缺血损伤的影响[J].中国药师,2009(6):704-706.
2) Christopher B,Elizabeth G.Wood(?),et al.A Comparative Evaluation of the Response to Peroxynitrite by a Brain Endothelial Cell Line and Control of the Effects by Drug Targeting.Cell Mol Neurobiol.2009;29(5):707-17。
3) Althaus J,Siegelin MD,Dehghani F,et al.The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion.Neurochem lnt.2007;50(1):172-80.
4) Xu J,He L,Ahmed SH,et al.Oxygen-Glucose Deprivation Induces Inducible Nitric Oxide Synthase and Nitrotyrosine Expression in Cerebral Endothelial Cells.Stroke.2000;31(7):1744-51.
5) Han F,Aliraie A,Shioda N,et al.Accumulation of beta-amyloid in the brain microvessels accompanies increased hyperphosphorylated tau proteins following microsphere embolism in aged rats.Neuroscience.2008;153(2):414-27.
6) Han F,Shirasaki Y,Fukunaga K,et al.Microsphere embolism-induced endothelial nitric oxide synthase expression mediates disruption of the blood-brain barrier in rat brain.J Neurochem.2006;99(1):97-106.
7) Trencia A,Fiory F,Maitan MA,et al.Omi/HtrA2 Promotes Cell Death by Binding and Degrading the Anti-apoptotic Protein ped/pea-15.J Bio Chem.2004;279(45):46566-72.
8) Hart F,Fukunaga K.Beta-amyloid accumulation in neurovascular units following brain embolism.J Pharmacol Sci.2009;111(2):101-9.
9) Han F, Lu YM, Hasegawa H,et al. Inhibition of dystrophin breakdown and endothelial nitric oxide synthaseuncoupling accounts for cytoprotection by 3-[2-[4-(3-Chloro-2-methylphenyl)-1 -piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidaz olylmethyl)-1H-indazole Dihydrochloride 3.5 Hydrate (DY-9760e) in leftventricular hypertrophied mice. J Pharmacol Exp Ther. 2010;332(2):421-8.
10) Cilenti L, Lee Y, Hess S, et al. Characterization of a novel andspecific inhibitor for the pro-apoptotic protease Omi/HtrA2.J Bio Chem. 2003;278(13):11489-94.
11) Rawal A, Muddeshwar A, Biswas S. Effect of Rubia cordifolia, Fagonia cretica linn, and Tinospora cordifolia on free radical generation and lipid peroxidation during oxygen-glucose deprivation in rat hippocampal slices. Biochem Bioph Res Co. 2004;4:11.
12) Bolton C , Wood EG,Scott GS,et al. A Comparative Evaluation of the Response to Peroxynitrite by a Brain Endothelial Cell Line and Control of the Effects by Drug Targeting. Cell Mol Neurobiol. 2009;29(5):707-17.
13) Gersch C,Palii SP, Kim KM,et al. Inactivation of Nitric Oxide by Uric Acid. Nucleosides Nucleotides Nucleic Acids. 2008;27(8):967-78.
14) Dickhout JG,Hossain GS,Pozza LM, et al. Peroxynitrite Causes Endoplasmic Reticulum Stress and Apoptosis in Human Vascular Endothelium Implications in Atherogenesis.Arterioscler Thromb Vasc biol. 2005;25(12):2623-9.
15) Banasiak KJ,Xia Y, Haddad GG. Mechanisms underlying hypoxia-induced neuronal apoptosis. Prog Neurobiol. 2000;62(3):215-49.
16) Walford GA, Moussignac RL,Scribner AW, et al. Hypoxia Potentiates Nitric Oxide-mediated Apoptosis in Endothelial Cells via Peroxynitrite-induced Activation of Mitochondria-dependent and -independent Pathways. J Bio Chem. 2004;279(6):4425-32.
17) Rami A, Bechmann I, Stehle JH. Exploiting endogenous anti-apoptotic proteins for novel therapeutic strategies in cerebral ischemia. Prog Neurobiol. 2008 ;85(3):273-96.
18) An P, Xue YX. Effects of preconditioning on tight junction and cell adhesion of cerebral endothelial cells.Brain Res.. 2009;1272:81-8.
19) Stoica BA,Movsesyan VA, Knoblach SM,et al. Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol. Cell. Neurosci. 2005;29(3):355-71.
20) Liu HR,Gao E, Hu AH, et al. Role of Omi/HtrA2 in Apoptotic Cell Death After Myocardial Ischemia and Reperfusion.Circulation. 2005;111(1):90-6.
21) Mitochondrial Control of Apoptosis. Cell sig. 2003-2007.
22) Bou(?)s D, Hospers GA, Meijer C,,etal.Endothelium in vitro:A review of human vascular endothelial cell lines for blood vessel-ralated research. Angiogensis. 2001;4(2):91-102.
23) Cilenti L, Lee Y, Hess S, et al.Characterization of a Novel and Specific Inhibitor for the Pro-apoptotic Protease Omi/HtrA2. JBio Chem. 2003;278(13):l 1489-94.
24) Goffredo D, Rigamonti D, Zuccato C, et al. Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntingdon's Disease. Pharmacol Res. 2005;52(2):140-50.
25) Klupsch K, Downward J.The protease inhibitor Ucf-101 induces cellular responses independently of its known target,HtrA2/Omi. Cell Death Differ. 2006;13(12):2157-9.
26) Fan YF, Lu CZ, Xie J, et al. Apoptosis inhibition in ischemic brain by intraperitoneal PTD-BIR3-RING (XIAP). Neurochem Int.2006;48(1):50-9.
27) Yu Z,Liu J,Guo S,et al.Neuroglobin-overexpression alters hypoxic response gene experssion in primary neuron culture following oxygen glucose deprivation.Neuroscience.2009;162(2):396-403.
28)王晓棵,王瑾,吕小萍;线粒体丝氨酸蛋白酶Omi/HtrA2与细胞凋亡。生理科学进展,2006,37(3):285-288;
29)刘聪,周晟,阮秋蓉;线粒体促凋亡因子Omi/HtrA2在乳腺癌中的表达及意义。中国组织化学与细胞化学杂志,2005,14(4):434-437;
30)张颖,李树清;线粒体-缺血神经元凋亡信号转导途径。中国微循环,2007(5):343-345;
31)刘乔飞,冯超,隆艳艳;缺氧诱导因子-1与脑缺血缺氧性损伤研究进展。亚太传统医药,2008(4):23-27;
32)张力明;短暂脑缺血发作的诊断与治疗新进展.。中国实用神经疾病杂志,2008(11):137-138;
33)李子广;C-jun氨基末端激酶与脑缺血性损伤。中国现代医药杂志,2008(10):118-120;
34)李桂香,董林森,王运良;全脑缺血后脑损伤的机制。中国实用神经疾病杂志,2008(11):126-129;
35)柳挺,尹金鹏;脑缺血损伤的病理生理机制。包头医学,2008(32):216-218;
36)[李培添;短暂性脑缺血发作新进展。健康大视野·医学分册,2006:45;
1.彭争荣 肖平田 郭华 刘清红.早期高压氧对脑缺血再灌注损伤大鼠神经细胞凋亡及学习记忆的影响[J].中南大学学报:医学版,2009,34(6):468-475.
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