缺血后处理对缺血再灌注后海马CA1区神经细胞内蛋白聚集的影响
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摘要
一过性的全脑缺血在临床上主要在短暂的呼吸心跳骤停、心肺分流手术等情况下发生。在大鼠模拟人的一过性脑缺血模型中，研究人员发现海马CA1区的损伤并非在脑血流停止时即已形成，而是在再灌注后，由于CA1区细胞的死亡，从而导致了大鼠的出现记忆及空间认知功能的障碍。同样，在临床研究中研究人员也发现海马CA1区的病变可导致人的认知功能下降。这些研究说明，在一过性缺血再灌注损伤发生后，抑制CA1区的神经细胞损伤或死亡可以有效地改善预后。
蛋白聚集是一种发生在细胞内、外的由于异常蛋白发生聚积的一种细胞生物学现象。直到Hu等研究发现脑缺血再灌注后神经细胞内出现异常蛋白及错误折叠蛋白的聚集，同时这种毒性蛋白聚集的产物是导致神经细胞死亡的主要原因，人们才逐渐的发现异常蛋白的聚积在Parkinson’s病和Alzheimer’s病等神经退行性病变中发挥关键性的作用。尽管一些研究提出了钙离子超载及氧化应激等一些机制，但蛋白聚积仍然是缺血再灌注损伤最重要的病理生理机制之一。这些异常聚积的蛋白不能正常的工作，它们可以锚靠在细胞内的膜性结构上，如线粒体、内质网，导致细胞失去正常的功能甚至死亡。因此，抑制蛋白聚集物的形成，是降低缺血再灌注后海马CA1区神经细胞死亡的直接方式。
近年来研究发现，缺血后处理对局灶或全脑缺血再灌注所致的神经细胞延迟性死亡的保护作用与其能够降低氧化应激反应、激活细胞内的信号传导途径密切相关。缺血后处理是在脑缺血结束后再灌注开始时对再灌注进行一系列指定的有规则的机械性的终止，然后才给予脑组织充分的再灌注。最近研究表明，缺血后处理也能对抗神经组织的缺血再灌注损伤，这就为临床应用提供了必要的理论依据。缺血后处理对脑缺血再灌注所致的神经细胞延迟性死亡的保护作用与其能够抑制炎症、降低氧化应激反应、激活细胞内的信号传导途径或抑制细胞凋亡有关，但是其对脑缺血再灌注过程中蛋白聚集的影响尚不清楚。
实验目的：探讨缺血后处理对短暂性脑缺血再灌注后海马CA1区蛋白聚集的影响及其可能的机制。
实验方法：制备大鼠全脑缺血再灌注模型，分为假手术组、缺血组及缺血后处理组。缺血后处理方法为缺血结束后恢复脑血流30s再阻断30s为1个循环，共3个循环。采用HE染色光镜下观察缺血再灌注后CA1区的神经细胞形态变化情况，存活的神经细胞在光镜下用细胞计数法计数；体外用荧光分光计法用20S-蛋白酶体荧光底物Succinyl-LLVY-AMC来测定蛋白酶体活性的改变；用分光光度计法测量蛋白氧化产物羟基含量而分析蛋白氧化水平；免疫组化及激光共聚焦显微镜观察泛素在CA1区神经细胞内的分步情况；免疫蛋白印迹实验（Western blot）分析蛋白集聚、蛋白酶体、热体克蛋白70、热休克蛋白40在不同脑缺血处理组细胞内的表达情况。
实验结果：
组织学检查结果显示，通过缺血后处理的干预存活的神经细胞在CA1区的比例从5.21%±1.21%上升至55.32%±5.34%。在激光共聚焦显微镜图片中，缺血后处理组中泛素标记的蛋白积聚明显较缺血组减少。Western blot分析显示，与假手术组相比，再灌注12h，24h，48h，缺血组的蛋白集聚分别增加了32.12±4.87，41.86±4.71，34.51±5.18倍。然而，在缺血后处理组，蛋白积聚水平在上述时间点上却降低了2.84±0.97，13.72±2.31，14.37±2.42倍。进一步的研究显示，在缺血再灌注损伤病理生理过程中，缺血后处理抑制了蛋白质羰基的衍生，从而提高了蛋白酶体的活性，进一步增加了分子伴侣Hsp70的表达，并抑制了Hsp40表达的下降。
实验结论：
在一过性脑缺血再灌注损伤中，缺血后处理能够显著的抑制大鼠海马CA1区神经细胞的损伤，这与其抑制异常蛋白的积聚有密切关系。
Transient global cerebral ischemia is a clinical outcome related to cardiac arrest,cardiopulmonary bypass surgery and other situations that deprives the oxygen and glucose inbrain during a short period. In the rat model simulating human transient global cerebralischemia, it was found that neurons in the hippocampus CA1region were severely damagedduring the period of reperfusion, which leaded to the impairment of rats’ memory or spatiallearning. Similarly, in human being, a clinical study showed that the lesion in CA1regioncould result in place learning deficit. These indicate that protection of neuronal injury or deathin the CA1region would improve the prognosis of the patients with transient ischemia andreperfusion.
Protein aggregation is a biological phenomenon in which abnormal proteins accumulateand clump together either intra-or extracellularly. Until Hu et al found that abnormal proteinsaccumulated in the neurons destined to die after transient cerebral ischemia [6], proteinaggregation had been thought to play a pivotal role in neurodegenerative disease such asParkinson’s disease and Alzheimer’s disease. Currently, as well as other mechanisms such ascalcium overload and oxidative stress, protein aggregation is also regarded as one of theimportant pathological features of cerebral ischemia and reperfusion. Although theseaggregated proteins cannot function normally, they could stick to the intracellular membranestructures and result in cell losing its normal function and dying in the end. Therefore,aggregated proteins should be rescued or eliminated in order to keep neurons alive andfunction normally.
Recently, it had been reported that ischemic postconditioning has protective effects onneuronal injury or death caused by focal or global ischemia and reperfusion[9,10]. Ischemicpostconditioning is defined as a series of rapid intermittent interruptions of blood flow in theearly phase of reperfusion that mechanically alters the hydrodynamics of reperfusion. It could be performed before re-establishment of blood supply to brain, which makes it become afeasible method used potentially in clinical practice. Despite studies showed that ischemicpostconditioning could rescue neuronal injury or death via inhibiting inflammation,suppressing oxidative stress or preventing apoptosis, the effects of ischemic postconditioningon protein aggregation are still unclear. Studying the alteration of protein aggregation wouldcontribute further to clarify the protective mechanism of ischemic postconditioning. Therefore,in the current study, we investigated the role of ischemic postconditioning in proteinaggregation by using rat model of transient global ischemia.
Objective:
To investigate the effect of ischemic postconditioning on protein aggregation caused bytransient ischemia and reperfusion and to clarify its underlying mechanism.
Methods:
Two-vessel-occluded transient global ischemia rat model was used. The rats in ischemicpostconditioning group were subjected to three cycles of30-s/30-s reperfusion/clamping after15min of ischemia. Neuronal death in the CA1region was observed by hematoxylin-eosinstaining, and number of live neurons was assessed by cell counting under a light microscope.Succinyl-LLVY-AMC was used as substrate to assay proteasome activity in vitro. Proteincarbonyl content was spectrophotometrically measured to analyze protein oxidization.Immunochemistry and laser scanning confocal microscopy were used to observe thedistribution of ubiquitin in the CA1neurons. Western Blot was used to analyze thequantitative alterations of protein aggregates, proteasome, Hsp70and Hsp40in cellularfractions under different ischemic conditions. Results
Histological examination showed that the percentage of live neurons in the CA1regionwas elevated from5.21%±1.21%to55.32%±5.34%after administration of ischemicpostconditioning （P=0.0087）. Western Blot analysis showed that the protein aggregates inthe ischemia group was32.12±4.87,41.86±4.71and34.51±5.18times higher than that in thesham group at reperfusion12h,24h and48h, respectively. However, protein aggregates werealleviated significantly by ischemic postconditioning to2.84±0.97,13.72±2.13and14.37±2.42times at each indicated time point （P=0.000032,0.0000051and0.0000082）. Laser scanning confocal images showed ubiquitin labeled protein aggregates could not bediscerned in the ischemic postconditioning group. Further study showed that ischemicpostconditioning suppressed the production of carbonyl derivatives, elevated proteasomeactivity that was damaged by ischemia and reperfusion, increased the expression of chaperoneHsp70, and maintained the quantity of chaperone Hsp40.
Conclusion:
Ischemic postconditioning could rescue significantly neuronal death in the CA1regioncaused by transient ischemia and reperfusion, which is closely associated with suppressing theformation of protein aggregation.
蛋白聚集是一种发生在细胞内、外的由于异常蛋白发生聚积的一种细胞生物学现象。直到Hu等研究发现脑缺血再灌注后神经细胞内出现异常蛋白及错误折叠蛋白的聚集，同时这种毒性蛋白聚集的产物是导致神经细胞死亡的主要原因，人们才逐渐的发现异常蛋白的聚积在Parkinson’s病和Alzheimer’s病等神经退行性病变中发挥关键性的作用。尽管一些研究提出了钙离子超载及氧化应激等一些机制，但蛋白聚积仍然是缺血再灌注损伤最重要的病理生理机制之一。这些异常聚积的蛋白不能正常的工作，它们可以锚靠在细胞内的膜性结构上，如线粒体、内质网，导致细胞失去正常的功能甚至死亡。因此，抑制蛋白聚集物的形成，是降低缺血再灌注后海马CA1区神经细胞死亡的直接方式。
近年来研究发现，缺血后处理对局灶或全脑缺血再灌注所致的神经细胞延迟性死亡的保护作用与其能够降低氧化应激反应、激活细胞内的信号传导途径密切相关。缺血后处理是在脑缺血结束后再灌注开始时对再灌注进行一系列指定的有规则的机械性的终止，然后才给予脑组织充分的再灌注。最近研究表明，缺血后处理也能对抗神经组织的缺血再灌注损伤，这就为临床应用提供了必要的理论依据。缺血后处理对脑缺血再灌注所致的神经细胞延迟性死亡的保护作用与其能够抑制炎症、降低氧化应激反应、激活细胞内的信号传导途径或抑制细胞凋亡有关，但是其对脑缺血再灌注过程中蛋白聚集的影响尚不清楚。
实验目的：探讨缺血后处理对短暂性脑缺血再灌注后海马CA1区蛋白聚集的影响及其可能的机制。
实验方法：制备大鼠全脑缺血再灌注模型，分为假手术组、缺血组及缺血后处理组。缺血后处理方法为缺血结束后恢复脑血流30s再阻断30s为1个循环，共3个循环。采用HE染色光镜下观察缺血再灌注后CA1区的神经细胞形态变化情况，存活的神经细胞在光镜下用细胞计数法计数；体外用荧光分光计法用20S-蛋白酶体荧光底物Succinyl-LLVY-AMC来测定蛋白酶体活性的改变；用分光光度计法测量蛋白氧化产物羟基含量而分析蛋白氧化水平；免疫组化及激光共聚焦显微镜观察泛素在CA1区神经细胞内的分步情况；免疫蛋白印迹实验（Western blot）分析蛋白集聚、蛋白酶体、热体克蛋白70、热休克蛋白40在不同脑缺血处理组细胞内的表达情况。
实验结果：
组织学检查结果显示，通过缺血后处理的干预存活的神经细胞在CA1区的比例从5.21%±1.21%上升至55.32%±5.34%。在激光共聚焦显微镜图片中，缺血后处理组中泛素标记的蛋白积聚明显较缺血组减少。Western blot分析显示，与假手术组相比，再灌注12h，24h，48h，缺血组的蛋白集聚分别增加了32.12±4.87，41.86±4.71，34.51±5.18倍。然而，在缺血后处理组，蛋白积聚水平在上述时间点上却降低了2.84±0.97，13.72±2.31，14.37±2.42倍。进一步的研究显示，在缺血再灌注损伤病理生理过程中，缺血后处理抑制了蛋白质羰基的衍生，从而提高了蛋白酶体的活性，进一步增加了分子伴侣Hsp70的表达，并抑制了Hsp40表达的下降。
实验结论：
在一过性脑缺血再灌注损伤中，缺血后处理能够显著的抑制大鼠海马CA1区神经细胞的损伤，这与其抑制异常蛋白的积聚有密切关系。
Transient global cerebral ischemia is a clinical outcome related to cardiac arrest,cardiopulmonary bypass surgery and other situations that deprives the oxygen and glucose inbrain during a short period. In the rat model simulating human transient global cerebralischemia, it was found that neurons in the hippocampus CA1region were severely damagedduring the period of reperfusion, which leaded to the impairment of rats’ memory or spatiallearning. Similarly, in human being, a clinical study showed that the lesion in CA1regioncould result in place learning deficit. These indicate that protection of neuronal injury or deathin the CA1region would improve the prognosis of the patients with transient ischemia andreperfusion.
Protein aggregation is a biological phenomenon in which abnormal proteins accumulateand clump together either intra-or extracellularly. Until Hu et al found that abnormal proteinsaccumulated in the neurons destined to die after transient cerebral ischemia [6], proteinaggregation had been thought to play a pivotal role in neurodegenerative disease such asParkinson’s disease and Alzheimer’s disease. Currently, as well as other mechanisms such ascalcium overload and oxidative stress, protein aggregation is also regarded as one of theimportant pathological features of cerebral ischemia and reperfusion. Although theseaggregated proteins cannot function normally, they could stick to the intracellular membranestructures and result in cell losing its normal function and dying in the end. Therefore,aggregated proteins should be rescued or eliminated in order to keep neurons alive andfunction normally.
Recently, it had been reported that ischemic postconditioning has protective effects onneuronal injury or death caused by focal or global ischemia and reperfusion[9,10]. Ischemicpostconditioning is defined as a series of rapid intermittent interruptions of blood flow in theearly phase of reperfusion that mechanically alters the hydrodynamics of reperfusion. It could be performed before re-establishment of blood supply to brain, which makes it become afeasible method used potentially in clinical practice. Despite studies showed that ischemicpostconditioning could rescue neuronal injury or death via inhibiting inflammation,suppressing oxidative stress or preventing apoptosis, the effects of ischemic postconditioningon protein aggregation are still unclear. Studying the alteration of protein aggregation wouldcontribute further to clarify the protective mechanism of ischemic postconditioning. Therefore,in the current study, we investigated the role of ischemic postconditioning in proteinaggregation by using rat model of transient global ischemia.
Objective:
To investigate the effect of ischemic postconditioning on protein aggregation caused bytransient ischemia and reperfusion and to clarify its underlying mechanism.
Methods:
Two-vessel-occluded transient global ischemia rat model was used. The rats in ischemicpostconditioning group were subjected to three cycles of30-s/30-s reperfusion/clamping after15min of ischemia. Neuronal death in the CA1region was observed by hematoxylin-eosinstaining, and number of live neurons was assessed by cell counting under a light microscope.Succinyl-LLVY-AMC was used as substrate to assay proteasome activity in vitro. Proteincarbonyl content was spectrophotometrically measured to analyze protein oxidization.Immunochemistry and laser scanning confocal microscopy were used to observe thedistribution of ubiquitin in the CA1neurons. Western Blot was used to analyze thequantitative alterations of protein aggregates, proteasome, Hsp70and Hsp40in cellularfractions under different ischemic conditions. Results
Histological examination showed that the percentage of live neurons in the CA1regionwas elevated from5.21%±1.21%to55.32%±5.34%after administration of ischemicpostconditioning （P=0.0087）. Western Blot analysis showed that the protein aggregates inthe ischemia group was32.12±4.87,41.86±4.71and34.51±5.18times higher than that in thesham group at reperfusion12h,24h and48h, respectively. However, protein aggregates werealleviated significantly by ischemic postconditioning to2.84±0.97,13.72±2.13and14.37±2.42times at each indicated time point （P=0.000032,0.0000051and0.0000082）. Laser scanning confocal images showed ubiquitin labeled protein aggregates could not bediscerned in the ischemic postconditioning group. Further study showed that ischemicpostconditioning suppressed the production of carbonyl derivatives, elevated proteasomeactivity that was damaged by ischemia and reperfusion, increased the expression of chaperoneHsp70, and maintained the quantity of chaperone Hsp40.
Conclusion:
Ischemic postconditioning could rescue significantly neuronal death in the CA1regioncaused by transient ischemia and reperfusion, which is closely associated with suppressing theformation of protein aggregation.
引文
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