Cystatin C防治大鼠SAH后早期脑血管痉挛及其与自噬相关性的初步研究
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摘要
目的：探讨SD大鼠蛛网膜下腔出血(Subarachnoid Hemorrhage，SAH)后自噬在基底动脉壁的表达情况，研究经枕大池注入半胱氨酸蛋白酶抑制剂C（Cystatin C，CysC）对SD大鼠蛛网膜下腔出血后早期脑血管痉挛(Cerebral Vasospasm，CVS)的干预作用，并分析其与自噬的相关性。
材料和方法：五十只SD大鼠随机分为对照组（A组）、蛛网膜下腔出血组（B组）、安慰剂组（C组）、Cystatin C低浓度治疗组(DL组)和Cystatin C高浓度治疗组（DH组），每组10只。对照组在枕大池注入生理盐水但不注血，SAH组采用枕大池一次注血法制作SAH模型，治疗组在注血前30分钟经枕大池注入Cystatin C水溶剂0.1ml（其中低浓度和高浓度组剂量分别为2μg/0.1ml和10μg/0.1ml），而安慰剂组则在注血前30分钟经枕大池注入等量生理盐水。各组于术后48小时处死动物取脑基底动脉及周围脑干组织行病理检查，测定基底动脉血管内径周长和血管壁厚度，以此评价有无脑血管痉挛及程度。应用自噬标记抗体LC3和Beclin-1对各组基底动脉组织进行Western blot分析。
结果：SAH组和安慰剂组中大鼠基底动脉内径周长较对照组明显缩短（P＜0.01），血管壁厚度明显增加（P＜0.01），可见管腔狭窄，内膜皱褶，内皮细胞肿胀、变形，部分坏死，平滑肌细胞肥大、排列紊乱。CysC治疗组中基底动脉内径周长增大，管壁增厚程度减轻以及CVS值下降，与SAH组及安慰剂组对比有显著性差异（P＜0.01），在高浓度治疗组更明显，与低浓度组相比有统计学意义（P＜0.05）。Westernblot结果显示自噬相关指标LC3和Beclin-1在对照组的基底动脉壁是低表达的，在SAH组及安慰剂组表达明显增高，其LC3/GAPDH、Beclin-1/GAPDH值与对照组比较有统计学意义（P＜0.05）。而在CysC治疗组，LC3和Beclin-1的表达进一步增高，以CysC高浓度组更明显，与SAH组及安慰剂组比较有显著性差异（P＜0.01）；CysC高浓度组与CysC低浓度组相比有统计学意义（P＜0.05）。
结论：1、通过构建大鼠枕大池一次注血模型，能够观察到基底动脉发生明显的细胞形态改变、管壁的增厚以及管腔的狭窄，提示SAH后存在CVS。2、自噬在正常大鼠基底动脉壁的表达是低水平的。3、SAH后自噬在基底动脉壁被激活，提示自噬可能作为一种保护机制参与了CVS的病理及生理过程。4、经枕大池注入Cystatin C能诱导自噬在基底动脉壁的高表达，对CVS有一定的防治作用，并且这种作用与Cystatin C的浓度及其诱导的自噬的水平存在正相关性。
Objective: To investigate the expressions of autophagy in BA(basilar artery) wallsfollowing subarachnoid hemorrhage (SAH) in rats,and to study the effect of cystatin C inthe prevention of cerebral vasospasm （CVS）and its relationships to autophagy.
Methods:50health male Sprague-Dawley(SD) rats were assigned randomly intofollowing groups: Control group(injected normal sodium into cisterna magna only), SAHgroup, Vehicle group, Cystatin C therapy group（divided into high and low concentrationgroups）(n=10，respectively). All SAH animals were subjected to injection of0.3ml fresharterial, nonheparinized blood into Cisterna magna to establish SAH model in rats.30minutes before the blood injection, a amount of0.1ml different doses of the Cystatin C(2μg/0.1ml or10μg/0.1ml) was administered directly into the cisterna magna in the Cys-tatin C therapy groups, while Vehicle animals received an equal volume of NS into thecisterna magna.48hours later, we observed morphological changes and the expression ofautophagy in BA walls by pathological section and Western blot analysis.
Results: The inner perimeter of basal arteries (BA) in SAH group and Vehiclegroup gets smaller, and the wall thickness of basal arteries becomes thicker than controlgroup(P＜0.01), we can note the luminal narrowing, icreased wall thickness, and corruga-tion of the tunica intima in the above two groups. Compared with SAH and Vehicle groups,the inner perimeter of BA in treatment group was expanded and thickness of BA wallswere decreased with a statistical difference (P <0.01), especially in high concentrationgroup（Compared with low concentration group, P <0.05）. Western blot results showed:the expression of autophagy in BA walls was low in control group, the activity of auto-phagy was significantly increased in the rats of SAH and vehicle groups（Compared with
control group, P <0.05）,the increased activity of autophagy was further markedlyupregulated by CysC treatment, especially in high concentration group（Compared withSAH and low concentration group, P <0.01and P <0.05,respectively）.
Conclusions:1.The pathological changes including morphological changes, lu-minal narrowing, icreased wall thickness in BA wall suggest that CVS happens after SAH.2. The level of expression of autophagy is low in the normal control group.3. The in-creased expression of autophagy in the BA walls following SAH suggests that autophagymay participate the pathological course of CVS.4. Activation of autophagy induced byCysC resulted in attenuation of CVS in SAH models, and this effect was paralleled withthe intensity of autophagy in the BA wall induced by CysC.
材料和方法：五十只SD大鼠随机分为对照组（A组）、蛛网膜下腔出血组（B组）、安慰剂组（C组）、Cystatin C低浓度治疗组(DL组)和Cystatin C高浓度治疗组（DH组），每组10只。对照组在枕大池注入生理盐水但不注血，SAH组采用枕大池一次注血法制作SAH模型，治疗组在注血前30分钟经枕大池注入Cystatin C水溶剂0.1ml（其中低浓度和高浓度组剂量分别为2μg/0.1ml和10μg/0.1ml），而安慰剂组则在注血前30分钟经枕大池注入等量生理盐水。各组于术后48小时处死动物取脑基底动脉及周围脑干组织行病理检查，测定基底动脉血管内径周长和血管壁厚度，以此评价有无脑血管痉挛及程度。应用自噬标记抗体LC3和Beclin-1对各组基底动脉组织进行Western blot分析。
结果：SAH组和安慰剂组中大鼠基底动脉内径周长较对照组明显缩短（P＜0.01），血管壁厚度明显增加（P＜0.01），可见管腔狭窄，内膜皱褶，内皮细胞肿胀、变形，部分坏死，平滑肌细胞肥大、排列紊乱。CysC治疗组中基底动脉内径周长增大，管壁增厚程度减轻以及CVS值下降，与SAH组及安慰剂组对比有显著性差异（P＜0.01），在高浓度治疗组更明显，与低浓度组相比有统计学意义（P＜0.05）。Westernblot结果显示自噬相关指标LC3和Beclin-1在对照组的基底动脉壁是低表达的，在SAH组及安慰剂组表达明显增高，其LC3/GAPDH、Beclin-1/GAPDH值与对照组比较有统计学意义（P＜0.05）。而在CysC治疗组，LC3和Beclin-1的表达进一步增高，以CysC高浓度组更明显，与SAH组及安慰剂组比较有显著性差异（P＜0.01）；CysC高浓度组与CysC低浓度组相比有统计学意义（P＜0.05）。
结论：1、通过构建大鼠枕大池一次注血模型，能够观察到基底动脉发生明显的细胞形态改变、管壁的增厚以及管腔的狭窄，提示SAH后存在CVS。2、自噬在正常大鼠基底动脉壁的表达是低水平的。3、SAH后自噬在基底动脉壁被激活，提示自噬可能作为一种保护机制参与了CVS的病理及生理过程。4、经枕大池注入Cystatin C能诱导自噬在基底动脉壁的高表达，对CVS有一定的防治作用，并且这种作用与Cystatin C的浓度及其诱导的自噬的水平存在正相关性。
Objective: To investigate the expressions of autophagy in BA(basilar artery) wallsfollowing subarachnoid hemorrhage (SAH) in rats,and to study the effect of cystatin C inthe prevention of cerebral vasospasm （CVS）and its relationships to autophagy.
Methods:50health male Sprague-Dawley(SD) rats were assigned randomly intofollowing groups: Control group(injected normal sodium into cisterna magna only), SAHgroup, Vehicle group, Cystatin C therapy group（divided into high and low concentrationgroups）(n=10，respectively). All SAH animals were subjected to injection of0.3ml fresharterial, nonheparinized blood into Cisterna magna to establish SAH model in rats.30minutes before the blood injection, a amount of0.1ml different doses of the Cystatin C(2μg/0.1ml or10μg/0.1ml) was administered directly into the cisterna magna in the Cys-tatin C therapy groups, while Vehicle animals received an equal volume of NS into thecisterna magna.48hours later, we observed morphological changes and the expression ofautophagy in BA walls by pathological section and Western blot analysis.
Results: The inner perimeter of basal arteries (BA) in SAH group and Vehiclegroup gets smaller, and the wall thickness of basal arteries becomes thicker than controlgroup(P＜0.01), we can note the luminal narrowing, icreased wall thickness, and corruga-tion of the tunica intima in the above two groups. Compared with SAH and Vehicle groups,the inner perimeter of BA in treatment group was expanded and thickness of BA wallswere decreased with a statistical difference (P <0.01), especially in high concentrationgroup（Compared with low concentration group, P <0.05）. Western blot results showed:the expression of autophagy in BA walls was low in control group, the activity of auto-phagy was significantly increased in the rats of SAH and vehicle groups（Compared with
control group, P <0.05）,the increased activity of autophagy was further markedlyupregulated by CysC treatment, especially in high concentration group（Compared withSAH and low concentration group, P <0.01and P <0.05,respectively）.
Conclusions:1.The pathological changes including morphological changes, lu-minal narrowing, icreased wall thickness in BA wall suggest that CVS happens after SAH.2. The level of expression of autophagy is low in the normal control group.3. The in-creased expression of autophagy in the BA walls following SAH suggests that autophagymay participate the pathological course of CVS.4. Activation of autophagy induced byCysC resulted in attenuation of CVS in SAH models, and this effect was paralleled withthe intensity of autophagy in the BA wall induced by CysC.
引文
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[1] Rothoerl R D, Ringel F. Molecular mechanisms of cerebral vasospasm followinganeurysmal SAH[J]. Neurological Research,2007,29(7):636-642.
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