摘要
研究背景：
蛛网膜下腔出血(subarachnoid hemorrhage, SAH)的高死亡率和高致残率主要与早期脑损伤(Early brain injury, EBI)和接下来出现的脑血管痉挛(Cerebral vasospasm, CVS)有关。尽管现在有许多针对CAS的治疗方法,但成功治疗的情况并不多见,而脑血管痉挛的发生机制仍是困扰大多数研究者的难题之一。
哺乳动物雷帕霉素靶蛋白(Mammalian target of rapamycin, mTOR)是一种丝氨酸/苏氨酸激酶,在调节细胞的生长、增殖、存活和蛋白质合成中起着重要的作用。mTOR是PI3K/PKB (protein kinase B, PKB)信号通路下游的一个效应蛋白,包括2种下游底物蛋白：70S核糖体6激酶S6K1(p70S6kinase protein, S6K1)和4E-BP1(4E-binding protein1,4E-BP1)。
作为一种蛋白激酶,mTOR在细胞内形成了两种主要不同的多蛋白复合物,分别为mTORCl和mTORC2。雷帕霉素(rapamycin, mTOR抑制剂)仅能抑制mTORCl。AZD8055是一种新型的mTOR抑制剂,能抑制：mTORC1和mTORC2,进而抑制mTOR的活性。但mTOR抑制剂在血管痉挛中的作用尚未见报道。
目的：
采用犬两次注血法制作蛛网膜下腔出血(SAH)模型,旨为研究mTOR通路蛋白在SAH后发生CVS时在血管壁,尤其在血管平滑肌细胞上的表达情况,观察它们在调节脑血管痉挛中的作用。应用mTOR复合物1抑制剂(雷帕霉素)和mTOR复合物1/mTOR复合物2(mTOR Cl/mTOR C2)抑制剂(AZD8055),通过对mTOR通路下游蛋白P70S6K1和4E-BP1,以及增殖细胞核抗原(proliferating cell nuclear antigen, PCNA)等能够与增殖活动相关因子的表达情况观察,以研究mTOR信号通路中的重要因子,如mTCR、P70S6K1和4E-BP1在蛛网膜下腔出血病程中的作用及可能的引发CVS的机理。
材料与方法：
实验动物为30只比格犬,雌雄不分,体重15～20kg。随机平均分成5组,即假实验组(Sham, n=6),蛛网膜下腔注血组(SAH,n=6),蛛网膜下腔注血组结合应用二甲基亚砜(Dimethyl sulfoxide, DMSO)组(SAH+DMSO, n=6),蛛网膜下腔注血组结合应用雷帕酶素(2mg/kg体重,SAH+RAPA, mTORCl抑制剂,n=6)和蛛网膜下腔注血组结合应用AZD8055(2mg/kg体重,一种mTORCl/mTORC2抑制剂)组(SAH+AZD8055, n=6)。动物采用乙酰丙嗪、阿托品和甲苯噻嗪全身麻醉后,在实验当天(d0)和实验后的第2天(48h),穿刺针刺破寰枕膜,放出适量脑脊液,将自体股动脉的血液注射到蛛网膜下腔(小脑延髓池),建立犬的蛛网膜下腔的两次出血模型,在实验的当天(d0)和第实验后的第7天(d7)行血管造影,观测动物的临床行为学改变、基底动脉的直径。取基底动脉行组织学观察、免疫组织化学染色和Western blot,检测基底动脉的形态学变化及其血管壁中mTOR、P70S6K1、4E-BP1和PCNA的表达。
结果：
肉眼观察,蛛网膜下腔内有大量的凝血块分布于脑干的腹侧Willis环的周围,即出现在延髓腹侧的延池、中脑的脚间池和视交叉池,以及基底动脉的周围。血管造影图像中,7天(d7)的基底动脉的平均直径,与假实验组相比,SAH组和SAH+DMSO组均出现了严重的基底动脉痉挛p<0.05)。而SAH组和SAH+DMSO组的7天(d7)与0天(d0)的基底动脉的平均直径的百分比分别是34.3±19.84%和38.4±10.26%,而假实验组的基底动脉的平均直径百分比是93.9±5.01%。在SAH+RAPA组和SAH+AZD8055组可见中度的血管痉挛,SAH+RAPA组和SAH+AZD8055组的7天(d7)与0天(d0)基底动脉的平均直径的百分比分别是62.3±15.92%和65.2±10.34%,与SAH组和SAH+DMSO组相比,可见显著性差异(p<0.05)。
在临床行为学饮食评分方面：从第2天到第4天,与SAH组相比,SAH+RAPA组和SAH+AZD8055组动物的饮食情况明显好转,在实验后的5天至7天间,仍可见显著的统计学差异(p<0.05,ANOVA)。但SAH+RAPA组和SAH+AZD8055组之间未见统计学差异(p>0.05,ANOVA)。在活动度评分方面：在实验后的6天至7天,与SAH组和SAH+DMSO组相比,SAH+RAPA组和SAH+AZD8055组动物的活动度明显增强,可见显著的统计学差异(p<0.05,ANOVA)o但SAH+RAPA组和SAH+AZD8055组之间未见统计学差异(p>0.05,ANOVA)。在神经功能障碍评分方面：大多数的实验动物并没有表现出明显地神经功能障碍的症状和体征,在所观察的各组间的统计学差异不明显(p>0.05)。
通过对基底动脉的HE染色后的形态学观察,SAH组可见明显的血管痉挛,即基底动脉发生了明显的收缩,管壁增厚,管腔直径明显缩小,内皮细胞和血管平滑肌由于收缩而变短,内弹力膜弯曲呈锯齿状,部分内皮细胞失去了连续性并从内弹力膜上脱离。SAH+RAPA和SAH+AZD8055组动物的基底动脉可见中等程度的血管痉挛。而假实验组(Sham)动物的基底动脉未见血管痉挛的表现。
与假实验组的动物相比,在SAH组和SAH+DMSO组中,基底动脉各层中,尤其是平滑肌细胞中的mTOR、P70S6K1、4E-BP1和PCNA的免疫组化染色均很明显。用雷帕霉素和AZD8055治疗的两组动物中,mTOR、P70S6K1、4E-BP1和PCNA的染色则都有明显的减弱。双荧光和三荧光免疫组化染色显示,基底动脉的各层中,尤其是在平滑肌层中,均可见mTOR、P70S6K1和PCNA的表达。双色和三色免疫荧光图像提示：mTOR与P70S6K1和PCNA共存。使用高变焦放大摄像,染色证实mTOR、P70S6K1和PCNA共同定位于血管平滑肌细胞中。
Western blotting显示了血管痉挛动脉中(?)mTOR通路分子标志物的表达,与假实验组相比,在蛋白电泳条带上,可见SAH组和SAH+DMSO组动物中,痉挛的基底动脉中的mTOR、P70S6K1、4E-BP1和PCNA的表达均有明显增加。雷帕霉素和AZD8055明显抑制了mTOR、P70S6K1、4E-BP1和PCNA的表达,可见显著地统计学差异(p<0.05)。而在两种抑制剂治疗组之间、SAH组和SAH+DMSO组之间,mTOR、P70S6K1、4E-BP1和PCNA的表达未见明显的统计学差异。
结论：
本研究显示：在SAH后,mTOR通路的活化可能通过启动血管平滑肌细胞的增殖,从而参与了基底动脉痉挛的调控；在基底动脉中观察到了mTOR通路的mTOR、P70S6K1和4E-BP1与PCNA等多种因子的表达；应用mTOR抑制剂----雷帕霉素和AZD8055后,mTOR、P70S6K1、4E-BP1和PCNA等因子的表达出现明显的变化,并可明显解除基底动脉的痉挛,改善动物的饮食和活动度等临床表现。而受(?)mTOR蛋白信号通路调节的血管平滑肌细胞的增殖,在蛛网膜下腔出血的脑血管痉挛中发挥着重要的作用。通过抑制(?)mTOR通路的活性,脑血管痉挛出现缓解,这可能是治疗蛛网膜下腔出血脑血管痉挛的重要途径。
Background:
Subarachnoid hemorrhage (SAH) is a subtype of devastating stroke that can lead to a variety of consequences including early brain injury and cerebral vasospasm. Despite promising therapeutic approaches, successful treatment following SAH remains inadequate. This is partly attributed to the poor strategic approach when dealing with cerebral ischemia as a result of cerebral vasospasm (CVS), one of the major consequences seen following an SAH. Although much has been discovered with regards to the mechanistic understanding of CVS, it continues to puzzle most scientists.
Mammalian target of rapamycin (mTOR) pathway is a serine/threonine protein kinase that plays a vital role in regulating growth, proliferation, survival, and protein synthesis among cells. As a member of the PI3K family (phosphatidylinositol3-kinase-related kinase), mTOR has been shown to orchestrate the phosphorylation of key downstream proteins including P70S6K1(proteins p70ribosomal S6kinase) and4E-BP1(eukaryotic initiation factor4E binding protein1).
As a protein kinase, mTOR forms two distinct multiprotein complexes called mTORC1and mTORC2. The mTORC1is inhibited by rapamycin. On the other hand, AZD8055is a potent and selective mTOR kinase inhibitor that acts on both the C1and C2prototypes, along with other downstream substrates. However, mTOR inhibitors role in cerebral vasospasm has not been investigated.
Subject:
In the present study, we investigated the role of the mTOR protein kinase following SAH brain injury in canines, specifically investigating its position as a key orchestrator of cerebral vasospasm. We used an mTOR C1inhibitor (rapamycin) and an mTOR C1/mTOR C2simultaneous inhibitor (AZD8055) to explore potential mechanistic theories while measuring direct anti-proliferation activity through P70S6K1,4E-BP1and PCNA (proliferating cell nuclear antigen) expression.
Materials and Methods:
Thirty male/female beagle dogs weighing15to20kg were housed in a12-hour light/dark cycle at a controlled temperature and humidity with free access to food and water. All animals were randomly assigned to one of five groups-Sham (n=6), SAH (n=6), SAH+DMSO (Dimethyl sulfoxide; n=6), SAH+RAPA (Rapamycin,2mg/kg, mTORC1inhibitor, n=6), and SAH+AZD8055(2mg/kg, a mTORC1/mTORC2inhibitor, n=6). Animals were anesthetized with a cepromazine, atropine, and xylazine cocktail. An established canine double-hemorrhage model of SAH was used by injecting autologous arterial blood into the cisterna magna on days0and2. Angiography was performed at days0and7. Iodixanol was injected to acquire an image of the basilar artery. After angiography,0.5mL/kg of blood taken from the femoral artery was injected into the cisterna magna at day0and then repeated at day2. Three behavioral examinations were modified from a previous study and performed daily after SAH to record appetite, activity, and neurological deficits. In groups, histology, immunohistochemistry, and Western blot of mTOR, P70S6K1,4E-BP1and PCNA (proliferating cell nuclear antigen) in the basilar arteries were examined.
Results:
Severe SAH was particularly pronounced around the Circle of Willis and along the ventral brainstem following injury. The animals in the SAH and SAH+DMSO groups developed severe vasospasm (p<0.05vs Sham) as shown by angiography on day7. The mean values of the residual diameter of the basilar artery on day7, as a percentage of that on day0, was34.3±19.84%in SAH,38.4±10.26in SAH+DMSO, and93.9±5.01%in Sham respectively. In the SAH+RAPA and SAH+AZD8055groups, a moderate vasospasm,62.3±15.92%and65.2±10.34%was observed (p <0.05versus SAH and SAH+DMSO).
The behavior scores are shown that the appetite score in both Rapamycin and AZD8055treatment groups were better than in the SAH group from days2to4, even though statistical significance was achieved at day5to7(p<0.05, ANOVA). No statistical difference was found between SAH+Rapamycin and SAH+AZD8055groups (p>0.05, ANOVA). The activity scores in Rapamycin and AZD8055treatment groups were significantly better than in the SAH and SAH+DMSO groups (p<0.05, ANOVA) at day6and7. Most animals did not show any signs of serious neurological deficits which was evident by the lack of statistical significance among the observed groups.
Morphological vasospasm was observed in animals assigned to the SAH group. This was characterized by corrugation of the internal elastic lamina, contraction of smooth muscle cells, and increased thickness of the vessel wall, which was a sign of severe vasospasm. Treatment with vehicle of DMSO did not get any improvement. Moderate vasospasm was observed in the SAH+RAPA and SAH+AZD8055animal groups. Sham animals were the only group that did not show any signs of vasospasm.
In the SAH and SAH+DMSO groups, notable immunohistochemical staining of mTOR, P70S6K1,4E-BP1, and PCNA were observed across all layers of the basilar artery, especially among smooth muscle cells compared to Sham animals. Animals treated with both Rapamycin and AZD8055where characterized by a notable reduction in staining of mTOR, P70S6K1,4E-BP1, and PCNA. Double and triple fluorescence immunohistochemistry staining revealed a marked elevation in staining with mTOR, P70S6K1and PCNA across all layers of the basilar artery, especially in smooth muscle layer; merging double and triple of these images indicated that mTOR co-localized with P70S6K1and PCNA. Using a high magnification zoom, the stain demonstrated that mTOR, P70S6K1and PCNA co-localized in the smooth muscle cells.
Western blotting revealed that the expressions of mTOR, P70S6K1,4E-BP1, and PCNA in the basilar artery samples in Sham, SAH, SAH+DMSO, SAH+RAPA and SAH+AZD8055groups. When the values in the sham basilar arteries were regarded as100%, there was a significant enhancement of expression of mTOR, P70S6K1,4E-BP1, and PCNA in the spastic basilar arteries from the SAH and SAH+DMSO animals sacrificed at day7(p<0.05vs. Sham). Treatment with Rapamycin and AZD8055significantly suppressed the expression of mTOR, P70S6K1,4E-BP1, and PCNA (p<0.05vs. Sham). No significant differences were noted between the two inhibitor treatment groups and between the SAH and SAH+DMSO groups.
Conclusion:
Our study suggests that vascular smooth muscle cell proliferation mediated by the mTOR pathway may in fact play a significant role in cerebral vasospasm following SAH injury. The expressions of mTOR, P70S6K1and4E-BP1were accompanied with PCNA in the basilar arteries. By blocking the activation of the mTOR pathway, the attenuation of angiographic vasospasm was attributed to the anti-proliferation that ensues following cerebral vasospasm.
The mTOR molecular signaling pathway plays a significant role in cerebral vasospasm following SAH, and the inhibition of the mTOR pathway has the potential to become an attractive strategy to treat vasospasm following SAH. However, More studies evaluating the exact mechanistic target of the mTOR pathway within vasospasm are warranted.
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