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中华妇幼临床医学杂志(电子版) ›› 2020, Vol. 16 ›› Issue (01) : 32 -41. doi: 10.3877/cma.j.issn.1673-5250.2020.01.005

所属专题： 文献；

论著

Sestrin2参与调控新生鼠缺氧缺血性脑损伤后细胞自噬机制
马慧顺1, 陈洪菊1,†(), 唐军1   
  1. 1. 四川大学华西第二医院儿科、出生缺陷与相关妇儿疾病教育部重点实验室，成都　610041
  • 收稿日期:2018-12-29 修回日期:2019-08-30 出版日期:2020-02-01
  • 通信作者: 陈洪菊

Mechanisms of Sestrin2 regulating cell autophagy after hypoxic-ischemic brain damage in neonatal rats

Huishun Ma1, Hongju Chen1,†(), Jun Tang1   

  1. 1. Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
  • Received:2018-12-29 Revised:2019-08-30 Published:2020-02-01
  • Corresponding author: Hongju Chen
  • About author:
    Corresponding author: Chen Hongju, Email:
  • Supported by:
    National Natural Science Foundation of China(81501304, 81330016, 81630038, 81771634, 81842011); National Clinical Key Professional Fund(1311200003303); Youth Technology Innovation Team Fund of Sichuan Province(2016TD0002)
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引用本文：

马慧顺, 陈洪菊, 唐军. Sestrin2参与调控新生鼠缺氧缺血性脑损伤后细胞自噬机制[J/OL]. 中华妇幼临床医学杂志(电子版), 2020, 16(01): 32-41.

Huishun Ma, Hongju Chen, Jun Tang. Mechanisms of Sestrin2 regulating cell autophagy after hypoxic-ischemic brain damage in neonatal rats[J/OL]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2020, 16(01): 32-41.

目的

探讨应激诱导蛋白Sestrin2，对新生SD大鼠缺氧缺血性脑损伤(HIBD)后神经细胞自噬作用及其机制。

方法

选择80只新生10日龄SD大鼠(受试鼠)为研究对象。对其中60只建立HIBD模型，并根据这60只受试鼠缺氧缺血(HI)后的处死时间点，将其分别纳入HI后4、8、12、24、72 h组(除HI后24 h组为20只受试鼠外，其余均为10只)。对剩余的20只受试鼠仅分离右颈总动脉，既不结扎右颈总动脉，亦不进行缺氧处理，处死时间对应于HI后24 h组，纳入假手术组(n＝20)。①对HI后4、8、12、24、72 h组及假手术组(各组受试鼠均为10只)，获取海马组织标本后，采用蛋白质印迹法，检测Sestrin2、肝酶B1(LKB1)、磷酸化LKB1(p-LKB1)、AMP活化蛋白激酶(AMPK)、磷酸化AMPK(p-AMPK)、哺乳动物雷帕霉素靶蛋白(mTOR)、磷酸化mTOR(p-mTOR)、自噬相关蛋白Beclin1、微管相关蛋白1轻链(LC)3及凋亡相关蛋白活化型天冬氨酸特异性半胱氨酸蛋白酶(CC)3在受试鼠海马组织中的相对表达量，并采用方差分析及最小显著性差异(LSD)-t法，对上述指标进行6组之间，或HI后4、8、12、24、72 h组分别与假手术组的组间比较。②对于HI后24 h组与假手术组各组剩余的10只受试鼠，获取大脑标本后，采用免疫组织化学SP法，检测海马组织中p-AMPK、LC3及CC3表达水平，包括积分吸光度(IA)值测定及染色结果，并采用t检验，对这3项指标的IA值进行2组比较。本研究通过四川大学动物实验伦理委员会批准[审批文号：SYXK(川)2013-185]。

结果

①蛋白质印迹法检测结果显示，HI后4、8 h组受试鼠海马组织中p-mTOR及CC3水平，均分别高于假手术组；HI后12、24 h组受试鼠海马组织中Sestrin2、p-LKB1、p-AMPK、p-mTOR、Beclin1、LC3及CC3水平，均分别高于假手术组；HI后72 h组受试鼠海马组织中Sestrin2及CC3水平，均高于假手术组；并且这些差异均有统计学意义(P<0.05)。其中，HI后8 h组受试鼠海马组织中p-mTOR水平最高，HI后24 h组受试鼠海马组织中Sestrin2、p-LKB1、p-AMPK、Beclin1、LC3及CC3水平均最高。6组受试鼠海马组织中LKB1、AMPK及mTOR水平比较，以及HI后4、8、12、24、72 h组受试鼠海马组织中LKB1、AMPK及mTOR水平分别与假手术组比较，差异均无统计学意义(P>0.05)。②免疫组织化学SP法IA值检测结果显示，HI后24 h组受试鼠海马组织中p-AMPK、LC3及CC3表达水平分别为(24 106±2 393)、(41 892±4 094)、(61 670±4 696)，均高于假手术组的(15 593±1 575)、(18 941±2 131)、(20 279±1 912)，并且差异有统计学意义(t＝9.398、P＝0.035，t＝15.723、P<0.001，t＝25.812、P<0.001)。免疫组织化学SP法染色结果显示，HI后24 h组受试鼠海马组织中p-AMPK、LC3及CC3呈阳性细胞的表达水平较高。

结论

10日龄新生SD大鼠发生HIBD时，其大脑海马组织中Sestrin2可能通过LKB1/AMPK/mTOR信号通路，参与调节神经细胞自噬及凋亡。

关键词: Sestrin 2蛋白，大鼠, 信号传导, 缺氧缺血，脑, 自噬, 细胞凋亡, 印迹法，蛋白质, 大鼠，Sprague-Dawley, 动物，新生
Objective

To investigate the role and mechanism of stress-inducing protein Sestrin2 in the regulation of nerve cell autophagy in neonatal rats after hypoxic-ischemic brain damage (HIBD).

Methods

Eighty postnatal 10 days newborn Sprague-Dawley rats (test rats) were selected as research subjects. For the 60 test rats, the HIBD model was established; then according to the sacrifice time of 4, 8, 12, 24, 72 h after hypoxia-ischemia (HI), 60 test rats were included into 4, 8, 12, 24, 72 h after HI group, which was 20 cases in 24 h after HI group and the rest were 10 cases in each group. For the remaining 20 test rats, the right common carotid artery was separated but not ligated, no hypoxia treatment was performed and the sacrifice time corresponded to 24 h after HI group, and they were included into sham operation group (n=20). ① After obtained hippocampal tissue samples of rats in 4, 8, 12, 24, 72 h after HI group and sham operation group (10 cases in each group), western blotting was used to detect relative expression levels of Sestrin2, liver kinase B1 (LKB1), phosphorylated LKB1 (p-LKB1), adenosine monophosphate-activated protein kinase (AMPK), phosphorylated AMPK (p-AMPK), mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), autophagy-related protein Beclin1, microtubule-associated protein 1 light chain (LC)3, and apoptosis-related protein cleaved-caspase 3 (CC3) in hippocampus tissue of rats, and analysis of variance and least significant difference (LSD)-t methods were used to compare the above indicators among 6 groups or between 4, 8, 12, 24, 72 h after HI groups and sham operation group, respectively. ② After obtained cerebrum samples of remaining rats in 24 h after HI group and sham operation group (10 cases in each group), immunohistochemistry SP method was used to detect the expression levels of p-AMPK, LC3 and CC3, including integrated absorbance (IA) values and staining results in rats′ hippocampus tissue. And using t test to compare the IA values of the three indicators between two groups. This study was approved by the Animal Experimental Ethics Committee of Sichuan University [Approval No. SYXK (Chuan) 2013-185].

Results

① The results of western blotting showed that the levels of p-mTOR and CC3 in rats′ hippocampus tissue of 4 h and 8 h after HI groups were higher than those in sham operation group, respectively; the levels of Sestrin2, p-LKB1, p-AMPK, p-mTOR, Beclin1, LC3 and CC3 in rats′ hippocampus tissue of 12 h and 24 h after HI groups were higher than those in sham operation group, respectively; the levels of Sestrin2 and CC3 in rats′ hippocampus tissue of 72 h group after HI group were higher than those in sham operation group; and all of these differences were statistically significant (P<0.05). Among them, the level of p-mTOR was the highest in rats′ hippocampus tissue of 8 h after HI group; and the highest levels of Sestrin2, p-LKB1, p-AMPK, Beclin1, LC3 and CC3 in rats′ hippocampus tissue were all in 24 h after HI group. There were no significant differences among 6 groups, also between 4, 8, 12, 24, 72 h after HI groups with sham operation group, respectively, in levels of LKB1, AMPK and mTOR in rats′ hippocampus tissue (P>0.05). ② IA value detected results of immunohistochemical SP method showed that the expression levels of p-AMPK, LC3 and CC3 in rats′ hippocampus tissue of 24 h after HI group were (24 106±2 393), (41 892±4 094), (61 670±4 696), respectively, which were higher than those of (15 593±1 575), (18 941±2 131) and (20 279±1 912) in sham operation group, and the differences were statistically significant (t=9.398, P=0.035; t=15.723, P<0.001; t=25.812, P<0.001). Immunohistochemical SP method staining results showed that the expression level of p-AMPK, LC3 and CC3 positive cells were higher in rats′ hippocampus tissue of 24 h after HI group.

Conclusion

When HIBD occurs in postnatal 10 days newborn SD rats, the Sestrin2 in hippocampus tissue may be involved in the regulation of nerve cell autophagy and apoptosis via LKB1/AMPK/mTOR signaling pathway.

Key words: Sestrin 2 protein, rat, Signal transduction, Hypoxia-ischemia, brain, Autophagy, Apoptosis, Blotting, western, Rats, Sprague-Dawley, Animals, newborn
表1 6组受试鼠海马组织中各蛋白相对表达量比较(±s)
组别 鼠数 Sestrin2 LKB1 p-LKB1 AMPK p-AMPK
①HI后4 h组 10 0.21±0.03 1.44±0.11 0.44±0.09 1.90±0.18 0.51±0.08
②HI后8 h组 10 0.19±0.03 1.39±0.08 0.38±0.07 1.79±0.10 0.45±0.06
③HI后12 h组 10 0.41±0.06 1.48±0.13 0.70±0.10 1.89±0.17 0.80±0.06
④HI后24 h组 10 0.50±0.06 1.41±0.14 1.09±0.12 1.80±0.19 1.01±0.09
⑤HI后72 h组 10 0.40±0.06 1.37±0.14 0.53±0.08 1.78±0.12 0.66±0.09
⑥假手术组 10 0.17±0.03 1.38±0.11 0.39±0.07 1.76±0.12 0.45±0.05
总体比较 ? ? ? ? ? ?
? F值 ? 82.781 1.154 93.335 1.360 92.327
? P值 ? <0.001 0.344 <0.001 0.254 <0.001
多重比较的P值a ? ? ? ? ? ?
? ① vs ⑥ ? 0.052 0.254 0.222 0.059 0.133
? ② vs ⑥ ? 0.252 0.835 0.802 0.663 0.903
? ③ vs ⑥ ? 0.023 0.082 0.034 0.082 0.025
? ④ vs ⑥ ? 0.014 0.545 0.018 0.562 0.013
? ⑤ vs ⑥ ? 0.025 0.818 0.086 0.847 0.076
组别 鼠数 mTOR p-mTOR Beclin1 LC3 CC3
①HI后4 h组 10 1.34±0.09 0.44±0.06 0.23±0.04 0.33±0.04 0.29±0.04
②HI后8 h组 10 1.29±0.15 0.83±0.07 0.20±0.07 0.31±0.05 0.36±0.06
③HI后12 h组 10 1.27±0.12 0.61±0.05 0.37±0.07 0.61±0.04 0.51±0.05
④HI后24 h组 10 1.23±0.11 0.55±0.07 0.63±0.05 0.76±0.06 0.69±0.08
⑤HI后72 h组 10 1.25±0.09 0.38±0.04 0.30±0.06 0.53±0.07 0.50±0.06
⑥假手术组 10 1.26±0.14 0.36±0.05 0.19±0.03 0.29±0.03 0.22±0.04
总体比较 ? ? ? ? ? ?
? F值 ? 0.898 85.534 88.384 143.492 82.375
? P值 ? 0.490 <0.001 <0.001 <0.001 <0.001
多重比较的P值a ? ? ? ? ? ?
? ① vs ⑥ ? 0.138 0.011 0.117 0.121 0.014
? ② vs ⑥ ? 0.575 <0.001 0.580 0.438 <0.001
? ③ vs ⑥ ? 0.751 <0.001 0.044 0.036 <0.001
? ④ vs ⑥ ? 0.696 <0.001 <0.001 <0.001 <0.001
? ⑤ vs ⑥ ? 0.928 0.562 0.068 0.057 <0.001
图1 6组受试鼠海马组织中各蛋白电泳图(蛋白质印迹法)
表2 2组受试鼠海马组织中p-AMPK、LC3及CC3积分吸光度值比较(±s)
组别 鼠数 p-AMPK LC3 CC3
HI后24 h组 10 24 106±2 393 41 892±4 094 61 670±4 696
假手术组 10 15 593±1 575 18 941±2 131 20 279±1 912
t值 ? 9.398 15.723 25.812
P值 ? 0.035 <0.001 <0.001
图2 10日龄SD大鼠海马组织免疫组织化学图(SP法，高倍镜)[图2A、2B、2C分别为HI后24 h组p-AMPK、LC3、CC3呈阳性的细胞表达水平较高(箭头所示)；图2D、2E、2F分别为假手术组p-AMPK、LC3、CC3呈阳性的细胞均为微量表达]
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