circ_HIPK3靶向miR-381-3p/ZNF217轴调控Aβ诱导的海马神经元功能和形态

doi:10.11958/20231013

天津医药 ›› 2024, Vol. 52 ›› Issue (3): 237-244.doi: 10.11958/20231013

circ_HIPK3靶向miR-381-3p/ZNF217轴调控Aβ诱导的海马神经元功能和形态

李伟¹(), 陈亮¹, 吕昌迎²^,^△()

1.济南市中西医结合医院脑病一科（邮编271100），2.脑病三科

收稿日期:2023-07-27 修回日期:2023-09-18 出版日期:2024-03-15 发布日期:2024-03-13
通讯作者: ^△E-mail：lvchangying@sohu.com
作者简介:李伟（1979），男，副主任医师，主要从事脑血管病、神经变性病基础与临床方面研究。E-mail：elgamk@163.com
基金资助:
山东省中医药科技项目(Q-2022003)

circ_HIPK3 regulates function and morphology of Aβ induced hippocampal neurons by targeting miR-381-3p/ZNF217 axis

LI Wei¹(), CHEN Liang¹, LYU Changying²^,^△()

1. Department 1 of Encephalopathy, 2. Department 3 of Encephalopathy, Jinan Integrated Traditional Chinese and Western Medicine Hospital, Jinan 271100, China

Received:2023-07-27 Revised:2023-09-18 Published:2024-03-15 Online:2024-03-13
Contact: ^△E-mail: lvchangying@sohu.com

李伟, 陈亮, 吕昌迎. circ_HIPK3靶向miR-381-3p/ZNF217轴调控Aβ诱导的海马神经元功能和形态[J]. 天津医药, 2024, 52(3): 237-244.

LI Wei, CHEN Liang, LYU Changying. circ_HIPK3 regulates function and morphology of Aβ induced hippocampal neurons by targeting miR-381-3p/ZNF217 axis[J]. Tianjin Medical Journal, 2024, 52(3): 237-244.

摘要/Abstract

摘要：

目的分析环状RNA同源结构域相互作用蛋白激酶3（circ_HIPK3）靶向miR-381-3p/锌指蛋白217（ZNF217）轴对β淀粉样蛋白（Aβ）诱导的海马神经元功能和形态的影响。方法制备新生大鼠海马神经元，分为对照组、Aβ组、si NC1组、si HIPK3组、si HIPK3+inhibitor NC组、si HIPK3+miR-381-3p inhibitor组、si HIPK3+miR-381-3p inhibitor+si NC2组、si HIPK3+miR-381-3p inhibitor+si ZNF217组，除对照组外其余组均通过40 μmol/L Aβ_1~42诱导。qRT-PCR法测定海马神经元circ_HIPK3、miR-381-3p、ZNF217 mRNA表达，透射电镜观察细胞形态，CCK-8法测定海马神经元存活率，Hochesst 33342法测定海马神经元凋亡，流式细胞仪检测海马神经元内Ca²⁺荧光强度，Western blot法测定海马神经元磷酸化Tau蛋白（P-Tau）、B淋巴细胞瘤-2（Bcl-2）、Bcl-2相关X蛋白（Bax）、胱天蛋白酶-3（Caspase-3）、ZNF217蛋白表达，双萤光素酶报告基因分析miR-381-3p与circ_HIPK3、ZNF217靶向关系。结果对照组海马神经元结构正常，胞核形态正常，线粒体、内质网无病理改变；Aβ组海马神经元呈退行性改变，核形态异常，膜内陷，可见大量线粒体肿胀，胞浆内含大量脂滴空泡；与Aβ组相比，si HIPK3组海马神经元结构部分恢复；与si HIPK3组相比，si HIPK3+miR-381-3p inhibitor组海马神经元结构损伤严重；与si HIPK3+miR-381-3p inhibitor组相比，si HIPK3+miR-381-3p inhibitor+si ZNF217组海马神经元结构损伤减轻。与对照组相比，Aβ组海马神经元circ_HIPK3、ZNF217 mRNA和蛋白表达、凋亡率、Ca²⁺荧光强度、P-Tau、Bax、Caspase-3蛋白表达升高，miR-381-3p表达、存活率、Bcl-2蛋白表达降低（P<0.05）；与Aβ组相比，si HIPK3组海马神经元circ_HIPK3、ZNF217 mRNA和蛋白表达、凋亡率、Ca²⁺荧光强度、P-Tau、Bax、Caspase-3蛋白表达降低，miR-381-3p表达、存活率、Bcl-2蛋白表达升高（P<0.05）；与si HIPK3组相比，si HIPK3+miR-381-3p inhibitor组海马神经元circ_HIPK3、ZNF217 mRNA和蛋白表达、凋亡率、Ca²⁺荧光强度、P-Tau、Bax、Caspase-3蛋白表达升高，miR-381-3p水平、存活率、Bcl-2蛋白表达降低（P<0.05）；与si HIPK3+miR-381-3p inhibitor组相比，si HIPK3+miR-381-3p inhibitor+si ZNF217组海马神经元ZNF217 mRNA和蛋白表达水平、凋亡率、Ca²⁺荧光强度、P-Tau、Bax、Caspase-3蛋白表达降低，存活率、Bcl-2蛋白表达升高（P<0.05）；miR-381-3p与circ_HIPK3、ZNF217均靶向结合。结论 circ_HIPK3沉默可能通过调控miR-381-3p/ZNF217轴改善Aβ诱导的海马神经元结构功能损伤。

关键词: 海马, 神经元, Tristetraprolin蛋白, circ_HIPK3, miR-381-3p, ZNF217

Abstract:

Objective To analyze the influence of cyclic RNA homologous domain interacting protein kinase 3 (circ_HIPK3) on function and morphology of myloid β-protein (Aβ) induced hippocampal neurons by targeting miR-381-3p/zinc finger protein 217 (ZNF217) axis. Methods Hippocampal neurons of neonatal rats were prepared and divided into the control group, the Aβ group, the si NC1 group, the si HIPK3 group, the si HIPK3+inhibitor NC group, the si HIPK3+miR-381-3p inhibitor group, the si HIPK3+miR-381-3p inhibitor+si NC2 group and the si HIPK3+miR-381-3p inhibitor+si ZNF217 group. Except the control group, all the other groups were modeled by 40 μmol/L Aβ_1~42. qRT-PCR was used to determine the circ of hippocampal neurons circ_HIPK3, miR-381-3p and ZNF217 mRNA levels. Cell morphology was observed by transmission electron microscope, and the survival rate of hippocampal neurons was measured by CCK-8 method. Hochesst 33342 method was used to measure apoptosis of hippocampal neurons. The intracellular Ca²⁺fluorescence intensity of hippocampal neurons was detected by flow cytometry. The expression levels of P-Tau, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3 and ZNF217 proteins in hippocampal neurons were measured by Western blot assay. Double luciferase reporter genes were used to analyze the targeting relationship between miR-381-3p and circ_HIPK3, ZNF217. Results In the control group, the structure of hippocampal neurons was normal, the morphology of nucleus was normal, and there were no pathological changes in mitochondria and endoplasmic reticulum. In the Aβ group, hippocampal neurons showed degenerative changes, abnormal nuclear morphology, membrane invagination, a large number of mitochondria swelling and a large number of lipid droplets vacuoles in cytoplasm. Compared with the Aβ group, the hippocampal neuronal structure was partially restored in the si HIPK3 group. Compared with the si HIPK3 group, the hippocampal neuronal structure was severely damaged in the si HIPK3+miR-381-3p inhibitor group. Compared with the si HIPK3+miR-381-3p inhibitor group, the damage of hippocampal neurons in the si HIPK3+miR-381-3p inhibitor+si ZNF217 group was reduced. Compared with the control group, the circ_HIPK3, ZNF217 mRNA and ZNF217 protein levels, apoptosis rate, Ca²⁺ fluorescence intensity, P-Tau, Bax, Caspase-3 protein expression of hippocampal neurons were increased in the Aβ group, and the miR-381-3p level, survival rate and Bcl-2 protein expression decreased (P<0.05). Compared with the Aβ group, the circ_HIPK3, ZNF217 mRNA and ZNF217 protein levels, apoptosis rate, Ca²⁺ fluorescence intensity, P-Tau, Bax and Caspase-3 protein expression of hippocampal neurons were decreased in the si HIPK3 group, and miR-381-3p level, survival rate and Bcl-2 protein expression increased (P<0.05). Compared with the si HIPK3 group, the circ_HIPK3, ZNF217 mRNA and ZNF217 protein levels, apoptosis rate, Ca²⁺ fluorescence intensity, P-Tau, Bax and Caspase-3 protein expression of hippocampal neurons in the si HIPK3+miR-381-3p inhibitor group were increased, and the miR-381-3p level, survival rate and Bcl-2 protein expression decreased (P<0.05). Compared with the si HIPK3+miR-381-3p inhibitor group, the ZNF217 mRNA and ZNF217 protein levels, apoptosis rate, Ca²⁺ fluorescence intensity, P-Tau, Bax and Caspase-3 protein expression of hippocampal neurons in the si HIPK3+miR-381-3p inhibitor+si ZNF217 group were decreased, and the survival rate and Bcl-2 protein expression increased (P<0.05). miR-381-3p targeted and combined with HIPK3 and ZNF217. Conclusion circ_HIPK3 silencing may ameliorate Aβ-induced damage of hippocampal neuronal structure and function by regulating miR-381-3p/ZNF217 axis.

Key words: hippocampus, neurons, tristetraprolin, circ_HIPK3, miR-381-3p, ZNF217

中图分类号:

R749.16

图/表 13

参考文献 18

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基因名称	引物序列（5′→3′）	产物大小/bp
circ_HIPK3	上游：ATGGCCTCACAAGTCTTGGTC	189
circ_HIPK3	下游：GCACTACCTTTCGTGGAGGAT	189
ZNF217	上游：TCCAAATGTGCTGACTGTTC	201
ZNF217	下游：CTCTTTTGTGCCATGCTGTT	201
GAPDH	上游：AATCCCATCACCATCTTCCAG	128
GAPDH	下游：CCTTCTCCATGGTGGTGAAGAC	128
miR-381-3p	上游：TAATCTGACTATACAAGGGCAAGCT	87
miR-381-3p	下游：TATGGTTGTTCTGCTCTCTGTCTC	87
U6	上游：CTCGCTTCGGCAGCACA	96
U6	下游：AACGCTTCACGAATTTGCGT	96

基因名称	引物序列（5′→3′）	产物大小/bp
circ_HIPK3	上游：ATGGCCTCACAAGTCTTGGTC	189
circ_HIPK3	下游：GCACTACCTTTCGTGGAGGAT	189
ZNF217	上游：TCCAAATGTGCTGACTGTTC	201
ZNF217	下游：CTCTTTTGTGCCATGCTGTT	201
GAPDH	上游：AATCCCATCACCATCTTCCAG	128
GAPDH	下游：CCTTCTCCATGGTGGTGAAGAC	128
miR-381-3p	上游：TAATCTGACTATACAAGGGCAAGCT	87
miR-381-3p	下游：TATGGTTGTTCTGCTCTCTGTCTC	87
U6	上游：CTCGCTTCGGCAGCACA	96
U6	下游：AACGCTTCACGAATTTGCGT	96

组别	circ_HIPK3	miR-381-3p	ZNF217
组别	circ_HIPK3	miR-381-3p	mRNA	蛋白
对照组	1.01±0.14	1.00±0.16	1.02±0.12	0.32±0.04
Aβ组	2.97±0.42^a	0.42±0.07^a	2.54±0.31^a	0.78±0.09^a
si NC1组	2.99±0.42	0.43±0.07	2.52±0.31	0.76±0.09
si HIPK3组	1.62±0.23^b	0.62±0.10^b	2.02±0.25^b	0.41±0.05^b
si HIPK3+inhibitor NC组	1.63±0.23	0.63±0.10	2.01±0.25	0.42±0.05
si HIPK3+miR-381-3p inhibitor组	2.05±0.29^c	0.51±0.08^c	2.16±0.27^c	0.45±0.05^c
si HIPK3+miR-381-3p inhibitor+si NC2组	2.04±0.29	0.51±0.08	2.17±0.27	0.46±0.05
si HIPK3+miR-381-3p inhibitor+si ZNF217组	2.03±0.28	0.59±0.09	1.95±0.24^d	0.40±0.05^d
F	30.018^＊	21.379^＊	20.006^＊	46.846^＊

组别	circ_HIPK3	miR-381-3p	ZNF217
组别	circ_HIPK3	miR-381-3p	mRNA	蛋白
对照组	1.01±0.14	1.00±0.16	1.02±0.12	0.32±0.04
Aβ组	2.97±0.42^a	0.42±0.07^a	2.54±0.31^a	0.78±0.09^a
si NC1组	2.99±0.42	0.43±0.07	2.52±0.31	0.76±0.09
si HIPK3组	1.62±0.23^b	0.62±0.10^b	2.02±0.25^b	0.41±0.05^b
si HIPK3+inhibitor NC组	1.63±0.23	0.63±0.10	2.01±0.25	0.42±0.05
si HIPK3+miR-381-3p inhibitor组	2.05±0.29^c	0.51±0.08^c	2.16±0.27^c	0.45±0.05^c
si HIPK3+miR-381-3p inhibitor+si NC2组	2.04±0.29	0.51±0.08	2.17±0.27	0.46±0.05
si HIPK3+miR-381-3p inhibitor+si ZNF217组	2.03±0.28	0.59±0.09	1.95±0.24^d	0.40±0.05^d
F	30.018^＊	21.379^＊	20.006^＊	46.846^＊

组别	细胞存活率/%	细胞凋亡率/%	Ca²⁺荧光强度
对照组	100.00±14.28	3.24±0.46	30.22±4.31
Aβ组	47.26±6.75^a	25.66±3.66^a	76.17±10.88^a
si NC2组	46.57±6.66	25.17±3.59	75.89±10.84
si HIPK3组	79.81±11.40^b	13.22±1.88^b	42.66±6.09^b
si HIPK3+inhibitor NC组	78.66±11.23	13.50±1.92	42.57±6.09
si HIPK3+miR-381-3p inhibitor组	62.55±8.93^c	19.86±2.83^c	61.98±8.85^c
si HIPK3+miR-381-3p inhibitor+si NC2组	62.79±8.97	19.79±2.83	62.05±8.86
si HIPK3+miR-381-3p inhibitor+si ZNF217组	71.28±10.18^d	14.55±2.08^d	50.42±7.21^d
F	18.801^＊	54.344^＊	24.552^＊

circ_HIPK3靶向miR-381-3p/ZNF217轴调控Aβ诱导的海马神经元功能和形态

circ_HIPK3 regulates function and morphology of Aβ induced hippocampal neurons by targeting miR-381-3p/ZNF217 axis

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参考文献 18

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组别	P-Tau	Bcl-2	Bax	Caspase-3
对照组	0.84±0.12	0.76±0.12	0.22±0.03	0.36±0.05
Aβ组	1.96±0.28^a	0.31±0.05^a	0.83±0.11^a	0.75±0.10^a
si NC2组	1.97±0.28	0.30±0.05	0.82±0.11	0.76±0.10
si HIPK3组	1.12±0.16^b	0.55±0.09^b	0.41±0.05^b	0.43±0.06^b
si HIPK3+inhibitor NC组	1.13±0.16	0.54±0.09	0.40±0.05	0.44±0.06
si HIPK3+miR-381-3p inhibitor组	1.45±0.20^c	0.37±0.06^c	0.68±0.09^c	0.61±0.08^c
si HIPK3+miR-381-3p inhibitor+si NC2组	1.46±0.21	0.36±0.06	0.67±0.09	0.62±0.08
si HIPK3+miR-381-3p inhibitor+si ZNF217组	1.02±0.10^d	0.54±0.07^d	0.45±0.06^d	0.45±0.07^d
F	26.997^＊	25.414^＊	47.107^＊	23.892^＊

组别	WT HIPK3	MUT HIPK3	WT ZNF217	MUT ZNF217
mimics NC组	1.03±0.12	1.02±0.11	1.11±0.11	1.12±0.10
miR-381-3p mimics组	0.26±0.04^a	1.00±0.11	0.29±0.02^a	1.14±0.10
t	14.911^＊	0.315	17.965^＊	0.346

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