脑缺血大鼠再灌注后组蛋白去乙酰化酶2与O-GlcNAc转移酶表达变化及锌离子的调控作用

doi:10.3969/j.issn.1006-7795.2026.02.011

首都医科大学学报 ›› 2026, Vol. 47 ›› Issue (2): 299-307.doi: 10.3969/j.issn.1006-7795.2026.02.011

• 脑血管病的基础与临床研究 • 上一篇下一篇

脑缺血大鼠再灌注后组蛋白去乙酰化酶2与O-GlcNAc转移酶表达变化及锌离子的调控作用

刘鹤,朱玥荃,周英楠,白尚颖,赵海苹,赵咏梅^*

首都医科大学宣武医院中心实验室北京市老年病医疗研究中心，北京 100053

收稿日期:2025-12-16 修回日期:2026-01-21 出版日期:2026-04-21 发布日期:2026-04-21
通讯作者: 赵咏梅 E-mail:zhaoym@ccmu.edu.cn
基金资助:
国家自然科学基金项目(82271309,81971095,82301570)。

Alterations in histone deacetylase 2 and O-GlcNAc transferase expression following cerebral ischemia-reperfusion and the modulatory effects of zinc ions in a rat model

Liu He, Zhu Yuequan, Zhou Yingnan, Bai Shangying, Zhao Haiping, Zhao Yongmei^*

Central Laboratory, Xuanwu Hospital, Capital Medical University, Beijing Geriatric Medical Research Center, Beijing 100053, China

Received:2025-12-16 Revised:2026-01-21 Online:2026-04-21 Published:2026-04-21
Supported by:
This study was supported by National Natural Science Foundation of China (82271309,81971095, 82301570).

摘要/Abstract

摘要： 目的探讨脑缺血再灌注后神经元内锌离子稳态失衡对脑组织中组蛋白去乙酰化酶 2（histone deacetylase 2, HDAC2）与神经系统中关键的表观糖基化酶O-GlcNAc转移酶（O-GlcNAc transferase, OGT）表达及其潜在相互作用的影响，以明确锌离子失衡是否参与二者介导的表观遗传调控过程，为揭示脑缺血再灌注损伤中新型的表观遗传调控机制提供依据。方法采用SD大鼠制备大脑中动脉闭塞（middle cerebral artery occlusion, MCAO）模型，缺血90 min后再灌注6 h或24 h。采用数字表法将大鼠随机分为假手术（Sham）组、MCAO组和MCAO+N,N,N′,N′-四-(2-吡啶基甲基)乙二胺［N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine, TPEN］组，每组6只。使用蛋白质免疫印迹（Western blotting）法检测脑组织中HDAC2和OGT的表达水平。使用HDOCK服务器进行蛋白-蛋白分子对接，并使用PyMOL进行可视化，分析HDAC2和OGT之间的相互作用。结果 ①脑缺血再灌注6 h及24 h后大鼠缺血侧脑组织中HDAC2蛋白表达较假手术组显著下调。 ②使用锌离子螯合剂TPEN处理明显上调脑缺血再灌注大鼠6 h及24 h后脑组织中HDAC2蛋白表达。 ③脑缺血再灌注24 h后大鼠缺血侧脑组织中OGT蛋白表达较假手术组显著下调。 ④使用锌离子螯合剂TPEN处理明显上调脑缺血再灌注6 h及24 h后大鼠缺血侧脑组织中OGT蛋白表达。 ⑤分子对接分析表明HDAC2与OGT具有高可信度的结合构象，提示二者在结构上具备潜在相互作用可能性。结论脑缺血再灌注可导致大鼠缺血侧脑组织中HDAC2与OGT的表达下调，且与锌离子异常聚集密切相关。OGT与HDAC2可能存在蛋白-蛋白相互作用，提示缺血后锌离子过度积聚可能同时影响HDAC2和OGT的表达水平，并干扰二者之间的相互作用，进而破坏神经元的表观遗传调控过程。

关键词: 脑缺血再灌注, 锌离子, 组蛋白去乙酰化酶2（HDAC2）, O-GlcNAc 转移酶（OGT）, 表观遗传调控, 脑损伤, 神经元损伤

Abstract: Objective To investigate the effect of disrupted neuronal zinc homeostasis on the expression of histone deacetylase 2 (HDAC2) and O-GlcNAc transferase (OGT), as well as their potential interaction in brain tissue following cerebral ischemia/reperfusion (I/R), in order to elucidate whether zinc dyshomeostasis participates in the synergistic epigenetic regulatory mechanisms during cerebral I/R injury. Methods Adult Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 min, followed by reperfusion for 6 h or 24 h. The animals were randomly divided into the Sham, MCAO, and MCAO + N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine（TPEN） groups (n=6 per group). Protein expression levels of HDAC2 and OGT in brain tissue were analyzed by Western blotting. Protein-protein docking between HDAC2 and OGT was performed using the HDOCK server, and the interaction interface was visualized with PyMOL. Results ①Compared with the Sham group, HDAC2 protein expression in rat ischemic brain tissue was significantly downregulated at 6 h and 24 h after reperfusion. ②TPEN treatment significantly upregulated HDAC2 expression in rat ischemic brain tissue at both 6 h and 24 h after reperfusion.③Compared with the Sham group, OGT protein expression in rat ischemic brain tissue was markedly reduced at 24 h after reperfusion.④TPEN treatment significantly increased OGT expression in rat ischemic brain tissue at both 6 h and 24 h after reperfusion. ⑤ Molecular docking analysis revealed high-confidence binding conformations between HDAC2 and OGT, suggesting a potential protein-protein interaction based on structural complementarity. Conclusion Cerebral ischemia-reperfusion leads to a marked downregulation of HDAC2 and OGT expression in rat ischemic brain tissue, which is closely associated with excessive zinc accumulation. The potential protein-protein interaction between OGT and HDAC2 further suggests that zinc overload after ischemia may simultaneously alter their expression levels and disrupt their interaction, thereby impairing neuronal epigenetic regulatory processes.

Key words: cerebral ischemia-reperfusion, zinc, histone deacetylase 2 (HDAC2), O-GlcNAc transferase (OGT), epigenetic regulation, brain injury, neuronal injury

中图分类号:

R743.3

刘鹤, 朱玥荃, 周英楠, 白尚颖, 赵海苹, 赵咏梅. 脑缺血大鼠再灌注后组蛋白去乙酰化酶2与O-GlcNAc转移酶表达变化及锌离子的调控作用[J]. 首都医科大学学报, 2026, 47(2): 299-307.

Liu He, Zhu Yuequan, Zhou Yingnan, Bai Shangying, Zhao Haiping, Zhao Yongmei. Alterations in histone deacetylase 2 and O-GlcNAc transferase expression following cerebral ischemia-reperfusion and the modulatory effects of zinc ions in a rat model[J]. Journal of Capital Medical University, 2026, 47(2): 299-307.

参考文献

［1］Zhao Y M, Ding M, Yang N, et al. Zinc accumulation aggravates cerebral ischemia/reperfusion injury through inducing endoplasmic reticulum stress［J］. Neurochem Res, 2022, 47(5): 1419-1428.
［2］Elmadhoun A, Wang H R, Ding Y C. Impacts of futile reperfusion and reperfusion injury in acute ischemic stroke［J］. Brain Circ, 2024, 10(1): 1-4.
［3］Li Z, Liu Y, Wei R X, et al. The important role of zinc in neurological diseases［J］. Biomolecules, 2022, 13(1): 28.
［4］Kitamura Y, Iida Y, Abe J, et al. Protective effect of zinc against ischemic neuronal injury in a middle cerebral artery occlusion model［J］. J Pharmacol Sci, 2006, 100(2): 142-148.
［5］Benarroch E. What are the functions of zinc in the nervous system?［J］. Neurology, 2023, 101(16): 714-720.
［6］Choi S, Hong D K, Choi B Y, et al. Zinc in the brain: friend or foe?［J］. Int J Mol Sci, 2020, 21(23): 8941.
［7］Lu D T, Yang Y K, Huang G D, et al. MFN2 and BAG6 synergistically protect against cerebral reperfusion injury by regulating ROS levels and autophagic flux［J］. Stroke, 2025, 56(12): 3468-3483.
［8］Zhao Y M, Pan R, Li S, et al. Chelating intracellularly accumulated zinc decreased ischemic brain injury through reducing neuronal apoptotic death［J］. Stroke, 2014, 45(4): 1139-1147.
［9］De Ruijter A J M, Van Gennip A H, Caron H N, et al. Histone deacetylases (HDACs): characterization of the classical HDAC family［J］. Biochem J, 2003, 370(Part 3): 737-749.
［10］Patil R S, Maloney M E, Lucas R, et al. Zinc-dependent histone deacetylases in lung endothelial pathobiology［J］. Biomolecules, 2024, 14(2): 140.
［11］Quaas C E, Lin B C, Long D T. Transcription suppression is mediated by the HDAC1-Sin3 complex in Xenopus nucleoplasmic extract［J］. J Biol Chem, 2022, 298(11): 102578.
［12］Yang X Y, Zhang F X, Kudlow J E. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression［J］. Cell, 2002, 110(1): 69-80.
［13］Lewis B A, Hanover J A. O-GlcNAc and the epigenetic regulation of gene expression［J］. J Biol Chem, 2014, 289(50): 34440-34448.
［14］Fan J, Guo F, Mo R, et al. O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission［J］. J Clin Invest, 2023, 133(7): e160016.
［15］Li X, Yang W. Targeting O-GlcNAcylation in ischemic stroke［J］. Neural Regen Res, 2022, 17(11): 2427-2428.
［16］Omelková M, Fenger C D, Murray M, et al. An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal［J］. Dis Model Mech, 2023, 16(6): dmm049132.
［17］Delcuve G P, Khan D H, Davie J R. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors［J］. Clin Epigenetics, 2012, 4(1): 5.
［18］Zhao Y M, Yan F, Yin J, et al. Synergistic interaction between zinc and reactive oxygen species amplifies ischemic brain injury in rats［J］. Stroke, 2018, 49(9): 2200-2210.
［19］Yan Y M, Tao H Y, He J H, et al. The HDOCK server for integrated protein-protein docking［J］. Nat Protoc, 2020, 15(5): 1829-1852.
［20］Yan Y M, Zhang D, Zhou P, et al. HDOCK: a web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy［J］. Nucleic Acids Res, 2017, 45(W1): W365-W373.
［21］Berman H M, Westbrook J, Feng Z, et al. The protein data bank［J］. Nucleic Acids Res, 2000, 28(1): 235-242.
［22］Martí-Renom M A, Stuart A C, Fiser A, et al. Comparative protein structure modeling of genes and genomes［J］. Annu Rev Biophys Biomol Struct, 2000, 29: 291-325.
［23］Larkin M A, Blackshields G, Brown N P, et al. Clustal W and clustal X version 2.0［J］. Bioinformatics, 2007, 23(21): 2947-2948.
［24］Sievers F, Wilm A, Dineen D, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using clustal omega［J］. Mol Syst Biol, 2011, 7: 539.
［25］Pearson W R, Lipman D J. Improved tools for biological sequence comparison［J］. Proc Natl Acad Sci U S A, 1988, 85(8): 2444-2448.
［26］Remmert M, Biegert A, Hauser A, et al. HHblits: lightning-fast iterative protein sequence searching by HMM-HMM alignment［J］. Nat Methods, 2011, 9(2): 173-175.
［27］Flores B M, Uppalapati C K, Pascual A S, et al. Biological effects of HDAC inhibitors vary with zinc binding group: differential effects on zinc bioavailability, ROS production, and R175H p53 mutant protein reactivation［J］. Biomolecules, 2023, 13(11): 1588.［28］Jia T X, Wang M J, Yan W J, et al. Upregulation of miR-489-3p attenuates cerebral ischemia/reperfusion injury by targeting histone deacetylase 2 (HDAC2)［J］. Neuroscience, 2022, 484: 16-25.
［29］Hawash M. Next-generation HDAC inhibitors: advancing zinc-binding group design for enhanced cancer therapy［J］. Cells, 2025, 14(24): 1997.
［30］Zhao J R, Dong L P, Huo T T, et al. O-GlcNAc transferase (OGT) protects cerebral neurons from death during ischemia/reperfusion (I/R) injury by modulating Drp1 in mice［J］. Neuromolecular Med, 2022, 24(3): 299-310.
［31］Morales M M, Pratt M R. The post-translational modification O-GlcNAc is a sensor and regulator of metabolism［J］. Open Biol, 2024, 14(10): 240209.

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脑缺血大鼠再灌注后组蛋白去乙酰化酶2与O-GlcNAc转移酶表达变化及锌离子的调控作用

Alterations in histone deacetylase 2 and O-GlcNAc transferase expression following cerebral ischemia-reperfusion and the modulatory effects of zinc ions in a rat model

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