Role of microglial histone deacetylases 3 in hypobaric hypoxia-induced oxidative stress

doi:10.3969/j.issn.1006-7795.2022.01.016

Abstract

Abstract: Objective To investigate the effect of hypobaric hypoxiaon the brain tissue oxidative stress level and whether microglial HDAC3 is involved in this process. Methods First, wild type mice were treated in a hypobaric chamber at a simulated altitude of 6 000 meters for 7 days.The mRNA levels of hypoxia inducible factors-1α (HIF-1α), inducible nitric oxide synthase(iNOS), superoxidase dismutase(SOD) and histone deacetylases 3 (HDAC3) in the hippocampus were analyzed by real-time quantitative polymerase chain reaction (real-time PCR). Then, BV2 cells were treated in atmosphere with 0.1% O₂ in a hypoxia incubator and the mRNA and protein levels of iNOS, SOD, HDAC3 and HIF-1α were determined by Western blotting and real-time PCR.The levels of reactive oxygen species (ROS) were analyzed by flow cytometry.Furthermore, HDAC3-silenced and wild type BV2 cells were cultured in 0.1% O₂ atmosphere and the levels of ROS, iNOS and SOD were analyzed as above. Last, microglial HDAC3 conditional knockout mice and wild type mice were treated in hypoxia atmosphere, and the mRNA level of iNOS were analyzed by real-time PCR. Results The mRNA levels of iNOS, SOD and HDAC3 were upregulated in the hippocampus from mice underwent hypobaric hypoxia.The in vitro experiments indicated that the protein levels of iNOS, HDAC3 and HIF-1α were increased in BV2 cells treated 0.1% O₂, and the mRNA levels of iNOS and SOD were increased as well. By flow cytometry, we found the level of ROS was increased when BV2 cells were cultured in hypoxia atmosphere. Inhibition of HDAC3 significantly reduced the production of hypoxia-induced ROS, as well as decreased expression of SOD and iNOS. In addition, knockout of HDAC3 in microglia inhibited the hypoxia-induced upregulation iNOS. Conclusion The hypoxia treatment resulted in increased oxidative stress in the hippocampus and microglia, and inhibition of microglial HDAC3 ameliorated hypoxia-induced oxidative stress.

Key words: hypoxia, anoxia, oxidative stress, microglia, histone deacetylases 3

CLC Number:

Li Jun, Li Shuoshuo, Peng Zhixin, Liao Yajin, Cheng Jinbo, Yuan Zengqiang. Role of microglial histone deacetylases 3 in hypobaric hypoxia-induced oxidative stress[J]. Journal of Capital Medical University, 2022, 43(1): 91-98.

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URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2022.01.016

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2022/V43/I1/91

References

[1] Burtscher J, Millet G P, Burtscher M. Does living at moderate altitudes in Austria affect mortality rates of various causes? An ecological study[J]. BMJ Open, 2021, 11(6): e048520.
[2] Coulson S Z, Robertson C E, Mahalingam S, et al. Plasticity of non-shivering thermogenesis and brown adipose tissue in high-altitude deer mice[J]. J Exp Biol, 2021, 224(10): jeb242279.
[3] 吴剑, 谷亚坤, 刘佳. 缺血/缺氧预适应的神经保护作用研究进展[J]. 首都医科大学学报, 2020, 41(4): 664-670.
[4] Aebi M R, Bourdillon N, Noser P, et al. Cognitive impairment during combined normobaric vs. hypobaric and normoxic vs. hypoxic acute exposure[J]. Aerosp Med Hum Perform, 2020, 91(11): 845-851.
[5] Steinman Y, Groen E, Frings-Dresen M H W. Exposure to hypoxia impairs helicopter pilots' awareness of environment[J]. Ergonomics, 2021, 64(11): 1481-1490.
[6] Swiderska A, Coney A M, Alzahrani A A, et al. Mitochondrial succinate metabolism and reactive oxygen species are important but not essential for eliciting carotid body and ventilatory responses to hypoxia in the rat[J]. Antioxidants, 2021, 10(6): 840.
[7] Berríos-Cárcamo P, Quezada M, Quintanilla M E, et al. Oxidative stress and neuroinflammation as a pivot in drug abuse. A focus on the therapeutic potential of antioxidant and anti-inflammatory agents and biomolecules[J]. Antioxidants, 2020, 9(9): 830.
[8] Solleiro-Villavicencio H, Rivas-Arancibia S. Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4⁺ T cells in neurodegenerative diseases[J]. Front Cell Neurosci, 2018, 12: 114.
[9] Chi Z X, Chen S, Xu T, et al. Histone deacetylase 3 couples mitochondria to drive IL-1β-dependent inflammation by configuring fatty acid oxidation[J]. Mol Cell, 2020, 80(1): 43-58.e7.
[10] Liao Y J, Cheng J B, Kong X X, et al. HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway[J]. Theranostics, 2020, 10(21): 9644-9662.
[11] Celora G L, Byrne H M, Zois C E, et al. Phenotypic variation modulates the growth dynamics and response to radiotherapy of solid tumours under normoxia and hypoxia[J]. J Theor Biol, 2021, 527: 110792.
[12] Vanderborght B, De Muynck K, Lefere S, et al. Effect of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides on tumorigenesis, inflammation and fibrosis in a hepatocellular carcinoma mouse model[J]. Oncotarget, 2020, 11(48): 4504-4520.
[13] Yang M, Zhu M M, Song K, et al. VHL gene methylation contributes to excessive erythrocytosis in chronic mountain sickness rat model by upregulating the HIF-2α/EPO pathway[J]. Life Sci, 2021, 266: 118873.
[14] Coimbra-Costa D, Garzón F, Alva N, et al. Intermittent hypobaric hypoxic preconditioning provides neuroprotection by increasing antioxidant activity, erythropoietin expression and preventing apoptosis and astrogliosis in the brain of adult rats exposed to acute severe hypoxia[J]. Int J Mol Sci, 2021, 22(10): 5272.
[15] Albadari N, Deng S S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy[J]. Expert Opin Drug Discov, 2019, 14(7): 667-682.
[16] McGettrick A F, O'Neill L A J. The role of HIF in immunity and inflammation[J]. Cell Metab, 2020, 32(4): 524-536.
[17] Picca A, Calvani R, Coelho-Junior H J, et al. Mitochondrial dysfunction, oxidative stress, and neuroinflammation: intertwined roads to neurodegeneration[J]. Antioxidants, 2020, 9(8): 647.
[18] Broide R S, Redwine J M, Aftahi N, et al. Distribution of histone deacetylases 1-11 in the rat brain[J]. J Mol Neurosci, 2007, 31(1): 47-58.
[19] Donovan L L, Magnussen J H, Dyssegaard A, et al. Imaging HDACs in vivo: cross-validation of the [¹¹C] Martinostat radioligand in the pig brain[J]. Mol Imaging Biol, 2020, 22(3): 569-577.
[20] Hecklau K, Mueller S, Koch S P, et al. The effects of selective inhibition of histone deacetylase 1 and 3 in Huntington's disease mice[J]. Front Mol Neurosci, 2021, 14: 616886.
[21] Sies H, Berndt C, Jones D P. Oxidative stress[J]. Annu Rev Biochem, 2017, 86: 715-748.
[22] Cordaro M, Trovato Salinaro A, Siracusa R, et al. Hidrox^© roles in neuroprotection: biochemical links between traumatic brain injury and Alzheimer's disease[J]. Antioxidants, 2021, 10(5): 818.
[23] Najafi A, Pourfarzam M, Zadhoush F. Oxidant/antioxidant status in type-2 diabetes mellitus patients with metabolic syndrome[J]. J Res Med Sci, 2021, 26: 6.
[24] Berríos-Cárcamo P, Quezada M, Quintanilla M E, et al. Oxidative stress and neuroinflammation as a pivot in drug abuse. A focus on the therapeutic potential of antioxidant and anti-inflammatory agents and biomolecules[J]. Antioxidants, 2020, 9(9): 830.