Skip to main content

Advertisement

SpringerLink
Log in

miR-452-3p Targets HDAC3 to Inhibit p65 Deacetylation and Activate the NF-κB Signaling Pathway in Early Brain Injury after Subarachnoid Hemorrhage

  • Original work
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

Objectives

Subarachnoid hemorrhage (SAH) is a subtype of stroke, and early brain injury (EBI) is a contributor to its unfavorable outcome. microRNA (miRNA) is abundantly expressed in the brain and participates in brain injury. This study investigated the effect of miR-452-3p on EBI after SAH.

Methods

The murine model of SAH was established. miR-452-3p expression was detected 48 h after the model establishment. Neurobehavioral function, blood–brain barrier permeability, brain water content, neuronal apoptosis, and inflammatory factors were evaluated. The cell model of SAH was induced by oxygen hemoglobin. Apoptosis rate, lactate dehydrogenase, and reactive oxygen species were detected. The targeting relationship between miR-452-3p and histone deacetylase 3 (HDAC3) was verified. The acetylation of p65 and the binding of HDAC3 to p65 were detected. The inhibitory protein of the nuclear factor κB pathway (IκBα) was detected. Suberoylanilide hydroxamic acid was injected into the SAH mice treated with miR-452-3p inhibitor.

Results

SAH mice showed upregulated miR-452-3p expression; reduced the neurological score; increased blood–brain barrier permeability, brain water content, and neuronal apoptosis; elevated pro-inflammatory factors; and reduced anti-inflammatory factors. SAH increased the apoptosis rate, lactate dehydrogenase release, and reactive oxygen species levels in oxygen-hemoglobin-treated neuron cells. Inhibition of miR-452-3p reversed the above trends. miR-452-3p targeted HDAC3. SAH upregulated p65 acetylation. miR-452-3p inhibitor promoted the binding of HDAC3 to p65, decreased p65 acetylation, and upregulated IκBα. Suberoylanilide hydroxamic acid reversed the protective effect of miR-452-3p inhibitor on SAH mice and aggravated brain injury.

Conclusions

miR-452-3p targeted HDAC3 to inhibit the deacetylation of p65 and activate the nuclear factor κB pathway, thus aggravating EBI after SAH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

All the data generated or analyzed during this study are included in this published article.

References

  1. Muehlschlegel S. Subarachnoid hemorrhage. Continuum (Minneap Minn). 2018;24(6):1623–57.

    Google Scholar 

  2. Martinez B, Peplow PV. Blood microRNAs as potential diagnostic markers for hemorrhagic stroke. Neural Regen Res. 2017;12(1):13–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Abraham MK, Chang WW. Subarachnoid hemorrhage. Emerg Med Clin North Am. 2016;34(4):901–16.

    Article  PubMed  Google Scholar 

  4. Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389(10069):655–66.

    Article  PubMed  Google Scholar 

  5. Rass V, Helbok R. Early brain injury after poor-grade subarachnoid hemorrhage. Curr Neurol Neurosci Rep. 2019;19(10):78.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kusaka G, Ishikawa M, Nanda A, et al. Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2004;24(8):916–25.

    Article  CAS  PubMed  Google Scholar 

  7. Leclerc JL, Garcia JM, Diller MA, et al. A comparison of pathophysiology in humans and rodent models of subarachnoid hemorrhage. Front Mol Neurosci. 2018;11:71.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Liu W, Li R, Yin J, et al. Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch. J Neuroinflammation. 2019;16(1):8.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Nampoothiri SS, Menon HV, Das D, Krishnamurthy RG. ISCHEMIRs: finding a way through the obstructed cerebral arteries. Curr Drug Targets. 2016;17(7):800–10.

    Article  CAS  PubMed  Google Scholar 

  10. Yu XH, Deng WY, Chen JJ, et al. LncRNA kcnq1ot1 promotes lipid accumulation and accelerates atherosclerosis via functioning as a ceRNA through the miR-452-3p/HDAC3/ABCA1 axis. Cell Death Dis. 2020;11(12):1043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lamontanara AJ, Georgeon S, Tria G, et al. The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility. Nat Commun. 2014;5:5470.

    Article  PubMed  Google Scholar 

  12. Shein NA, Shohami E. Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries. Mol Med. 2011;17(5–6):448–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Reddy DS, Wu X, Golub VM, et al. Measuring histone deacetylase inhibition in the brain. Curr Protoc Pharmacol. 2018;81(1): e41.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yang X, Wu Q, Zhang L, Feng L. Inhibition of histone deacetylase 3 (HDAC3) mediates ischemic preconditioning and protects cortical neurons against ischemia in rats. Front Mol Neurosci. 2016;9:131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhao H, Li G, Zhang S, et al. Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke. J Cereb Blood Flow Metab. 2019;39(12):2392–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Deng R, Zhang P, Liu W, et al. HDAC is indispensable for IFN-gamma-induced B7–H1 expression in gastric cancer. Clin Epigenetics. 2018;10(1):153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Garcia JH, Wagner S, Liu KF, Hu XJ. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Stat Validation Stroke. 1995;26(4):627–34.

    CAS  Google Scholar 

  18. Hasegawa Y, Suzuki H, Altay O, Zhang JH. Preservation of tropomyosin-related kinase B (TrkB) signaling by sodium orthovanadate attenuates early brain injury after subarachnoid hemorrhage in rats. Stroke. 2011;42(2):477–83.

    Article  CAS  PubMed  Google Scholar 

  19. Deng X, Liang C, Qian L, Zhang Q. miR-24 targets HMOX1 to regulate inflammation and neurofunction in rats with cerebral vasospasm after subarachnoid hemorrhage. Am J Transl Res. 2021;13(3):1064–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Song H, Yuan S, Zhang Z, et al. Sodium/hydrogen exchanger 1 participates in early brain injury after subarachnoid hemorrhage both in vivo and in vitro via promoting neuronal apoptosis. Cell Transplant. 2019;28(8):985–1001.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lai N, Wu D, Liang T, et al. Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice. J Neuroinflammation. 2020;17(1):74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chawla M, Roy P, Basak S. Role of the NF-kappaB system in context-specific tuning of the inflammatory gene response. Curr Opin Immunol. 2021;68:21–7.

    Article  CAS  PubMed  Google Scholar 

  23. Zhou Y, Tao T, Liu G, et al. TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-kappaB pathways. Cell Death Dis. 2021;12(1):10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Daou BJ, Koduri S, Thompson BG, et al. Clinical and experimental aspects of aneurysmal subarachnoid hemorrhage. CNS Neurosci Ther. 2019;25(10):1096–112.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Al-Mufti F, Amuluru K, Smith B, et al. Emerging markers of early brain injury and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage. World Neurosurg. 2017;107:148–59.

    Article  PubMed  Google Scholar 

  26. Chan MTH, Wong JYY, Leung AKT, et al. Plasma and CSF miRNA dysregulations in subarachnoid hemorrhage reveal clinical courses and underlying pathways. J Clin Neurosci. 2019;62:155–61.

    Article  CAS  PubMed  Google Scholar 

  27. Ji C, Chen G. Signaling pathway in early brain injury after subarachnoid hemorrhage: news update. Acta Neurochir Suppl. 2016;121:123–6.

    Article  PubMed  Google Scholar 

  28. Muroi C, Hugelshofer M, Seule M, et al. Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2013;72(3):367–75.

    Article  PubMed  Google Scholar 

  29. Geraghty JR, Davis JL, Testai FD. Neuroinflammation and microvascular dysfunction after experimental subarachnoid hemorrhage: emerging components of early brain injury related to outcome. Neurocrit Care. 2019;31(2):373–89.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Garcia JM, Stillings SA, Leclerc JL, et al. Role of interleukin-10 in acute brain injuries. Front Neurol. 2017;8:244.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ayer RE, Zhang JH. Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl. 2008;104:33–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fumoto T, Naraoka M, Katagai T, et al. The role of oxidative stress in microvascular disturbances after experimental subarachnoid hemorrhage. Transl Stroke Res. 2019;10(6):684–94.

    Article  CAS  PubMed  Google Scholar 

  33. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14(11):709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Anan M, Nagai Y, Fudaba H, Fujiki M. Lactate and lactate dehydrogenase in cistern as biomarkers of early brain injury and delayed cerebral ischemia of subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 2020;29(5): 104765.

    Article  PubMed  Google Scholar 

  35. Mo J, Enkhjargal B, Travis ZD, et al. AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats. Redox Biol. 2019;20:75–86.

    Article  CAS  PubMed  Google Scholar 

  36. Wu L, Zeng S, Cao Y, et al. Inhibition of HDAC4 attenuated JNK/c-Jun-dependent neuronal apoptosis and early brain injury following subarachnoid hemorrhage by transcriptionally suppressing MKK7. Front Cell Neurosci. 2019;13:468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang MJ, Zhao QC, Xia MX, et al. The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome. FASEB J. 2020;34(1):648–62.

    Article  CAS  PubMed  Google Scholar 

  38. Liao Y, Cheng J, Kong X, et al. HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway. Theranostics. 2020;10(21):9644–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Meng Q, Yang G, Yang Y, et al. Protective effects of histone deacetylase inhibition by Scriptaid on brain injury in neonatal rat models of cerebral ischemia and hypoxia. Int J Clin Exp Pathol. 2020;13(2):179–91.

    PubMed  PubMed Central  Google Scholar 

  40. You WC, Li W, Zhuang Z, et al. Biphasic activation of nuclear factor-kappa B in experimental models of subarachnoid hemorrhage in vivo and in vitro. Mediators Inflamm. 2012;2012:786242.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shabab T, Khanabdali R, Moghadamtousi SZ, et al. Neuroinflammation pathways: a general review. Int J Neurosci. 2017;127(7):624–33.

    Article  CAS  PubMed  Google Scholar 

  42. Sozen T, Tsuchiyama R, Hasegawa Y, et al. Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice. Stroke. 2009;40(7):2519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pawlowska E, Szczepanska J, Wisniewski K, et al. NF-kappaB-mediated inflammation in the pathogenesis of intracranial aneurysm and subarachnoid hemorrhage does autophagy play a role? Int J Mol Sci. 2018;19(4):871.

    Article  Google Scholar 

  44. Yu X, Yu W, Wu L, et al. Chitotriosidase attenuates brain inflammation via HDAC3/NF-kappaB pathway in D-galactose and aluminum-induced rat model with cognitive impairments. Neurosci Res. 2021;172:73–9.

    Article  CAS  PubMed  Google Scholar 

  45. Tian Y, Sun L, Qi T. Long noncoding RNA GAS5 ameliorates chronic constriction injury induced neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis. Can J Physiol Pharmacol. 2020;98(12):870–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, Shaanxi, People’s Republic of China

    Junti Lu & Shiwen Guo

  2. Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, 32 People’s South Road, Shiyan, 442000, Hubei, People’s Republic of China

    Junti Lu, Xiaodong Huang, Aiping Deng, Hong Yao, Gao Wu, Na Wang, Hui Gui & Mojie Ren

Authors
  1. Junti Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaodong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aiping Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Na Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Gui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mojie Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shiwen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JTL and SWG are responsible for the concept and design of the study; XDH is responsible for the definition of knowledge content, literature research; SWG is responsible for clinical research, final approval of the version to be published; HG is responsible for experimental research; HY is responsible for data collection; APD is responsible for data analysis and statistical analysis; NW is responsible for manuscript preparation; GW, MJR is responsible for manuscript editing and comment. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shiwen Guo.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Human and animal rights

All procedures were approved by Taihe Hospital. The experiments were conducted in strict accordance with the guidelines for the management and use of laboratory animals issued by the Chinese Association of Laboratories. All the experimental procedures are used to relieve the animals’ pain. The animal experiments have been conducted in accordance with the ARRIVE guidelines.

Source of support

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

The online version of this article (https://doi.org/10.1007/s12028-022-01509-z) contains supplementary material.

Supplementary file1 (TIFF 561 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, J., Huang, X., Deng, A. et al. miR-452-3p Targets HDAC3 to Inhibit p65 Deacetylation and Activate the NF-κB Signaling Pathway in Early Brain Injury after Subarachnoid Hemorrhage. Neurocrit Care 37, 558–571 (2022). https://doi.org/10.1007/s12028-022-01509-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-022-01509-z

Keywords

Search

Navigation