HIF-1α Knockdown Attenuates Inflammation and Oxidative Stress in Ischemic Stroke Male Rats Via CXCR4/NF-κB Pathway

Overview

Journal Brain Behav

Specialty Psychology

Date 2024 Sep 19

PMID 39295108

Authors

Gao Chen

Xi Wang

Zhan Jin

Gao-Bo Hu

Qi-Hui Yu

Hai-Yan Jiang

Affiliations

Soon will be listed here.

Abstract

Background: Hypoxia inducible factor-1α (HIF-1α) is a sensitive indicator of oxygen homeostasis, of which the expression elevates following hypoxia/ischemia. This study reveals the specific mechanisms underlying the effects of HIF-1α on ischemic stroke (IS).

Methods: IS model was established using middle cerebral artery occlusion (MCAO)-modeled male rats and oxygen glucose deprivation/reoxygenation (OGD/R)-treated mice hippocampal cells HT22, followed by the silencing of HIF-1α and the overexpression of C-X-C motif chemokine receptor 4 (CXCR4) and nuclear factor-kappa B (NF-κB). Following the surgery, Garcia's grading scale was applied for neurological evaluation. Cerebral infarcts and injuries were visualized using 2,3,5-triphenyltetrazolium chloride and hematoxylin-eosin staining. The levels of tumor necrosis factor-α, Interleukin (IL)-6, IL-1β, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine, were calculated via ELISA. MTT assay and lactate dehydrogenase (LDH) assay kit were adopted to determine the viability and cytotoxicity of OGD/R-modeled cells. Reactive oxygen species (ROS) generation was evaluated using a 2'-7'dichlorofluorescin diacetate (DCFH-DA) probe. The levels of HIF-1α, CXCR4, and NF-κB p65 were quantified via Western blot and immunofluorescence, respectively.

Results: HIF-1α knockdown improved Garcia's score, attenuated the cerebral infarct, inflammation, and ROS generation, and alleviated the levels of inflammatory cytokines and CXCR4/NF-κB p65 in MCAO-modeled rats. Such effects were reversed following the overexpression of CXCR4 and NF-κB. Also, in OGD/R-treated HT22 cells, HIF-1α silencing diminished the cytotoxicity and ROS production and reduced the expressions of CXCR4/NF-κB p65, while promoting viability. However, CXCR4/NF-κB p65 overexpression did the opposite.

Conclusion: HIF-1α knockdown alleviates inflammation and oxidative stress in IS through the CXCR4/NF-κB pathway.

Citing Articles

HIF-1α knockdown attenuates inflammation and oxidative stress in ischemic stroke male rats via CXCR4/NF-κB pathway.

Chen G, Wang X, Jin Z, Hu G, Yu Q, Jiang H Brain Behav. 2024; 14(9):e70039.

PMID: 39295108 PMC: 11410888. DOI: 10.1002/brb3.70039.

References

Chen J, Lin X, Yao C, Bingwa L, Wang H, Lin Z . Transplantation of Roxadustat-preconditioned bone marrow stromal cells improves neurological function recovery through enhancing grafted cell survival in ischemic stroke rats. CNS Neurosci Ther. 2022; 28(10):1519-1531. PMC: 9437235. DOI: 10.1111/cns.13890. View

Qin C, Yang S, Chu Y, Zhang H, Pang X, Chen L . Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022; 7(1):215. PMC: 9259607. DOI: 10.1038/s41392-022-01064-1. View

Lee J, Tae H, Kim I, Cho J, Lee T, Park J . Roles of HIF-1α, VEGF, and NF-κB in Ischemic Preconditioning-Mediated Neuroprotection of Hippocampal CA1 Pyramidal Neurons Against a Subsequent Transient Cerebral Ischemia. Mol Neurobiol. 2016; 54(9):6984-6998. DOI: 10.1007/s12035-016-0219-2. View

Gojska-Grymajlo A, Zielinski M, Gasecki D, Kowalczyk K, Kwarciany M, Seroczynska B . CD271+, CXCR7+, CXCR4+, and CD133+ Stem/Progenitor Cells and Clinical Characteristics of Acute Ischemic Stroke Patients. Neuromolecular Med. 2018; 20(3):301-311. PMC: 6097064. DOI: 10.1007/s12017-018-8494-x. View

Della Corte V, Tuttolomondo A, Pecoraro R, Di Raimondo D, Vassallo V, Pinto A . Inflammation, Endothelial Dysfunction and Arterial Stiffness as Therapeutic Targets in Cardiovascular Medicine. Curr Pharm Des. 2016; 22(30):4658-4668. DOI: 10.2174/1381612822666160510124801. View

Maida C, Norrito R, Daidone M, Tuttolomondo A, Pinto A . Neuroinflammatory Mechanisms in Ischemic Stroke: Focus on Cardioembolic Stroke, Background, and Therapeutic Approaches. Int J Mol Sci. 2020; 21(18). PMC: 7555650. DOI: 10.3390/ijms21186454. View

Cummins E, Seeballuck F, Keely S, Mangan N, Callanan J, Fallon P . The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology. 2008; 134(1):156-65. DOI: 10.1053/j.gastro.2007.10.012. View

Candelario-Jalil E, Dijkhuizen R, Magnus T . Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities. Stroke. 2022; 53(5):1473-1486. PMC: 9038693. DOI: 10.1161/STROKEAHA.122.036946. View

Turovsky E, Varlamova E, Plotnikov E . Mechanisms Underlying the Protective Effect of the Peroxiredoxin-6 Are Mediated via the Protection of Astrocytes during Ischemia/Reoxygenation. Int J Mol Sci. 2021; 22(16). PMC: 8396200. DOI: 10.3390/ijms22168805. View

10.

Su X, Wang L, Ma S, Cao Y, Yang N, Lin L . Mechanisms of Acupuncture in the Regulation of Oxidative Stress in Treating Ischemic Stroke. Oxid Med Cell Longev. 2020; 2020:7875396. PMC: 7644298. DOI: 10.1155/2020/7875396. View

11.

DIgnazio L, Shakir D, Batie M, Muller H, Rocha S . HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6. Int J Mol Sci. 2020; 21(8). PMC: 7216149. DOI: 10.3390/ijms21083000. View

12.

Huang X, Wan M, Yang Q, Ding X, Zhou Z . The stromal cell-derived factor-1 α (SDF-1α)/cysteine-X-cysteine chemokine receptor 4 (CXCR4) axis: a possible prognostic indicator of acute ischemic stroke. J Int Med Res. 2019; 47(5):1897-1907. PMC: 6567759. DOI: 10.1177/0300060519827173. View

13.

Malkov M, Lee C, Taylor C . Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines. Cells. 2021; 10(9). PMC: 8466990. DOI: 10.3390/cells10092340. View

14.

Limatola V, Ward P, Cattano D, Gu J, Giunta F, Maze M . Xenon preconditioning confers neuroprotection regardless of gender in a mouse model of transient middle cerebral artery occlusion. Neuroscience. 2009; 165(3):874-81. DOI: 10.1016/j.neuroscience.2009.10.063. View

15.

Bonham L, Karch C, Fan C, Tan C, Geier E, Wang Y . CXCR4 involvement in neurodegenerative diseases. Transl Psychiatry. 2018; 8(1):73. PMC: 5893558. DOI: 10.1038/s41398-017-0049-7. View

16.

Ekkert A, Sliachtenko A, Grigaite J, Burnyte B, Utkus A, Jatuzis D . Ischemic Stroke Genetics: What Is New and How to Apply It in Clinical Practice?. Genes (Basel). 2022; 13(1). PMC: 8775228. DOI: 10.3390/genes13010048. View

17.

Bonkhoff A, Karch A, Weber R, Wellmann J, Berger K . Female Stroke: Sex Differences in Acute Treatment and Early Outcomes of Acute Ischemic Stroke. Stroke. 2021; 52(2):406-415. DOI: 10.1161/STROKEAHA.120.032850. View

18.

Chen G, Wang X, Jin Z, Hu G, Yu Q, Jiang H . HIF-1α knockdown attenuates inflammation and oxidative stress in ischemic stroke male rats via CXCR4/NF-κB pathway. Brain Behav. 2024; 14(9):e70039. PMC: 11410888. DOI: 10.1002/brb3.70039. View

19.

Zhang R, Liu C, Ji Y, Teng L, Guo Y . Neuregulin-1β Plays a Neuroprotective Role by Inhibiting the Cdk5 Signaling Pathway after Cerebral Ischemia-Reperfusion Injury in Rats. J Mol Neurosci. 2018; 66(2):261-272. DOI: 10.1007/s12031-018-1166-3. View

20.

Yang R, Duan C, Yuan L, Engelbach J, Tsien C, Beeman S . Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain. Int J Radiat Oncol Biol Phys. 2018; 100(4):1016-1025. PMC: 6389273. DOI: 10.1016/j.ijrobp.2017.12.257. View