Electroacupuncture Alleviates Cerebral Ischemia-reperfusion Injury by Regulating the S1PR2/TLR4/NLRP3 Signaling Pathway via m6A Methylation of lncRNA H19

Page: [64 - 73] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Electroacupuncture (EA) treatment plays a protective role in cerebral ischemiareperfusion (CIR) injury. However, the underlying molecular mechanism is still not fully elucidated.

Methods: All rats were randomly divided into five groups: the SHAM group, MCAO group, MCAO+EA (MEA) group, MCAO+METTL3 overexpression+EA (METTL3) group and MCAO+lncRNA H19 overexpression+EA (lncRNA H19) group. The middle cerebral artery occlusion (MCAO) rats were established to mimic CIR injury. The overexpression of lncRNA H19 and METTL3 was induced by stereotactic injection of lentiviruses into the rat lateral ventricles. The rats in the MEA, METTL3, and lncRNA H19 groups were treated with EA therapy on “Renzhong” (DU26) and “Baihui” (DU20) acupoints (3.85/6.25Hz; 1mA). Besides, the neurological deficit scoring, cerebral infarction area, pathological changes in brain tissue, total RNA m6A level, and the expression of METTL3, S1PR2, TLR4, NLRP3 and lncRNA H19 were detected in this experiment.

Results: EA improved the neurological deficit scoring, cerebral infarction area, and pathological injury in MCAO rats, while these beneficial effects of EA on CIR injury were attenuated by the overexpression of METTL3 or lncRNA H19. More importantly, EA down-regulated the total RNA m6A level and the expression of METTL3, S1PR2, TLR4, NLRP3 and lncRNA H19 in MCAO rats. Instead, the overexpression of METTL3 or lncRNA H19 was found to reverse the EA-induced down-regulation.

Conclusion: The findings indicated that EA might down-regulate the S1PR2/TLR4/NLRP3 signaling pathway via m6A methylation of lncRNA H19 to alleviate CIR injury. Our findings provide a new insight into the molecular mechanism of EA on CIR injury.

[1]
Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ 2020; 368: l6983.
[http://dx.doi.org/10.1136/bmj.l6983] [PMID: 32054610]
[2]
Pu L, Wang L, Zhang R, Zhao T, Jiang Y, Han L. Projected Global Trends in Ischemic Stroke Incidence, Deaths and Disability-Adjusted Life Years From 2020 to 2030. Stroke 2023; 54(5): 1330-9.
[http://dx.doi.org/10.1161/STROKEAHA.122.040073] [PMID: 37094034]
[3]
Cheng X, Yang YL, Li WH, Liu M, Zhang SS, Wang YH. Dynamic Alterations of Brain Injury, Functional Recovery, and Metabolites Profile after Cerebral Ischemia/Reperfusion in Rats Contributes to Potential Biomarkers. J Molecular Neurosci 2021; 70(5): 667-76.
[4]
Tang C, Hong J, Hu C, et al. Palmatine Protects against Cerebral Ischemia/Reperfusion Injury by Activation of the AMPK/Nrf2 Pathway. Oxid Med Cell Longev 2021; 2021: 1-12.
[http://dx.doi.org/10.1155/2021/6660193] [PMID: 33777318]
[5]
Zhang B, Shi H, Cao S, et al. Revealing the magic of acupuncture based on biological mechanisms: A literature review. Biosci Trends 2022; 16(1): 73-90.
[http://dx.doi.org/10.5582/bst.2022.01039] [PMID: 35153276]
[6]
Tang B, Li Y, Xu X, Du G, Wang H. Electroacupuncture Ameliorates Neuronal Injury by NLRP3/ASC/Caspase-1 Mediated Pyroptosis in Cerebral Ischemia-Reperfusion. Mol Neurobiol 2023; 10: 24.
[http://dx.doi.org/10.1007/s12035-023-03712-1] [PMID: 37874480]
[7]
Han Q, Wang F. Electroacupuncture at GB20 improves cognitive ability and synaptic plasticity via the CaM-CaMKII-CREB signaling pathway following cerebral ischemia-reperfusion injury in rats. Acupunct Med 2023; 42(1): 23-31.
[PMID: 38126262]
[8]
Zhang W, Han L, Wen Y, Su L, Li Y, Luo X. Electroacupuncture reverses endothelial cell death and promotes angiogenesis through the VEGF/Notch signaling pathway after focal cerebral ischemia‐reperfusion injury. Brain Behav 2023; 13(3): e2912.
[http://dx.doi.org/10.1002/brb3.2912] [PMID: 36786352]
[9]
Cai L, Yao ZY, Yang L, et al. Mechanism of Electroacupuncture Against Cerebral Ischemia–Reperfusion Injury: Reducing Inflammatory Response and Cell Pyroptosis by Inhibiting NLRP3 and Caspase-1. Front Mol Neurosci 2022; 15: 822088.
[http://dx.doi.org/10.3389/fnmol.2022.822088] [PMID: 35600074]
[10]
Chang H, Yang J, Wang Q, Zhao J, Zhu R. Role of N6-methyladenosine modification in pathogenesis of ischemic stroke. Expert Rev Mol Diagn 2022; 22(3): 295-303.
[http://dx.doi.org/10.1080/14737159.2022.2049246] [PMID: 35236212]
[11]
Suo L, Liu C, Zhang QY, et al. METTL3-mediated N6 -methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication. Theranostics 2022; 12(1): 277-89.
[http://dx.doi.org/10.7150/thno.63441] [PMID: 34987645]
[12]
Su Y, Xu R, Zhang R, et al. N-methyladenosine methyltransferase plays a role in hypoxic preconditioning partially through the interaction with lncRNA H19. Acta Biochim Biophys Sin (Shanghai) 2020; 52(12): 1306-15.
[http://dx.doi.org/10.1093/abbs/gmaa130] [PMID: 33197240]
[13]
Ye Y, Feng Z, Tian S, et al. HBO Alleviates Neural Stem Cell Pyroptosis via lncRNA-H19/miR-423-5p/NLRP3 Axis and Improves Neurogenesis after Oxygen Glucose Deprivation. Oxid Med Cell Longev 2022; 2022: 1-15.
[http://dx.doi.org/10.1155/2022/9030771] [PMID: 35178162]
[14]
Mao L, Wu DH, Hu GH, Fan JH. TLR4 Enhances Cerebral Ischemia/Reperfusion Injury via Regulating NLRP3 Inflammasome and Autophagy. Mediators Inflamm 2023; 2023: 1-9.
[http://dx.doi.org/10.1155/2023/9335166] [PMID: 36879557]
[15]
Yan Z, Deng Y, Zou Y, et al. Analysis of regulatory effect of miR-149-5p on Sphingosine-1-phosphate receptor 2 of pericytes and its neuroprotective molecular mechanism after acute cerebral ischemia reperfusion in rats. Bioengineered 2021; 12(1): 3348-57.
[http://dx.doi.org/10.1080/21655979.2021.1947167] [PMID: 34224319]
[16]
Cruz-Orengo L, Daniels BP, Dorsey D, et al. Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest 2014; 124(6): 2571-84.
[http://dx.doi.org/10.1172/JCI73408] [PMID: 24812668]
[17]
Wan Y, Jin HJ, Zhu YY, et al. MicroRNA‐149–5p regulates blood–brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes. FASEB J 2018; 32(6): 3133-48.
[http://dx.doi.org/10.1096/fj.201701121R] [PMID: 29401609]
[18]
O’Sullivan SA, O’Sullivan C, Healy LM, Dev KK, Sheridan GK. Sphingosine 1‐phosphate receptors regulate TLR 4‐induced CXCL 5 release from astrocytes and microglia. J Neurochem 2018; 144(6): 736-47.
[http://dx.doi.org/10.1111/jnc.14313] [PMID: 29377126]
[19]
Cui L, Li C, Zhang G, et al. S1P/S1PR2 promote pancreatic stellate cell activation and pancreatic fibrosis in chronic pancreatitis by regulating autophagy and the NLRP3 inflammasome. Chem Biol Interact 2023; 380: 110541.
[http://dx.doi.org/10.1016/j.cbi.2023.110541] [PMID: 37169277]
[20]
Peng Y, Wang H, Sun J, Chen L, Xu M, Chu J. Electroacupuncture reduces injury to the blood-brain barrier following cerebral ischemia/reperfusion injury. Neural Regen Res 2012; 7(36): 2901-6.
[PMID: 25317142]
[21]
Peng YJ, Zhou F, Gu J, Yang R, Yang YQ, Cheng JS. [Regulative effect of electroacupuncture on aquaporin-4 in rats with focal cerebral ischemia/reperfusion]. Zhen Ci Yan Jiu 2007; 32(2): 83-7.
[22]
Al-Mufti F, Amuluru K, Roth W, Nuoman R, El-Ghanem M, Meyers PM. Cerebral Ischemic Reperfusion Injury Following Recanalization of Large Vessel Occlusions. Neurosurgery 2018; 82(6): 781-9.
[http://dx.doi.org/10.1093/neuros/nyx341] [PMID: 28973661]
[23]
Yang M, Wang Y, Wang S, et al. Electroacupuncture pretreatment induces ischemic tolerance by neuronal TREM2-mediated enhancement of autophagic flux. Brain Res Bull 2023; 193: 27-36.
[http://dx.doi.org/10.1016/j.brainresbull.2022.11.021] [PMID: 36470555]
[24]
Mei ZG, Huang YG, Feng ZT, et al. Electroacupuncture ameliorates cerebral ischemia/reperfusion injury by suppressing autophagy via the SIRT1-FOXO1 signaling pathway. Aging (Albany NY) 2020; 12(13): 13187-205.
[http://dx.doi.org/10.18632/aging.103420] [PMID: 32620714]
[25]
Ting Z, Jianbin Z, Luqi H. Protective effect of electroacupuncture on neurons autophagy in perfusion period of cerebral ischemia. Neurosci Lett 2017; 661: 41-5.
[http://dx.doi.org/10.1016/j.neulet.2017.06.043] [PMID: 28663053]
[26]
Wang GL, Xu SY, Lv HQ, Zhang C, Peng YJ. Electroacupuncture Inhibits Ferroptosis Induced by Cerebral Ischemiareperfusion. Curr Neurovasc Res 2023; 20(3): 346-53.
[http://dx.doi.org/10.2174/1567202620666230623153728] [PMID: 37357521]
[27]
Duc Nguyen M, Van Tran T, Vinh Nguyen Q, Khac Nguyen N, Truong Vu S, Trong Nguyen L. Effectiveness on post-stroke hemiplegia in patients: Electroacupuncture plus cycling electroacupuncture alone. J Trad Chin Med 2023; 43(2): 352-8.
[28]
Liu AJ, Li JH, Li HQ, et al. Electroacupuncture for Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials. Am J Chin Med 2015; 43(8): 1541-66.
[http://dx.doi.org/10.1142/S0192415X15500883] [PMID: 26621442]
[29]
Yu BH, Xing Y, Zhang F. The Therapeutic Effect of Electroacupuncture Therapy for Ischemic Stroke. eCAM 2020; 6415083.
[http://dx.doi.org/10.1155/2020/6415083]
[30]
Xu SY, Lv HQ, Li WQ, Hong H, Peng YJ, Zhu BM. Electroacupuncture Alleviates Cerebral Ischemia/Reperfusion Injury in Rats by Histone H4 Lysine 16 Acetylation-Mediated Autophagy. Front Psychiatry 2020; 11: 576539.
[http://dx.doi.org/10.3389/fpsyt.2020.576539] [PMID: 33391046]
[31]
Shao L, Chen B, Wu Q, et al. N6-methyladenosine-modified lncRNA and mRNA modification profiles in cerebral ischemia-reperfusion injury. Front Genet 2022; 13: 973979.
[http://dx.doi.org/10.3389/fgene.2022.973979] [PMID: 36479246]
[32]
Huang G, Qiu Y, Fan Y, Liu J. METTL3-deficiency Suppresses Neural Apoptosis to Induce Protective Effects in Cerebral I/R Injury via Inhibiting RNA m6A Modifications: A Pre-clinical and Pilot Study. Neurochem Res 2023.
[PMID: 37610605]
[33]
Hu S, Zheng J, Du Z, Wu G. Knock down of lncRNA H19 promotes axon sprouting and functional recovery after cerebral ischemic stroke. Brain Res 2020; 1732: 146681.
[http://dx.doi.org/10.1016/j.brainres.2020.146681] [PMID: 31991123]
[34]
Tourkochristou E, Mouzaki A, Triantos C. Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases. World J Gastroenterol 2023; 29(1): 110-25.
[http://dx.doi.org/10.3748/wjg.v29.i1.110] [PMID: 36683721]
[35]
Alam S, Afsar SY, Wolter MA, et al. S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling. Cells 2023; 12(14): 1844.
[http://dx.doi.org/10.3390/cells12141844] [PMID: 37508508]
[36]
Adada M, Canals D, Hannun YA, Obeid LM. Sphingosine-1-phosphate receptor 2. FEBS J 2013; 280(24): 6354-66.
[http://dx.doi.org/10.1111/febs.12446] [PMID: 23879641]
[37]
Gaire BP, Choi JW. Sphingosine 1-Phosphate Receptors in Cerebral Ischemia. Neuromolecular Med 2021; 23(1): 211-23.
[http://dx.doi.org/10.1007/s12017-020-08614-2] [PMID: 32914259]
[38]
Rahman Z, Ghuge S, Dandekar MP. Partial blood replacement ameliorates middle cerebral artery occlusion generated neurological aberrations by intervening TLR4 and NLRP3 cascades in rats. Metab Brain Dis 2023; 38(7): 2339-54.
[http://dx.doi.org/10.1007/s11011-023-01259-7] [PMID: 37402080]
[39]
Long JX, Tian MZ, Chen XY, et al. The role of NLRP3 inflammasome-mediated pyroptosis in ischemic stroke and the intervention of traditional Chinese medicine. Front Pharmacol 2023; 14: 1151196.
[http://dx.doi.org/10.3389/fphar.2023.1151196] [PMID: 37153784]
[40]
Yang B, Sun Y, Lv C, Zhang W, Chen Y. Procyanidins exhibits neuroprotective activities against cerebral ischemia reperfusion injury by inhibiting TLR4-NLRP3 inflammasome signal pathway. Psychopharmacology (Berl) 2020; 237(11): 3283-93.
[http://dx.doi.org/10.1007/s00213-020-05610-z] [PMID: 32729095]
[41]
Dai M, Wu L, Yu K, Xu R, Wei Y, Chinnathambi A. D-Carvone inhibit cerebral ischemia/reperfusion induced inflammatory response TLR4/NLRP3 signaling pathway. Biomed Pharmacother =. Biomed Pharmacother 2020; 123: 110870.