https://doi.org/10.4081/ejh.2021.3224
Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis
Submitted: 4 February 2021
Accepted: 12 August 2021
Published: 30 September 2021
Accepted: 12 August 2021
Abstract Views: 2428
PDF: 1532
HTML: 32
HTML: 32
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Individuals with diabetes are exposed to a higher risk of perioperative stroke than non-diabetics mainly due to persistent hyperglycemia. LncRNA Meg3 has been considered as an important mediator in regulating ischemic stroke. However, the functional and regulatory roles of Meg3 in diabetic brain ischemic injury remain unclear. In this study, rat brain microvascular endothelial cells (RBMVECs) were exposed to 6 h of oxygen and glucose deprivation (OGD), and subsequent reperfusion via incubating cells with glucose of various high concentrations for 24 h to imitate in vitro diabetic brain ischemic injury. It was shown that the marker events of ferroptosis and increased Meg3 expression occurred after the injury induced by OGD combined with hyperglycemia. However, all ferroptotic events were reversed with the treatment of Meg3-siRNA. Moreover, in this in vitro model, p53 was also characterized as a downstream target of Meg3. Furthermore, p53 knockdown protected RBMVECs against OGD + hyperglycemic reperfusion-induced ferroptosis, while the overexpression of p53 exerted opposite effects, implying that p53 served as a positive regulator of ferroptosis. Additionally, the overexpression or knockdown of p53 significantly modulated GPX4 expression in RBMVECs exposed to the injury induced by OGD combined with hyperglycemic treatment. Furthermore, GPX4 expression was suppressed again after the reintroduction of p53 into cells silenced by Meg3. Finally, chromatin immunoprecipitation assay uncovered that p53 was bound to GPX4 promoter. Altogether, these data revealed that, by modulating GPX4 transcription and expression, the Meg3-p53 signaling pathway mediated the ferroptosis of RBMVECs upon injury induced by OGD combined with hyperglycemic reperfusion.
Vlisides P, Mashour GA. Perioperative stroke. Can J Anaesth 2016;63:193-204.
DOI: https://doi.org/10.1007/s12630-015-0494-9
Pai SL, Wang RD, Aniskevich S. Perioperative stroke: incidence, etiologic factors, and prevention. Minerva Anestesiol 2017;83:1178-89.
DOI: https://doi.org/10.23736/S0375-9393.17.11976-0
Chen R, Ovbiagele B, Feng W. Diabetes and stroke: Epidemiology, pathophysiology, pharmaceuticals and outcomes. Am J Med Sci 2016;351:380-6.
DOI: https://doi.org/10.1016/j.amjms.2016.01.011
Alloubani A, Saleh A, Abdelhafiz I. Hypertension and diabetes mellitus as a predictive risk factors for stroke. Diabetes Metab Syndr 2018;12:577-84.
DOI: https://doi.org/10.1016/j.dsx.2018.03.009
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060-72.
DOI: https://doi.org/10.1016/j.cell.2012.03.042
Almutairi MMA, Xu G, Shi H. Iron pathophysiology in stroke. Adv Exp Med Biol 2019;1173:105-23.
DOI: https://doi.org/10.1007/978-981-13-9589-5_6
Tuo QZ, Lei P, Jackman KA, Li XL, Xiong H, Li XL, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry 2017;22:1520-30.
DOI: https://doi.org/10.1038/mp.2017.171
Sanchez Calle A, Kawamura Y, Yamamoto Y, Takeshita F, Ochiya T. Emerging roles of long non-coding RNA in cancer. Cancer Sci 2018;109:2093-100.
DOI: https://doi.org/10.1111/cas.13642
Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 2016;17:47-62.
DOI: https://doi.org/10.1038/nrg.2015.10
Deng Y, Chen D, Wang L, Gao F, Jin B, Lv H, et al. Silencing of long noncoding RNA nespas aggravates microglial cell death and neuroinflammation in ischemic stroke. Stroke 2019;50:1850-8.
DOI: https://doi.org/10.1161/STROKEAHA.118.023376
Zhang X, Zhu XL, Ji BY, Cao X, Yu LJ, Zhang Y, et al. LncRNA-1810034E14Rik reduces microglia activation in experimental ischemic stroke. J Neuroinflammation 2019;16:75.
DOI: https://doi.org/10.1186/s12974-019-1464-x
Liang J, Wang Q, Li JQ, Guo T, Yu D. Long non-coding RNA MEG3 promotes cerebral ischemia-reperfusion injury through increasing pyroptosis by targeting miR-485/AIM2 axis. Exp Neurol 2020;325:113139.
DOI: https://doi.org/10.1016/j.expneurol.2019.113139
Zhang P, Sun Y, Peng R, Chen W, Fu X, Zhang L, et al. Long non-coding RNA Rpph1 promotes inflammation and proliferation of mesangial cells in diabetic nephropathy via an interaction with Gal-3. Cell Death Dis 2019;10:526.
DOI: https://doi.org/10.1038/s41419-019-1765-0
Abdulle LE, Hao JL, Pant OP, Liu XF, Zhou DD, Gao Y, et al. MALAT1 as a diagnostic and therapeutic target in diabetes-related complications: A promising long-noncoding RNA. Int J Med Sci 2019;16:548-55.
DOI: https://doi.org/10.7150/ijms.30097
Sommerkamp P, Renders S, Ladel L, Hotz-Wagenblatt A, Schonberger K, Zeisberger P, et al. The long non-coding RNA Meg3 is dispensable for hematopoietic stem cells. Sci Rep 2019;9:2110.
DOI: https://doi.org/10.1038/s41598-019-38605-8
Zhao H, Wang X, Feng X, Li X, Pan L, Liu J, et al. Long non-coding RNA MEG3 regulates proliferation, apoptosis, and autophagy and is associated with prognosis in glioma. J Neurooncol 2018;140:281-8.
DOI: https://doi.org/10.1007/s11060-018-2874-9
Yan H, Yuan J, Gao L, Rao J, Hu J. Long noncoding RNA MEG3 activation of p53 mediates ischemic neuronal death in stroke. Neuroscience 2016;337:191-9.
DOI: https://doi.org/10.1016/j.neuroscience.2016.09.017
Liu J, Li Q, Zhang KS, Hu B, Niu X, Zhou SM, et al. Downregulation of the long non-coding RNA meg3 promotes angiogenesis after ischemic brain injury by activating notch signaling. Mol Neurobiol 2017;54:8179-90.
DOI: https://doi.org/10.1007/s12035-016-0270-z
Yan H, Rao J, Yuan J, Gao L, Huang W, Zhao L, et al. Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway. Cell Death Dis 2017;8:3211.
DOI: https://doi.org/10.1038/s41419-017-0047-y
Lyu Y, Lou J, Yang Y, Feng J, Hao Y, Huang S, et al. Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways. Leukemia 2017;31:2543-51.
DOI: https://doi.org/10.1038/leu.2017.116
Uroda T, Anastasakou E, Rossi A, Teulon JM, Pellequer JL, Annibale P, et al. Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway. Mol Cell 2019;75:982-95.e9.
DOI: https://doi.org/10.1016/j.molcel.2019.07.025
Mao C, Wang X, Liu Y, Wang M, Yan B, Jiang Y, et al. A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res 2018;78:3484-96.
DOI: https://doi.org/10.1158/0008-5472.CAN-17-3454
Chu B, Kon N, Chen D, Li T, Liu T, Jiang L, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol 2019;21:579-91.
DOI: https://doi.org/10.1038/s41556-019-0305-6
Li W, Chen Z, Yan M, He P, Chen Z, Dai H. The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation. J Neurochem 2016;136:651-9.
DOI: https://doi.org/10.1111/jnc.13436
Zhan R, Xu K, Pan J, Xu Q, Xu S, Shen J. Long noncoding RNA MEG3 mediated angiogenesis after cerebral infarction through regulating p53/NOX4 axis. Biochem Biophys Res Commun 2017;490:700-6.
DOI: https://doi.org/10.1016/j.bbrc.2017.06.104
Pan Y, Wang N, Xia P, Wang E, Guo Q, Ye Z. Inhibition of Rac1 ameliorates neuronal oxidative stress damage via reducing Bcl-2/Rac1 complex formation in mitochondria through PI3K/Akt/mTOR pathway. Exp Neurol 2018;300:149-66.
DOI: https://doi.org/10.1016/j.expneurol.2017.10.030
Xia P, Pan Y, Zhang F, Wang N, Wang E, Guo Q, et al. Pioglitazone confers neuroprotection against ischemia-induced pyroptosis due to its inhibitory effects on HMGB-1/RAGE and Rac1/ROS pathway by activating PPAR. Cell Physiol Biochem 2018;45:2351-68.
DOI: https://doi.org/10.1159/000488183
Wang Z, Ye Z, Huang G, Wang N, Wang E, Guo Q. Sevoflurane post-conditioning enhanced hippocampal neuron resistance to global cerebral ischemia induced by cardiac arrest in rats through PI3K/Akt survival pathway. Front Cell Neurosci 2016;10:271.
DOI: https://doi.org/10.3389/fncel.2016.00271
Ye Z, Li Q, Guo Q, Xiong Y, Guo D, Yang H, et al. Ketamine induces hippocampal apoptosis through a mechanism associated with the caspase-1 dependent pyroptosis. Neuropharmacology 2018;128:63-75.
DOI: https://doi.org/10.1016/j.neuropharm.2017.09.035
Xia P, Zhang F, Yuan Y, Chen C, Huang Y, Li L, et al. ALDH 2 conferred neuroprotection on cerebral ischemic injury by alleviating mitochondria-related apoptosis through JNK/caspase-3 signing pathway. Int J Biol Sci 2020;16:1303-23.
DOI: https://doi.org/10.7150/ijbs.38962
Qiu GZ, Tian W, Fu HT, Li CP, Liu B. Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction. Biochem Biophys Res Commun 2016;471:135-41.
DOI: https://doi.org/10.1016/j.bbrc.2016.01.164
Tong P, Peng QH, Gu LM, Xie WW, Li WJ. LncRNA-MEG3 alleviates high glucose induced inflammation and apoptosis of retina epithelial cells via regulating miR-34a/SIRT1 axis. Exp Mol Pathol 2019;107:102-9.
DOI: https://doi.org/10.1016/j.yexmp.2018.12.003
Chanda K, Das S, Chakraborty J, Bucha S, Maitra A, Chatterjee R, et al. Altered levels of long NcRNAs meg3 and neat1 in cell and animal models of Huntington's disease. RNA Biol 2018;15:1348-63.
DOI: https://doi.org/10.1080/15476286.2018.1534524
Johnson R. Long non-coding RNAs in Huntington's disease neurodegeneration. Neurobiol Dis 2012;46:245-54.
DOI: https://doi.org/10.1016/j.nbd.2011.12.006
He C, Yang W, Yang J, Ding J, Li S, Wu H, et al. Long noncoding RNA MEG3 negatively regulates proliferation and angiogenesis in vascular endothelial cells. DNA Cell Biol 2017;36:475-81.
DOI: https://doi.org/10.1089/dna.2017.3682
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ 2016;23:369-79.
DOI: https://doi.org/10.1038/cdd.2015.158
Angeli JPF, Shah R, Pratt DA, Conrad M. Ferroptosis inhibition: Mechanisms and opportunities. Trends Pharmacol Sci 2017;38:489-98.
DOI: https://doi.org/10.1016/j.tips.2017.02.005
Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 2019;26:2284-99.
DOI: https://doi.org/10.1038/s41418-019-0299-4
Zhang W, Gai C, Ding D, Wang F, Li W. Targeted p53 on small-molecules-induced ferroptosis in cancers. Front Oncol 2018;8:507.
DOI: https://doi.org/10.3389/fonc.2018.00507
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015;520:57-62.
DOI: https://doi.org/10.1038/nature14344
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014;156:317-31.
DOI: https://doi.org/10.1016/j.cell.2013.12.010
Chen L, Hambright WS, Na R, Ran Q. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem 2015;290:28097-106.
DOI: https://doi.org/10.1074/jbc.M115.680090
Liu T, Jiang L, Tavana O, Gu W. The Deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res 2019;79:1913-24.
DOI: https://doi.org/10.1158/0008-5472.CAN-18-3037
Ye J, Jiang X, Dong Z, Hu S, Xiao M. Low-concentration PTX And RSL3 inhibits tumor cell growth synergistically by inducing ferroptosis in mutant p53 hypopharyngeal squamous carcinoma. Cancer Manag Res 2019;11:9783-92.
DOI: https://doi.org/10.2147/CMAR.S217944
Huang C, Yang M, Deng J, Li P, Su W, Jiang R. Upregulation and activation of p53 by erastin induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells. Oncol Rep 2018;40:2363-70.
DOI: https://doi.org/10.3892/or.2018.6585
How to Cite
Chen, C., Huang, Y., Xia, P., Zhang, F., Li, L., Wang, E., … Ye, Z. (2021). Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis. European Journal of Histochemistry, 65(3). https://doi.org/10.4081/ejh.2021.3224
Copyright (c) 2021 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Minkai Cao, Deping Yuan, Hongxiu Jiang, Guanlun Zhou, Chao Chen, Guorong Han, Long non-coding RNA WAC antisense RNA 1 mediates hepatitis B virus replication in vitro by reinforcing miR-192-5p/ATG7-induced autophagy , European Journal of Histochemistry: Vol. 66 No. 3 (2022)
- Huyi Liu, Xiangdao Cai , Jia Liu, Fengxiang Zhang , Andong He, Ruiman Li, The lncRNA MEG3 promotes trophoblastic cell growth and invasiveness in preeclampsia by acting as a sponge for miR-21, which regulates BMPR2 levels , European Journal of Histochemistry: Vol. 65 No. 4 (2021)
- A. Bolekova, T. Spakovska, D. Kluchova, S. Toth, J. Vesela, NADPH-diaphorase expression in the rat jejunum after intestinal ischemia/reperfusion , European Journal of Histochemistry: Vol. 55 No. 3 (2011)
- Antonella Vetuschi, Alfredo Cappariello, Paolo Onori, Eugenio Gaudio, Giovanni Latella, Simona Pompili, Roberta Sferra, Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis , European Journal of Histochemistry: Vol. 66 No. 3 (2022)
- G. Chene, N. Radosevic-Robin, A.S. Tardieu, A. Cayre, I. Raoelfils, P. Dechelotte, J. Dauplat, F. Penault Llorca, Morphological and immunohistochemical study of ovarian and tubal dysplasia associated with tamoxifen , European Journal of Histochemistry: Vol. 58 No. 2 (2014)
- Guoyue Liu, Cunzhi Yin, Mingjiang Qian, Xuan Xiao, Hang Wu, Fujian Fu, LncRNA gadd7 promotes mitochondrial membrane potential decrease and apoptosis of alveolar type II epithelial cells by positively regulating MFN1 in an in vitro model of hyperoxia-induced acute lung injury , European Journal of Histochemistry: Vol. 67 No. 2 (2023)
- Kazuhiko Hashimoto, Shunji Nishimura, Tomohiko Ito, Naohiro Oka, Ryosuke Kakinoki, Masao Akagi, Clinicopathological assessment of cancer/testis antigens NY‑ESO‑1 and MAGE‑A4 in osteosarcoma , European Journal of Histochemistry: Vol. 66 No. 3 (2022)
- E. Guerriero, F. Capone, M. Accardo, A. Sorice, M. Costantini, G. Colonna, G. Castello, S. Costantini, GPX4 and GPX7 over-expression in human hepatocellular carcinoma tissues , European Journal of Histochemistry: Vol. 59 No. 4 (2015)
- Cristian Turato, Mariapia Vairetti, Marta Cagna, Alessandra Biasiolo, Andrea Ferrigno, Santina Quarta, Mariagrazia Ruvoletto, Silvia De Siervi, Patrizia Pontisso, Laura Giuseppina Di Pasqua, SerpinB3 administration protects liver against ischemia-reperfusion injury , European Journal of Histochemistry: Vol. 66 No. 4 (2022)
- S. Huang, S. Guo, F. Guo, Q. Yang, X. Xiao, M. Murata, S. Ohnishi, S. Kawanishi, N. Ma, CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure , European Journal of Histochemistry: Vol. 57 No. 1 (2013)
You may also start an advanced similarity search for this article.
Publication Facts
Metric
This article
Other articles
Peer reviewers
2
2.4
Reviewer profiles N/A
Author statements
Author statements
This article
Other articles
Data availability
N/A
16%
External funding
N/A
32%
Competing interests
N/A
11%
Metric
This journal
Other journals
Articles accepted
57%
33%
Days to publication
237
145
- Editor & editorial board
- profiles
- Academic society
- N/A
- Publisher
- PAGEPress Publications, Pavia, Italy
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
