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Metabolic Brain Disease

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01-03-2022 | Stroke | Original Article

LncRNA NEAT1 ameliorate ischemic stroke via promoting Mfn2 expression through binding to Nova and activates Sirt3

Authors: Zhi-Wen Zhou, Xiang Ren, Li-Jun Zheng, Ai-Ping Li, Wen-Sheng Zhou

Published in: Metabolic Brain Disease | Issue 3/2022

Abstract

Background

Recent studies revealed that long non-coding RNAs (lncRNAs) have significant roles in regulating the pathogenesis of ischemia stroke, and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cell apoptosis. Aberrant expression of NEAT1 was found after the injury of ischemia-reperfusion, but the mechanism was not fully understood.

Methods

The expression of NEAT1 and Mfn2 were detected in BV-2 and N2a cell with or without OGD/R-induced by qRT-PCR. Inflammatory cytokines secretion was detected by enzyme-linked immunosorbent assay (ELISA). The oxidative stress was evaluated by the examination of ROS, MDA and SOD levels. Flow cytometry and apoptosis marker detection by western blot were performed to examined apoptosis.

Results

The expression of NEAT1 and Mfn2 were decreased in OGD/R-induced cell model. Overexpression of NEAT1 or Mfn2 reduced oxidative stress and apoptosis by OGD/R-induced in neuronal cells, while knockdown of Sirt3 reversed the protective effect of NEAT1 and Mfn2. NEAT1 stabilized Mfn2 mRNA via recruiting Nova. NEAT1 alleviates the oxidative stress and apoptosis by OGD/R-induced via activating Sirt3.

Conclusion

LncRNA NEAT1 stabilizes Mfn2 mRNA via recruiting Nova, therefore increase the expression of Mfn2 and alleviates ischemia-reperfusion induced oxidative stress and apoptosis via Mfn2/Sirt3 pathway.

An J, Lv W, Zhang Y (2017) LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR-194. OncoTargets and therapy 10:5377PubMedPubMedCentral

Bause AS, Haigis MC (2013) SIRT3 regulation of mitochondrial oxidative stress. Experimental gerontology 48(7):634–639PubMed

Campbell BC, De Silva DA, Macleod MR, Coutts SB, Schwamm LH, Davis SM, Donnan GA (2019) Ischaemic stroke. Nature Reviews Disease Primers 5(1):1–22

Chakravarty, D., Sboner, A., Nair, S. S., Giannopoulou, E., Li, R., Hennig, S., . . . Kossai, M. (2014). The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nature communications, 5(1), 1-16.

Chouchani, E. T., Pell, V. R., James, A. M., Work, L. M., Saeb-Parsy, K., Frezza, C., . . . Murphy, M. P. (2016). A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. Cell Metab, 23(2), 254-263. https://doi.org/10.1016/j.cmet.2015.12.009CrossRefPubMed

Dorn GW II (2020) Mitofusins as mitochondrial anchors and tethers. Journal of molecular and cellular cardiology 142:146–153PubMedPubMedCentral

Filadi R, Pendin D, Pizzo P (2018) Mitofusin 2: from functions to disease. Cell death & disease 9(3):1–13

Gao N, Tang H, Gao L, Tu G-L, Luo H, Xia Y (2020) LncRNA H19 Aggravates Cerebral Ischemia/Reperfusion Injury by Functioning as a ceRNA for miR-19a-3p to Target PTEN. Neuroscience 437:117–129PubMed

Goyal, M., Menon, B. K., van Zwam, W. H., Dippel, D. W., Mitchell, P. J., Demchuk, A. M., . . . De Miquel, M. A. (2016). Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. The Lancet, 387(10029), 1723-1731.

Han D, Zhou Y (2019) YY1-induced upregulation of lncRNA NEAT1 contributes to OGD/R injury-induced inflammatory response in cerebral microglial cells via Wnt/β-catenin signaling pathway. In Vitro Cellular & Developmental Biology-Animal 55(7):501–511

Hirschey, M. D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D. B., . . . Ilkayeva, O. R. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature, 464(7285), 121-125.PubMedPubMedCentral

Lei W, Wang Z-L, Feng H-J, Lin X-D, Li C-Z, Fan D (2018) Long non-coding RNA SNHG12promotes the proliferation and migration of glioma cells by binding to HuR. International journal of oncology 53(3):1374–1384PubMed

Lelli, A., Nolan, K. A., Santambrogio, S., Gonçalves, A. F., Schönenberger, M. J., Guinot, A., . . . Wenger, R. H. (2015). Induction of long noncoding RNA MALAT1 in hypoxic mice. Hypoxia, 3, 45.PubMedPubMedCentral

Lewis, H. A., Chen, H., Edo, C., Buckanovich, R. J., Yang, Y. Y., Musunuru, K., . . . Burley, S. K. (1999). Crystal structures of Nova-1 and Nova-2 K-homology RNA-binding domains. Structure, 7(2), 191-203.PubMed

Li, H., Lv, B., Kong, L., Xia, J., Zhu, M., Hu, L., . . . Zhu, S. (2017). Nova1 mediates resistance of rat pheochromocytoma cells to hypoxia-induced apoptosis via the Bax/Bcl-2/caspase-3 pathway. International journal of molecular medicine, 40(4), 1125-1133.PubMedPubMedCentral

Ling, ZA., Xiong, DD., Meng, RM., Cen, J.-M., Zhao, N., Chen, G., . . . Dang, Y. (2018). LncRNA NEAT1 promotes deterioration of hepatocellular carcinoma based on in vitro experiments, data mining, and RT-qPCR analysis. Cellular Physiology and Biochemistry, 48(2), 540-555.PubMed

Liu M, Li X, Huang D (2020). Mfn2 Overexpression Attenuates Cardio-Cerebrovascular Ischemia–Reperfusion Injury Through Mitochondrial Fusion and Activation of the AMPK/Sirt3 Signaling. Frontiers in Cell and Developmental Biology, 8

Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nature reviews neuroscience 4(5):399–414PubMed

Marchese FP, Raimondi I, Huarte M (2017) The multidimensional mechanisms of long noncoding RNA function. Genome biology 18(1):1–13

Monnier P, Martinet C, Pontis J, Stancheva I, Ait-Si-Ali S, Dandolo L (2013) H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1. Proceedings of the National Academy of Sciences 110(51):20693–20698

Olmez I, Ozyurt H (2012) Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int 60(2):208–212. https://doi.org/10.1016/j.neuint.2011.11.009CrossRefPubMed

Peng, C., Rao, W., Zhang, L., Gao, F., Hui, H., Wang, K., . . . Ma, Y. (2018). Mitofusin 2 exerts a protective role in ischemia reperfusion injury through increasing autophagy. Cellular Physiology and Biochemistry, 46(6), 2311-2324.PubMed

Peng, C., Rao, W., Zhang, L., Wang, K., Hui, H., Wang, L., . . . Tu, Y. (2015). Mitofusin 2 ameliorates hypoxia-induced apoptosis via mitochondrial function and signaling pathways. The international journal of biochemistry & cell biology, 69, 29-40.

Popa-Wagner A, Dumitrascu DI, Capitanescu B, Petcu EB, Surugiu R, Fang WH, Dumbrava DA (2020) Dietary habits, lifestyle factors and neurodegenerative diseases. Neural regeneration research 15(3):394PubMed

Popa-Wagner A, Buga AM, Doeppner TR, Hermann DM (2014) Stem cell therapies in preclinical models of stroke associated with aging. Frontiers in cellular neuroscience 8:347PubMedPubMedCentral

Sacco, R. L., Kasner, S. E., Broderick, J. P., Caplan, L. R., Connors, J., Culebras, A., . . . Higashida, R. T. (2013). An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 44(7), 2064-2089.PubMed

Shen, C., Liu, M., Tian, H., Li, J., Xu, R., Mwangi, J., . . . Lai, R. (2020a). Conformation-Specific Blockade of alphaIIbbeta3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia. Thromb Haemost, 120(10), 1432-1441. https://doi.org/10.1055/s-0040-1714215CrossRefPubMed

Shen, C., Liu, M., Xu, R., Wang, G., Li, J., Chen, P., . . . Duan, Z. (2020b). The 14-3-3ζ–c-Src–integrin-β3 complex is vital for platelet activation. Blood, The Journal of the American Society of Hematology, 136(8), 974-988.

Shi H, Deng H-X, Gius D, Schumacker PT, Surmeier DJ, Ma Y-C (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Human molecular genetics 26(10):1915–1926PubMedPubMedCentral

Souquere S, Beauclair G, Harper F, Fox A, Pierron G (2010) Highly ordered spatial organization of the structural long noncoding NEAT1 RNAs within paraspeckle nuclear bodies. Molecular biology of the cell 21(22):4020–4027PubMedPubMedCentral

Statello L, Guo C-J, Chen L-L, Huarte M (2020) Gene regulation by long non-coding RNAs and its biological functions. Nature Reviews Molecular Cell Biology:1–23

Strong K, Mathers C, Bonita R (2007) Preventing stroke: saving lives around the world. Lancet Neurol 6(2):182–187. https://doi.org/10.1016/S1474-4422(07)70031-5CrossRefPubMed

Sun S, Wang R, Yi S, Li S, Wang L, Wang J (2021) Roles of the microRNA-338-3p/NOVA1 axis in retinoblastoma. Molecular medicine reports 23(5):1–13

Tang, X., Fang, M., Cheng, R., Zhang, Z., Wang, Y., Shen, C., . . . Liu, Y. (2020). Iron-deficiency and estrogen are associated with ischemic stroke by up-regulating transferrin to induce hypercoagulability. Circulation research, 127(5), 651-663.PubMed

Teplova, M., Malinina, L., Darnell, J. C., Song, J., Lu, M., Abagyan, R., . . . Darnell, R. B. (2011). Protein-RNA and protein-protein recognition by dual KH1/2 domains of the neuronal splicing factor Nova-1. Structure, 19(7), 930-944.PubMedPubMedCentral

Verma R, Ritzel RM, Crapser J, Friedler BD, McCullough LD (2019) Evaluation of the neuroprotective effect of Sirt3 in experimental stroke. Translational stroke research 10(1):57–66PubMed

Wang, Q., Liu, J., You, Z., Yin, Y., Liu, L., Kang, Y., . . . Gong, Y. (2021). LncRNA TINCR favors tumorigenesis via STAT3–TINCR–EGFR-feedback loop by recruiting DNMT1 and acting as a competing endogenous RNA in human breast cancer. Cell death & disease, 12(1), 1-16.

Wang Q, Liu L, Zhang S, Ming Y, Liu S, Cheng K, Zhao Y (2020) Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation. Experimental & molecular medicine 52(3):461–472

Wang, S., Zuo, H., Jin, J., Lv, W., Xu, Z., Fan, Y., . . . Zuo, B. (2019). Long noncoding RNA Neat1 modulates myogenesis by recruiting Ezh2. Cell death & disease, 10(7), 1-15.

Wen Y, Yu Y, Fu X (2017) LncRNA Gm4419 contributes to OGD/R injury of cerebral microglial cells via IκB phosphorylation and NF-κB activation. Biochemical and biophysical research communications 487(4):923–929PubMed

Wu, M, Yiang, G, Liao, W.-T., Tsai, A. P.-Y., Cheng, Y.-L., Cheng, P.-W., . . . Li, C.-J. (2018). Current mechanistic concepts in ischemia and reperfusion injury. Cellular Physiology and Biochemistry, 46(4), 1650-1667.PubMed

Xian S, Ding R, Li M, Chen F (2021) LncRNA NEAT1/miR-128-3p/AQP4 axis regulating spinal cord injury-induced neuropathic pain progression. Journal of Neuroimmunology 351:577457PubMed

Xin Y, Li Z, Zheng H, Ho J, Chan MT, Wu WK (2017) Neuro-oncological ventral antigen 1 (NOVA 1): Implications in neurological diseases and cancers. Cell proliferation 50(4):e12348PubMedCentral

Yang X, Geng KY, Zhang YS, Zhang JF, Yang K, Shao JX, Xia WL (2018) Sirt3 deficiency impairs neurovascular recovery in ischemic stroke. CNS neuroscience & therapeutics 24(9):775–783

Yang X, Zhang Y, Geng K, Yang K, Shao J, Xia W (2020). Sirt3 Protects Against Ischemic Stroke Injury by Regulating HIF-1α/VEGF Signaling and Blood–Brain Barrier Integrity. Cellular and Molecular Neurobiology, 1-13

Yao X, Yao R, Huang F, Yi J (2019) LncRNA SNHG12 as a potent autophagy inducer exerts neuroprotective effects against cerebral ischemia/reperfusion injury. Biochemical and biophysical research communications 514(2):490–496PubMed

Yin WL, Yin WG, Huang BS, Wu LX (2019) LncRNA SNHG12 inhibits miR-199a to upregulate SIRT1 to attenuate cerebral ischemia/reperfusion injury through activating AMPK signaling pathway. Neurosci Lett 690:188–195. https://doi.org/10.1016/j.neulet.2018.08.026CrossRefPubMed

Yu HM, Wang C, Yuan Z, Chen GL, Ye T, Yang BW (2019b) LncRNA NEAT1 promotes the tumorigenesis of colorectal cancer by sponging miR-193a-3p. Cell proliferation 52(1):e12526PubMed

Yu P, Wang Y, Lv W, Kou D, Hu H, Guo S, Zhao Y (2019a) LncRNA NEAT1/miR-1224/KLF3 contributes to cell proliferation, apoptosis and invasion in lung cancer. Eur Rev Med Pharmacol Sci 23(19):8403–8410PubMed

Zhang, L., Luo, X., Chen, F., Yuan, W., Xiao, X., Zhang, X., . . . Liu, Y. (2018). LncRNA SNHG1 regulates cerebrovascular pathologies as a competing endogenous RNA through HIF-1alpha/VEGF signaling in ischemic stroke. J Cell Biochem, 119(7), 5460-5472. https://doi.org/10.1002/jcb.26705CrossRefPubMed

Zhang M, Wu W, Wang Z, Wang X (2017) lncRNA NEAT1 is closely related with progression of breast cancer via promoting proliferation and EMT. Eur Rev Med Pharmacol Sci 21(5):1020–1026PubMed

Zhang P, Cao L, Zhou R, Yang X, Wu M (2019) The lncRNA Neat1 promotes activation of inflammasomes in macrophages. Nature communications 10(1):1–17

Zhang, Z., Meng, P., Han, Y., Shen, C., Li, B., Hakim, M. A., . . . Lai, R. (2015). Mitochondrial DNA-LL-37 complex promotes atherosclerosis by escaping from autophagic recognition. Immunity, 43(6), 1137-1147.PubMed

Zhao J, He L, Yin L (2020) lncRNA NEAT1 binds to miR-339-5p to increase HOXA1 and alleviate ischemic brain damage in neonatal mice. Molecular Therapy-Nucleic Acids 20:117–127PubMedPubMedCentral

Zhi, F., Wang, Q., Deng, D., Shao, N., Wang, R., Xue, L., . . . Yang, Y. (2014). MiR-181b-5p downregulates NOVA1 to suppress proliferation, migration and invasion and promote apoptosis in astrocytoma. PLoS One, 9(10), e109124.PubMedPubMedCentral

Zhou Z-W, Zheng L-J, Ren X, Li A-P, Zhou W-S (2019) LncRNA NEAT1 facilitates survival and angiogenesis in oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs) via targeting miR-377 and upregulating SIRT1, VEGFA, and BCL-XL. Brain research 1707:90–98PubMed

Zhu W, Tian L, Yue X, Liu J, Fu Y, Yan Y (2019) LncRNA expression profiling of ischemic stroke during the transition from the acute to subacute stage. Frontiers in neurology 10:36PubMedPubMedCentral

Title: LncRNA NEAT1 ameliorate ischemic stroke via promoting Mfn2 expression through binding to Nova and activates Sirt3
Authors: Zhi-Wen Zhou
Xiang Ren
Li-Jun Zheng
Ai-Ping Li
Wen-Sheng Zhou
Publication date: 01-03-2022
Publisher: Springer US
Keyword: Stroke
Published in: Metabolic Brain Disease / Issue 3/2022
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-021-00895-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

LncRNA NEAT1 ameliorate ischemic stroke via promoting Mfn2 expression through binding to Nova and activates Sirt3

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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