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LncRNA MALAT1 Promoted Neuronal Necroptosis in Cerebral Ischemia-reperfusion Mice by Stabilizing HSP90

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Abstract

The objective of this research was to investigate the role of lncRNA MALAT1 and HSP90 in the regulation of neuronal necroptosis in mice with cerebral ischemia-reperfusion (CIR). We used male C57BL/6J mice to establish a middle cerebral artery occlusion (MCAO) model and conducted in vitro experiments using the HT-22 mouse hippocampal neuron cell line. The cellular localization of NeuN and MLKL, as well as the expression levels of neuronal necroptosis factors, MALAT1, and HSP90 were analyzed. Cell viability and necroptosis were assessed, and we also investigated the relationship between MALAT1 and HSP90. The results showed that MALAT1 expression increased after MCAO and oxygen-glucose deprivation/re-oxygenation (OGD/R) treatment in both cerebral tissues and cells compared with the control group. The levels of neuronal necroptosis factors and the co-localization of NeuN and MLKL were also increased in MCAO mice compared with the Sham group. MALAT1 was found to interact with HSP90, and inhibition of HSP90 expression led to decreased phosphorylation levels of neuronal necroptosis factors. Inhibition of MALAT1 expression resulted in decreased co-localization levels of NeuN and MLKL, decreased phosphorylation levels of neuronal necroptosis factors, and reduced necroptosis rate in cerebral tissues. Furthermore, inhibiting MALAT1 expression also led to a shorter half-life of HSP90, increased ubiquitination level, and decreased phosphorylation levels of neuronal necroptosis factors in cells. In conclusion, this study demonstrated that lncRNA MALAT1 promotes neuronal necroptosis in CIR mice by stabilizing HSP90.

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Funding

The work was supported by Hainan Provincial Natural Science Foundation of China (Grant Number: 2019RC386) and Hainan Clinical Research Center for Cerebrovascular disease.

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Authors and Affiliations

  1. Department of Neurology, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, No. 43 Renmin Avenue, Haikou, 570208, Hainan, China

    Shan Huang, Dan Hou, Lei Zhang, Chaoying Pei, Junqi Li, Guoshuai Yang & Dan Yu

  2. Department of Neurology, The First People’s Hospital of Changde, Changde, 415000, Hunan, China

    Ji Liang

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  1. Shan Huang
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Contributions

“Shan Huang, Guoshuai Yang, and Dan Yu contributed to the study conception and design. Material preparation, data collection were performed by Shan Huang, Dan Hou, Lei Zhang, Chaoying Pei, and Ji Liang. Data analysis was performed by Junqi Li and Guoshuai Yang. The first draft of the manuscript was written by Shan Huang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.“

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Correspondence to Guoshuai Yang or Dan Yu.

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This study was approved by the Animal Ethics Committee of Haikou Affiliated Hospital of Central South University Xiangya School of Medicine (Approval number: 2022-058) and performed in accordance with the guidelines of the animal care and ethics committee.

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Supplementary Figure S1. The negative parameters of Annexin V-FITC and PI.

11064_2023_3991_MOESM2_ESM.jpg

Supplementary Figure S2. The expression of MLKL protein in cerebral tissues was detected using WB. *P < 0.05 vs. Sham. t-test.

11064_2023_3991_MOESM3_ESM.jpg

Supplementary Figure S3. Supplementary experiments of Fig. 2D and E. (A) The changes of MALAT1 level in cells in Fig. 2D were detected using RT-qPCR in the control group (OGD/R-0 h) and the OGD/R group (OGD/R-48 h). (B) WB was used to detect RIPK1, p-RIPK1, RIPK3, p-RIPK3, MLKL, and p-MLKL levels in the control group (OGD/R-0 h) and OGD/R group (OGD/R-48 h) in cells of Fig. 2E. *P < 0.05 vs. control. #P < 0.05 vs.sh-NC. one-way ANOVA.

Supplementary text S1. The sequence of MALAT1, MALAT1-mut1, MALAT1-mut2 and MALAT1-mut3.

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Huang, S., Hou, D., Zhang, L. et al. LncRNA MALAT1 Promoted Neuronal Necroptosis in Cerebral Ischemia-reperfusion Mice by Stabilizing HSP90. Neurochem Res 48, 3457–3471 (2023). https://doi.org/10.1007/s11064-023-03991-z

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