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GATA6 Inhibits Neuronal Autophagy and Ferroptosis in Cerebral ischemia-reperfusion Injury Through a miR-193b/ATG7 axis-dependent Mechanism

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Abstract

Ferroptosis is a newly described form of regulated necrotic cell death, which is engaged in the pathological cell death related to stroke, contributing to cerebral ischemia-reperfusion (I/R) injury. Therefore, we performed this study to clarify the role of GATA6 in neuronal autophagy and ferroptosis in cerebral I/R injury. The cerebral I/R injury-related differentially expressed genes (DEGs) as well as the downstream factors of GATA6 were predicted bioinformatically. Moreover, the relations between GATA6 and miR-193b and that between miR-193b and ATG7 were evaluated by chromatin immunoprecipitation and dual-luciferase reporter assays. Besides, neurons were treated with oxygen-glucose deprivation (OGD), followed by overexpression of GATA6, miR-193b, and ATG7 alone or in combination to assess neuronal autophagy and ferroptosis. At last, in vivo experiments were performed to explore the impacts of GATA6/miR-193b/ATG7 on neuronal autophagy and ferroptosis in a rat model of middle cerebral artery occlusion (MCAO)-stimulated cerebral I/R injury. It was found that GATA6 and miR-193b were poorly expressed in cerebral I/R injury. GATA6 transcriptionally activated miR-193b to downregulate ATG7. Additionally, GATA6-mediated miR-193b activation suppressed neuronal autophagy and ferroptosis in OGD-treated neurons by inhibiting ATG7. Furthermore, GATA6/miR-193b relieved cerebral I/R injury by restraining neuronal autophagy and ferroptosis via downregulation of ATG7 in vivo. In summary, GATA6 might prevent neuronal autophagy and ferroptosis to alleviate cerebral I/R injury via the miR-193b/ATG7 axis.

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Data Availability

The datasets used and analysed in the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by grants from Science and Technology Commission of Shanghai Municipality (20Y11909700), Pudong New Area Clinical Plateau Discipline Project (PWYgy2021-03), the Science and Technology Project of Suzhou City of China (No. SYS2020186, SKY2021011, SLJ2022024) and Program for Medical Key subspecialty Department of Shanghai Pudong health system (PWZy2020-13). We acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

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Authors and Affiliations

  1. Department of Vascular Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201300, P. R. China

    Weijian Fan, Jie Wang, Bo Yu & Jindong Tong

  2. Department of Vascular Surgery, Huashan Hospital of Fudan University, No.12, Mid-Wulumuqi Road, Shanghai, 200040, P.R. China

    Weijian Fan, Weihao Shi, Jinyun Tan & Bo Yu

  3. Department of Vascular Surgery, Suzhou TCM Hospital, Nanjing University of Chinese Medicine, Suzhou215000, Nanjing, P.R. China

    Jianjie Rong

  4. Department of Neurology, Suzhou TCM Hospital, Nanjing University of Chinese Medicine, Suzhou215000, Nanjing, P.R. China

    Wei Liu

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Weijian Fan and Jindong Tong were responsible for project design and conducting experiments, data analysis and interpretation and manuscript and figure confection. Wei Liu and Bo Yu conducted experiments, data analysis and interpretation. Weihao Shi and Jianjie Rong provided technical support. Jie Wang and Jinyun Tan reviewed the manuscript and provided help with statistical analysis. All authors have approved the submitted manuscript.

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Correspondence to Bo Yu or Jindong Tong.

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Fan, W., Rong, J., Shi, W. et al. GATA6 Inhibits Neuronal Autophagy and Ferroptosis in Cerebral ischemia-reperfusion Injury Through a miR-193b/ATG7 axis-dependent Mechanism. Neurochem Res 48, 2552–2567 (2023). https://doi.org/10.1007/s11064-023-03918-8

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