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HDAC3 Downregulation Improves Cerebral Ischemic Injury via Regulation of the SDC1-Dependent JAK1/STAT3 Signaling Pathway Through miR-19a Upregulation

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Abstract

Histone deacetylase (HDAC) inhibitors can protect the brain from ischemic injury. This study aimed to identify the regulation of HDAC3 in cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was performed to establish a mouse model with cerebral ischemic injury, in which expression of HDAC3 and miR-19a was evaluated using RT-qPCR. In MCAO mice with silencing of HDAC3, infarct volume was determined using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, and serum levels of TNF-α, IL-6, and IL-8 were measured using ELISA. An in vitro model was constructed in human umbilical vein endothelial cells (HUVECs) with oxygen-glucose deprivation/reoxygenation (OGD/R), followed by gain- and loss-of-function experiments. Relationships among miR-19a, HDAC3, and syndecan-1 (SDC1) were explored using RIP, ChIP, and dual-luciferase reporter assays. The expression of HDAC3, SDC1, JAK1, and STAT3 along with the extent of JAK1 and STAT3 phosphorylation was measured by Western blot analysis. HUVEC viability, apoptosis, and angiogenesis were assessed by CCK-8, flow cytometry, and angiogenesis assays in vitro separately. We found elevated HDAC3 and downregulated miR-19a expression in the MCAO mice. Decreased TNF-α, IL-6, and IL-8 serum levels were observed in response to silencing of HDAC3. HDAC3 inhibited the expression of miR-19a, which in turn targeted SDC1, leading to JAK1/STAT3 signaling pathway activation. HDAC3 overexpression or miR-19a inhibition repressed HUVEC viability and angiogenesis but enhanced HUVEC apoptosis. Our data unraveled the mechanism whereby HDAC3 inhibition ameliorated cerebral ischemic injury by activating the JAK1/STAT3 signaling pathway through miR-19a-mediated SDC1 inhibition.

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Data Availability

The datasets generated/analyzed during the current study are available.

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Funding

This study was supported by the National Natural Science Foundation of China (No.81960239, to Dr. Hua Fang) and the Foundation of Science and Technology Department of Guizhou Province (No.GZSYQCC[2014]004, to Dr. Hua Fang); The National Key R&D Program of China (No.2018YFC2001800, to Dr. Hua-Feng Li); The National Natural Science Foundation of China (No.82060244, to Dr. Jian-Ping Zhang) and the Foundation of Science and Technology of Guizhou Province Health Commission(No.gzwjkj2020-1-133, to Dr. Jian-Ping Zhang) and the Traditional Chinese-Ethnic Medicine Science and Technology Project of Guizhou Administration of Traditional Chinese Medicine (No.QZYY-2020-002, to Dr. Jian-Ping Zhang).

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Authors and Affiliations

  1. Department of Anesthesiology, Guizhou Provincial People’s Hospital, No. 83, Zhongshan East Road, Guiyang, 550002, People’s Republic of China

    Hua Fang, Ming-Hai He, Miao Yang & Jian-Ping Zhang

  2. Department of Anesthesiology, Guizhou University People’s Hospital, Guiyang, 550002, People’s Republic of China

    Hua Fang, Ming-Hai He, Miao Yang & Jian-Ping Zhang

  3. Laboratory of Anesthesiology & Perioperative Medicine, Guizhou University School of Medicine, Guiyang, 550025, People’s Republic of China

    Hua Fang, Ming-Hai He, Miao Yang & Jian-Ping Zhang

  4. Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Hua-Feng Li

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Contributions

Hua Fang conceived and together with Hua-Feng Li designed the study. Ming-Hai He and Miao Yang were involved in data collection. Hua-Feng Li and Jian-Ping Zhang performed the statistical analysis and preparation of figures. Hua Fang and Jian-Ping Zhang drafted the paper. All authors read and approved the final manuscript.

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Correspondence to Jian-Ping Zhang.

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Mice were treated humanely using approved procedures in compliance with the recommendations in the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. The protocol was approved by the Institutional Animal Care and Use Committee of Guizhou Provincial People’s Hospital.

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The authors declare that they have no competing interests.

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Hua Fang and Hua-Feng Li are regarded as joint first authors.

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Fang, H., Li, HF., He, MH. et al. HDAC3 Downregulation Improves Cerebral Ischemic Injury via Regulation of the SDC1-Dependent JAK1/STAT3 Signaling Pathway Through miR-19a Upregulation. Mol Neurobiol 58, 3158–3174 (2021). https://doi.org/10.1007/s12035-021-02325-w

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