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Exploration of MST1-Mediated Secondary Brain Injury Induced by Intracerebral Hemorrhage in Rats via Hippo Signaling Pathway

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Abstract

Intracerebral hemorrhage (ICH) is a serious public health problem which causes high rates of disability and mortality in adults. Cell apoptosis is a sign of secondary brain injury (SBI) following ICH. Mammalian sterile 20-like kinase-1 (MST1), an apoptosis-promoting kinase, is a part of the Hippo signaling pathway and involved in cell death, oxidative stress, and inflammation. However, the role and underlying mechanism of MST1 in SBI induced by ICH have not yet been fully explained. The main purpose of present research was to explore the role of MST1 and its potential mechanism in SBI after ICH. An ICH model was established by injecting autologous blood into the right basal ganglia in male SD rats. We found that MST1 phosphorylation was significantly increased in brain tissues of rats after ICH. Additionally, inhibition of MST1 phosphorylation by a chemical inhibitor (Xmu-mp-1) and genetic knockdown could effectively reduce the activation of P-LATS1 and P-YAP which are downstream proteins of MST1 and decrease neuronal cell death and inflammation reaction in ICH rats. Furthermore, the decreased of MST1 phosphorylation reduced brain edema, blood-brain barrier (BBB) damage, and neurobehavioral impairment during ICH. Over-expression of MST1 resulted in opposite effects. Finally, deletion of MST1 significantly reduced neuronal apoptosis in vitro. In summary, our study revealed that MST1 played an important role in the SBI following ICH, and inhibition of MST1 could alleviate ICH-induced SBI. Therefore, MST1 may be considered as a potential therapeutic target for SBI following ICH.

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Funding

This study was funded by the National Key R&D Program of China (No. 2018YFC1312600 and 2018YFC1312601), Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), Jiangsu Provincial Medical Youth Talent (No. QNRC2016728), Suzhou Key Medical Centre (No. Szzx201501), Scientific Department of Jiangsu Province (No. BE2017656), and Suzhou Government (LCZX201601).

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Author notes

  1. Peng Zhang, Tianyi Wang and Dongping Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, China

    Peng Zhang, Tianyi Wang, Dongping Zhang, Zhuwei Zhang, Shuai Yuan, Juyi Zhang, Jie Cao, Haiying Li, Xiang Li, Haitao Shen & Gang Chen

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  1. Peng Zhang
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  2. Tianyi Wang
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  3. Dongping Zhang
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  11. Gang Chen
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Correspondence to Haitao Shen or Gang Chen.

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Zhang, P., Wang, T., Zhang, D. et al. Exploration of MST1-Mediated Secondary Brain Injury Induced by Intracerebral Hemorrhage in Rats via Hippo Signaling Pathway. Transl. Stroke Res. 10, 729–743 (2019). https://doi.org/10.1007/s12975-019-00702-1

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