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Thioredoxin-interacting protein mediates mitochondrion-dependent apoptosis in early brain injury after subarachnoid hemorrhage

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Abstract

Early brain injury (EBI) was reported to be the primary cause of high mortality and poor outcomes in subarachnoid hemorrhage (SAH) patients, and apoptosis is regarded as the most important physiopathologic mechanism during EBI. Recently, our team found that thioredoxin-interacting protein (TXNIP) links endoplasmic reticulum stress (ER stress) to neuronal apoptosis and aggravates EBI. However, the other underlying mechanisms remain unknown. Mitochondria are considered to be the central points in integrating apoptotic cell death. However, whether crosstalk between TXNIP and the mitochondria-mediated intrinsic apoptotic pathway is effective on EBI has not been previously reported. Therefore, we created an endovascular perforation SAH model in Sprague–Dawley rats to determine the possible mechanism. We found that TXNIP expression in apoptotic neurons significantly increased in the SAH group compared with the sham group. In addition, increased TXNIP expression was accompanied by remarkable changes in mitochondrial-related antiapoptotic and proapoptotic factors. Furthermore, resveratrol (RES, a TXNIP inhibitor) administration significantly downregulated the expression of TXNIP and mitochondria-related proapoptotic factors. Additionally, it attenuated SAH prognostic indicators, such as brain edema, blood–brain barrier permeability, and neurological deficits. Therefore, our study further confirms that TXNIP may participate in neuronal apoptosis through the mitochondrial signaling pathway and that TXNIP may be a target for SAH treatment.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81371309, Zhaohui He).

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  1. Co first authors: Yidan Liang, Xudong Che.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Yidan Liang, Xudong Che, Qing Zhao, Rami Darwazeh, Hongxia Zhang, Dengzhi Jiang, Jun Zhao, Xiang Xiang, Wang Qin, Liu Liu & Zhaohui He

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Contributions

ZH and XC designed the project, YL and XC contributed to all experiments and to writing the manuscript. QZ, HZ, DJ, WQ, and LL helped to finish part of the experiments. JZ and XX were mainly responsible for the analysis of data and for writing the manuscript. RD helped to revise the manuscript, especially the language. All authors read and provided their approval for the final version of the manuscript.

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Correspondence to Zhaohui He.

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The authors have no conflicts of interest to declare.

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All animal experiments were conducted according to a protocol approved by the Animal Ethics and Use Committee of Chongqing Medical University (Permit no. SCXK (Chongqing) 2007–0001).

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Liang, Y., Che, X., Zhao, Q. et al. Thioredoxin-interacting protein mediates mitochondrion-dependent apoptosis in early brain injury after subarachnoid hemorrhage. Mol Cell Biochem 450, 149–158 (2019). https://doi.org/10.1007/s11010-018-3381-1

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