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Potential Contribution of Hypoxia-Inducible Factor-1α, Aquaporin-4, and Matrix Metalloproteinase-9 to Blood–Brain Barrier Disruption and Brain Edema After Experimental Subarachnoid Hemorrhage

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Abstract

The current research aimed to investigate the role of hypoxia-inducible factor-1α (HIF-1α), aquaporin-4 (AQP-4), and matrix metalloproteinase-9 (MMP-9) in blood–brain barrier (BBB) dysfunction and cerebral edema formation in a rat subarachnoid hemorrhage (SAH) model. The SAH model was induced by injection of 0.3 ml fresh arterial, non-heparinized blood into the prechiasmatic cistern in 20 s. Anti-AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2-methoxyestradiol (an inhibitor of HIF-1α), was administered intravenously at 2 and 24 h after SAH. Brain samples were extracted at 48 h after SAH and examined for protein expressions, BBB impairment, and brain edema. Following SAH, remarkable edema and BBB extravasations were observed. Compared with the control group, the SAH animals have significantly upregulated expressions of HIF-1α, AQP-4, and MMP-9, in addition to decreased amounts of laminin and tight junction proteins. Brain edema was repressed after inhibition of AQP-4, MMP-9, or HIF-1α. Although BBB permeability was also ameliorated after inhibition of either HIF-1α or MMP-9, it was not modulated after inhibition of AQP-4. Inhibition of MMP-9 reversed the loss of laminin. Finally, inhibition of HIF-1α significantly suppressed the level of AQP-4 and MMP-9, which could induce the expression of laminin and tight junction proteins. Our results suggest that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular signaling pathway involving AQP-4 and MMP-9. Pharmacological intervention of this pathway in patients with SAH may provide a novel therapeutic strategy for early brain injury.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (nos. 81171105 and 81100872), Jiangsu Province’s Outstanding Medical Academic Leader program (no. LJ201139), and grants from the Education Department of Jiangsu Province (no. 11KJB320011) and Suzhou Government (no. SYS201109)

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People’s Republic of China

    Zhong Wang, Cheng-Jie Meng, Chao Ma, Xue-Bo Sun & Gang Chen

  2. Department of Surgery, Taicang People’s Hospital, Suzhou, Jiangsu Province, China

    Xu-Ming Shen & Zhang Shu

  3. Department of Surgery, Suzhou Municipal Hospital, Suzhou, Jiangsu Province, China

    Guo-Qing Zhu, Lei Huo & Jian Zhang

  4. Department of Neurosurgery, Zhangjiagang Hospital, Soochow University, Suzhou, Jiangsu Province, China

    Hui-Xiang Liu

  5. Department of Neurosurgery, Zhangjiagang Hospital of Traditional Chinese Medicine, Suzhou, China

    Wei-Chun He

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  1. Zhong Wang
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  2. Cheng-Jie Meng
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  3. Xu-Ming Shen
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  4. Zhang Shu
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  5. Chao Ma
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  11. Jian Zhang
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  12. Gang Chen
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Correspondence to Gang Chen.

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Zhong Wang, Cheng-Jie Meng, and Xu-Ming Shen equally contributed to this work.

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Wang, Z., Meng, CJ., Shen, XM. et al. Potential Contribution of Hypoxia-Inducible Factor-1α, Aquaporin-4, and Matrix Metalloproteinase-9 to Blood–Brain Barrier Disruption and Brain Edema After Experimental Subarachnoid Hemorrhage. J Mol Neurosci 48, 273–280 (2012). https://doi.org/10.1007/s12031-012-9769-6

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  • DOI: https://doi.org/10.1007/s12031-012-9769-6

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