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Metoprolol attenuates intracerebral hemorrhage-induced cardiac damage by suppression of sympathetic overactivity in mice

  • Author Footnotes
    1 These authors contributed equally to this manuscript.
    Liqun Zhang
    Footnotes
    1 These authors contributed equally to this manuscript.
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Author Footnotes
    1 These authors contributed equally to this manuscript.
    Jimusi Wuri
    Footnotes
    1 These authors contributed equally to this manuscript.
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Author Footnotes
    1 These authors contributed equally to this manuscript.
    Lulu An
    Footnotes
    1 These authors contributed equally to this manuscript.
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Xiaoxuan Liu
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Ye Wu
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Haotian Hu
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Ruixia Wu
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Yue Su
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Quan Yuan
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
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  • Tao Yan
    Correspondence
    Corresponding author at: Department of Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China.
    Affiliations
    Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this manuscript.

      Abstract

      The high rates of mortality and disability resulting from intracerebral hemorrhage (ICH) are closely related to subsequent cardiac complications. The mechanisms underlying ICH-induced cardiac dysfunction are not fully understood. In this study, we investigated the role of sympathetic overactivity in mediating cardiac dysfunction post ICH in mice. Collagenase-injection ICH model was established in adult male C57BL/6J mice. Neurological function was subsequently evaluated at multiple time points after ICH and cardiac function was measured by echocardiography on 3 and 14 days after ICH. Plasma adrenaline, noradrenaline, cortisol and heart β1 adrenergic receptor (β1-AR) levels were assessed to evaluate sympathetic activity. Picro Sirius Red (PSR) staining was performed to evaluate cardiomyocyte hypertrophy and interstitial fibrosis. Monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6(IL-6), nuclear factor kappa-B(NF-κB), NADPH oxidase-2 (NOX2), matrix metalloprotein (MMP-9) and transforming growth factor-beta (TGF-β) levels were assessed to evaluate inflammation, fibrosis and oxidative stress levels in heart after ICH. Macrophages and neutrophils were assessed to evaluate inflammatory cell infiltration in heart after ICH. ICH induced sympathetic excitability, as identified by increased circulating adrenaline, noradrenaline, cortisol levels and β1-AR expression in heart tissue. Metoprolol-treated ICH mice had improved cardiac and neurological function. The suppression of sympathetic overactivity by metoprolol attenuates cardiac inflammation, fibrosis and oxidative stress after ICH. In conclusion, ICH-induced secondary sympathetic overactivity which mediated inflammatory response may play an important role in post-ICH cardiac dysfunction.

      Keywords

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