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Heart, Lung and Circulation

Doxorubicin-Induced Myocardial Fibrosis Involves the Neurokinin-1 Receptor and Direct Effects on Cardiac Fibroblasts

  • Author Footnotes
    1 Present Address – Kolling Institute for Medical Research, University of Sydney.
    Scott P. Levick
    Footnotes
    1 Present Address – Kolling Institute for Medical Research, University of Sydney.
    Affiliations
    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

    Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
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  • David R. Soto-Pantoja
    Affiliations
    Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
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  • Jianli Bi
    Affiliations
    Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
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  • W. Gregory Hundley
    Affiliations
    Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Department of Radiological Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
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  • Author Footnotes
    1 Present Address – Kolling Institute for Medical Research, University of Sydney.
    Alexander Widiapradja
    Footnotes
    1 Present Address – Kolling Institute for Medical Research, University of Sydney.
    Affiliations
    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

    Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
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  • Edward J. Manteufel
    Affiliations
    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

    Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
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  • Tancia W. Bradshaw
    Affiliations
    Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
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  • Giselle C. Meléndez
    Correspondence
    Corresponding author at: Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157-1045. Tel.: (336) 713-7086; Fax: (336) 713-0163.
    Affiliations
    Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
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  • Author Footnotes
    1 Present Address – Kolling Institute for Medical Research, University of Sydney.
Published:August 30, 2018DOI:https://doi.org/10.1016/j.hlc.2018.08.003

      Background

      Cancer patients receiving anthracycline-based chemotherapy (Anth-bC) may experience early cardiac fibrosis, which could be an important contributing mechanism to the development of impaired left ventricular (LV) function. Substance P, a neuropeptide that predominantly acts via the neurokinin 1 receptor (NK-1R), contributes to adverse myocardial remodelling and fibrosis in other cardiomyopathies. We sought to determine if NK-1R blockade is effective against doxorubicin (Dox – a frequently used Anth-bC)-induced cardiac fibrosis and cardiomyocyte apoptosis. In addition, we explored the direct effects of Dox on cardiac fibroblasts.

      Methods

      Male Sprague-Dawley rats were randomised to receive saline, six cycles of Dox (1.5 mg Dox/kg/cycle) or Dox with an NK-1R antagonist (L732138, 5 mg/kg/daily through Dox treatment). At 8 weeks after the initial dose of Dox, LV function and histopathological myocardial fibrosis and cell apoptosis were assessed. Collagen secretion was measured in vitro to test direct Dox activation of cardiac fibroblasts.

      Results

      Rats undergoing Dox treatment (9 mg/kg cumulative dose) developed cardiac fibrosis and cardiomyocyte apoptosis. NK-1R blockade partially mitigated cardiac fibrosis while completely preventing cardiomyocyte apoptosis. This resulted in improved diastolic function. Furthermore, we found that Dox had direct effects on cardiac fibroblasts to cause increased collagen production and enhanced cell survival.

      Conclusions

      This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen.

      Keywords

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