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Histidine-rich glycoprotein plus zinc reverses growth inhibition of vascular smooth muscle cells by heparin

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Abstract

Vascular smooth muscle cell (SMC) hyperplasia is known to be an important component in the pathogenesis of arteriosclerosis and restenosis. Although heparin has been well recognized as the representative molecule suppressing SMC growth in vitro, attempts to use heparin as a therapeutic anti-restenosis drug have not favorably influenced the angiographic or clinical outcome after angioplasty in some clinical trials. In this study, we have examined the effect of histidine-rich glycoprotein (HRG), a relatively abundant serum glycoprotein (~100 μg/ml in human serum), on the growth inhibition of cultured vascular SMC by heparin. Vascular SMC growth was significantly inhibited by heparin, giving nearly 85% inhibition with 100 μg/ml heparin. HRG reversed heparin-induced SMC growth inhibition in a dose dependent manner; 75% restoration of cell growth was observed when 100 μg/ml of HRG was co-added with 100 μg/ml heparin. Interestingly, micromolar concentrations of the zinc ion (0–10 μM), compatible with concentrations released from activated platelets, were found to enhance the restorative action of HRG. Western blot experiment demonstrated no significant amounts of the HRG moiety in fetal bovine serum, eliminating the possible contribution of contaminant HRG from culture media. These findings indicate that HRG, in combination with the zinc ion, plays a role in modulating the SMC growth response in pathophysiological states and explain the lack of success of heparin as a therapeutic anti-restenosis drug in clinical trials.

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Authors and Affiliations

  1. Department of Pharmacology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan

    Shuji Mori, Ryoko Shinohata, Hideo Kohka Takahashi & Masahiro Nishibori

  2. Faculty of Health Sciences, Okayama University Medical School, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan

    Ryoko Shinohata, Kiyonori Yamaoka & Motoi Okamoto

  3. Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, 700-8530, Okayama, Japan

    Makoto Renbutsu & Itaru Yamamoto

  4. School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, 142-8555, Tokyo , Japan

    Yang-Il Fang

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  1. Shuji Mori
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  2. Ryoko Shinohata
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  3. Makoto Renbutsu
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  4. Hideo Kohka Takahashi
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  6. Kiyonori Yamaoka
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  8. Itaru Yamamoto
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  9. Masahiro Nishibori
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Correspondence to Masahiro Nishibori.

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Mori, S., Shinohata, R., Renbutsu, M. et al. Histidine-rich glycoprotein plus zinc reverses growth inhibition of vascular smooth muscle cells by heparin. Cell Tissue Res 312, 353–359 (2003). https://doi.org/10.1007/s00441-003-0737-x

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  • DOI: https://doi.org/10.1007/s00441-003-0737-x

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