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Pharmaceutical Research

, 26:1012 | Cite as

Characterization of the Enhancing Effect of Protamine on the Proliferative Activity of Hepatocyte Growth Factor in Rat Hepatocytes

  • Ke-Xin Liu
  • Yukio Kato
  • Kunio Matsumoto
  • Toshikazu Nakamura
  • Taiichi Kaku
  • Yuichi SugiyamaEmail author
Research Paper

Abstract

Purpose

The aim of the present study was to characterize the mechanism of the stimulatory effect of protamine on HGF activity.

Methods

The enhancing effects of protamine on the proliferative activity of HGF were investigated in vivo, in primary cultured rat hepatocytes, and in perfused rat liver.

Results

In α-naphthylisothiocyanate-intoxicated rats, pretreatment with protamine increased HGF-induced autophosphorylation of the HGF receptor in liver. The maximum enhancing effect of protamine on HGF-induced DNA synthesis of hepatocytes required a 10 min-pretreatment period both in vivo and in vitro, and the stimulatory effect of protamine was not observed when it was administered simultaneously with HGF. Preperfusion of the liver with protamine for 10 min decreased the non-saturable portion of hepatic clearance for 125I-HGF, which is mainly mediated by cell-surface heparan-sulfate proteoglycan (HSPG). Inhibition of HGF binding to heparin by protamine was confirmed using heparin-coated sepharose. This inhibition also required 10 min of pretreatment, for protamine to bind heparin.

Conclusion

The enhancing effect of protamine on the mitogenic activity of HGF on hepatocytes requires pretreatment with protamine for a short period presumably required for its binding to cell-surface heparin, implying possible regulation of c-met autophosphorylation by HSPG.

KEY WORDS

clearance heparan-sulfate proteoglycan (HSPG) heparin hepatocyte growth factor (HGF) protamine 

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ke-Xin Liu
    • 1
    • 3
    • 4
  • Yukio Kato
    • 1
    • 6
  • Kunio Matsumoto
    • 2
    • 5
  • Toshikazu Nakamura
    • 2
  • Taiichi Kaku
    • 4
  • Yuichi Sugiyama
    • 1
    Email author
  1. 1.Graduate School of Pharmaceutical SciencesUniversity of TokyoBunkyo-kuJapan
  2. 2.Biomedical Research CenterOsaka University School of MedicineSuitaJapan
  3. 3.College of PharmacyDalian Medical UniversityDalianChina
  4. 4.Japan Bioproducts Industry Co. Ltd.Shibuya-kuJapan
  5. 5.Cancer Research InstituteKanazawa UniversityKanazawaJapan
  6. 6.Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan

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