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

Shuji Mori, Ryouko Shinohata, Makoto Renbutsu, Hideo Kohka Takahashi, Yang Il Fang, Kiyonori Yamaoka, Motoi Okamoto, Itaru Yamamoto, Masahiro Nishibori

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)353-359
Number of pages7
JournalCell and Tissue Research
Volume312
Issue number3
DOIs
Publication statusPublished - Jun 1 2003

Fingerprint

Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Heparin
Zinc
Cells
Cell growth
Growth
Serum
Clinical Trials
Ions
histidine-rich proteins
Arteriosclerosis
Platelets
Angioplasty
Pharmaceutical Preparations
Restoration
Hyperplasia
Culture Media
Glycoproteins

Keywords

  • Heparin
  • Histidine-rich glycoprotein
  • Pig
  • Smooth muscle cell
  • Zinc

ASJC Scopus subject areas

  • Anatomy
  • Clinical Biochemistry
  • Cell Biology

Cite this

Histidine-rich glycoprotein plus zinc reverses growth inhibition of vascular smooth muscle cells by heparin. / Mori, Shuji; Shinohata, Ryouko; Renbutsu, Makoto; Takahashi, Hideo Kohka; Fang, Yang Il; Yamaoka, Kiyonori; Okamoto, Motoi; Yamamoto, Itaru; Nishibori, Masahiro.

In: Cell and Tissue Research, Vol. 312, No. 3, 01.06.2003, p. 353-359.

Research output: Contribution to journalArticle

Mori, Shuji ; Shinohata, Ryouko ; Renbutsu, Makoto ; Takahashi, Hideo Kohka ; Fang, Yang Il ; Yamaoka, Kiyonori ; Okamoto, Motoi ; Yamamoto, Itaru ; Nishibori, Masahiro. / Histidine-rich glycoprotein plus zinc reverses growth inhibition of vascular smooth muscle cells by heparin. In: Cell and Tissue Research. 2003 ; Vol. 312, No. 3. pp. 353-359.
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