Histidine-rich glycoprotein plus zinc reverses growth inhibition of vascular smooth muscle cells by heparin.
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 micrograms/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 micrograms/ml heparin. HRG reversed heparin-induced SMC growth inhibition in a dose dependent manner; 75% restoration of cell growth was observed when 100 micrograms/ml of HRG was co-added with 100 micrograms/ml heparin. Interestingly, micromolar concentrations of the zinc ion (0-10 microM), 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.
Mori
Shuji
S
Department of Pharmacology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan.
Shinohata
Ryoko
R
Renbutsu
Makoto
M
Takahashi
Hideo Kohka
HK
Fang
Yang-Il
YI
Yamaoka
Kiyonori
K
Okamoto
Motoi
M
Yamamoto
Itaru
I
Nishibori
Masahiro
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D013552:Swine; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D000099053:Histidine-Rich Glycoprotein
D011506:Proteins; D016212:Transforming Growth Factor beta; D000099053:Histidine-Rich Glycoprotein; D006493:Heparin; D015032:Zinc