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2000 Fiscal Year Final Research Report Summary

Role and clinical significance of heparin cofactor II as an anti-atherosclerotic factor

Research Project

Project/Area Number 11838011
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research InstitutionUniversity of Tokushima

Principal Investigator

AZUMA Hiroyuki  University of Tokushima, School of Medicine, Associate Professor, 医学部, 助教授 (10241275)

Co-Investigator(Kenkyū-buntansha) MITSUI Takao  University of Tokushima, University Hospital, Assistant Professor, 医学部・附属病院, 講師 (80294726)
MATSUMOTO Toshio  University of Tokushima, School of Medicine, Professor, 医学部, 教授 (20157374)
Project Period (FY) 1999 – 2000
Keywordsheparin cofactor II / atherosclerosis / thrombin / vascular smooth muscle cell / dermatan sulfate / knockout mouse
Research Abstract

We found a 66-year-old Japanese patient with type I congenital heparin cofactor (HC) II deficiency manifesting multiple atherosclerotic lesions. Sequencing analysis following amplification of each of all 5 exons and its flanking region showed a single C to T transition at nucleotide position 12,854 in exon 5, which changed a Pro^<443> codon (CCG) to Leu codon (CTG). Transient transfection, metabolic labeling and pulse-chase experiments followed by immunoprecipitation analysis showed that the recombinant mutant HC II molecules were secreted from COS-1 cells in reduced amounts compared with the wild-type, and that an enhanced intracellular association of the mutant molecules with a chaperon, GRP78/BiP, was observed in CHO-K1 cells. In addition, immunohistochemical study showed that the immunoreactivities against dermatan sulfate and HC II in resected aortic artery with stenosis were increased and decreased, respectively.
We also found that the plasma levels of HC II in patients with hyperthyroidism significantly decreased by treatment, and in vitro study showed that T_3 treatment enhanced dose-dependently the mRNA levels of HC II in cultured human hepatocytes. This result may indicate a possible mechanism whereby patients with hypothyroidism are prone to atherosclerotic disease.
Analysis of plasma HC II activity in patients with coronary heart disease treated with plain old balloon angioplasty (POBA) or stenting (stent) revealed that patients with more than 110% of plasma HC II activity showed significantly less frequent (p<0.0469) in restenosis after stent grafting than those with less than 110% of HC II activity.
Regarding HC II-knockout mouse, since targeting vector for desrupting mouse HC II gene has been prepared, G418-resintant clones are now screening by Southern blotting.

  • Research Products

    (2 results)

All Other

All Publications (2 results)

  • [Publications] Kanagawa et al.: "Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima"Thrombosis and Haemostasis. 85. 101-107 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kanagawa Y et al: "Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at P2 reactive site : HC II Tokushima"Thrombosis and Haemostasis. 85(1). 101-107 (2001)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2002-03-26  

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