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Role of polymorphisms of γ-glutamylcysteine synthetase genes in pathogenesis of coronary spastic angina

Research Project

Project/Area Number 13670728
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionUniversity of Yamanashi (Faculty of Medicine)

Principal Investigator

KUGIYAMA Kiyotaka  University of Yamanashi, Faculty of medicine, Professor, 医学部, 教授 (00225129)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥2,800,000 (Direct Cost: ¥2,800,000)
Keywordsglutathione / coronary spastic angina / oxidative stress / myocardial Infarction / endothelial function / polymorphism
Research Abstract

Human glutamate-cysteine ligase (GCL) is a rate-limiting enzyme for synthesis of glutathione (GSH) that plays a crucial role in antioxidant defense mechanisms in most mammalian cells, including vascular cells. GCL is a heterodimer composed of a heavy catalytic subunit (GCLC) and a light modifier subunit (GCLM). Oxidants transcriptionally upregulate GCL genes for GSH synthesis, providing a protective mechanism against oxidative stress-induced cellular dysfunction. We found a polymorphism (-588C/T) of GCLM gene and a polymorphism (-129C/T) of GCLC gene in which minor alleles showed lower promoter activity in response to oxidants in the luciferase reporter gene assay. The induction of GCLM mRNA expression in the cultured human monocytes-macrophages was less in the cells from subjects with the minor allele as compared with those without minor allele. Plasma GSH levels were significantly lower in subjects with the minor allele of GCLM polymorphism than those without the minor allele (2.1±0.3 versus 3.3±0.2 μmol/L; P=0.001). The frequency of each of the minor alleles was significantly higher in those with previous myocardial infarction than in the control. In multiple logistic regression analysis, each of the minor alleles of GCLC and GCLM genes was a risk factor for myocardial infarction independently of traditional coronary risk factors. Endothelium-dependent dilation of coronary arteries was impaired in the subjects with the minor allele of GCLC gene polymorphism as compared with the age-matched those without the minor allele. In conclusion the polymorphisms of GCLC and GCLM genes may suppress GCL genes induction response to an oxidant and it is implicated in coronary endothelial vasomotor dysfunction and myocardial infarction.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Koide S, Kugiyama K, et al.: "Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction"J Am Coll Cardiol. 41. 539-545 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamura S, Kugiyama K, et al.: "Polymorphism in the 5'-flanking region of human glutamate-cysteine ligasemodifier subunit gene is associated with myocardial infarction"Circulation. 105. 2968-2973 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kiode S, Kugiyama K, Sugiyama S, Nakamura S, Fukushima H, Honda O, Yoshimura M, Ogawa H: "Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction"J Am Coll Cardiol. 41. 539-545 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamura S, Kugiyama K, Sugiyama S, Miyamoto S, Koide S, Fukushima H, Honda O, Yoshimura M, Ogawa H: "Polymorphism in the 5'-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction"Circulation. 105. 2968-2973 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koide S, Kugiyama K, et al.: "Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction"J Am Coil Cardiol. 41. 539-545 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawano H, Kugiyama K, et al.: "Endothelial function fluctuates with diurnal variation in the frequency of ischemic episodes in patients with variant angina"J Am Coil Cardiol. 40. 266-270 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimomura H, Kugiyama K, et al.: "Comparison of urinary biopyrrin levels in acute myocardial infarction (after reperfusion therapy) versus stable angina pectoris and their usefulness in predicting subsequent cardiac events"Am J Cardiol. 90. 108-111 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamura S, Kugiyama K, et al.: "Polymorphism in the 5'-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction"Circulation. 105. 2963-2973 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakamoto T, Kugiyama K, et al.: "B-type natriuretic peptide after percutaneous transluminal septal myocardial ablation"Int J Cardiol. 83. 151-158 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawano H, Kugiyama K, et al.: "Endothelial dysfunction in hypercholesterolemia is improved by L-arginine administration : possible role of oxidative stress"Atherosclerosis. 161. 375-380 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukushima H, Kugiyama K, et al.: "Comparison of remnant-like lipoprotein particles in postmenopausal women with and without coronary artery disease and in men with coronary artery disease"Am J Cardiol. 88. 1370-1373 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawano H, Kugiyama K, et al.: "Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina"Ann Intern Med. 135. 977-981 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawano H, Kugiyama K, et al.: "Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina"J Am Coll Cardiol. 37. 735-740 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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