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Molecular Mechanisms of Vascular Oxidative Stress in the Insulin Resistant State

Research Project

Project/Area Number 12671108
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionSHIGA UNIVERSITY OF MEDICAL SCIENCE

Principal Investigator

KASHIWAGI Atsunori  DEPARTMEN OF MEDICINE,SHIGA UNIVERSITY OF MEDICAL SCIENCE, PROFESSOR, 医学部, 教授 (20127210)

Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsInsulin resistance / Oxidative stress / Nitric oxide (NO) / Endothelial NO synthase (eNOS) / Tetrahydrobioputerin (BH4) / NAD(P) Hoxidase / Vasospastic angina / High fructose diet / NO / テトラヒドロビオプテリン(BH4) / 内皮型NO合成酵素 / NADPHオキシダーゼ / 血管機能
Research Abstract

Insulin resistance syndrome (visceral fat syndrome, syndrome X) is characterized with accumulation of multiple atherogenic risk factors in single patient, which is induced by the present life style and the most significant cause of diabetes mellitus and atherosclerotic diseases. However, the pathogenetic mechanisms and genetic background as well as molecular mechanisms of vascular dysfunction in the syndrome are unknown. It is also unclear why endothelium-dependent vascular dilatation is disturbed in the insulin resistant state found in obesity, hypertension and diabetes mellitus. Thus, the present study studied molecular mechanisms of vascular dysfunction in the insulin resistance state of rats induced by high fructose diet. 1) Oxygenfree radicals were released from endothelial cells in the insulin resistance state. 2) The abnormality was induced by decreased activity of endothelial NO synthase (eNOS) and activation of NAD(P)H oxidase. 3) The main cause of decreased eNOS activity is associated with impairment of synthesis of tetrahydrobiopterine (BH4) and marked production of BH2. 4) In contrast to endogenous hyperinsulinemia, exogenous hyperinsulinemia was not a cause of vascular oxidative stress. 5) Acetylcholine-dependent vascular dilatation found in patients with insulin resistance was associated with plasma BH4/BH2 ratio as well as vascular oxidative stress. Finally, 6) High fructose-induced insulin resistance syndrome was associated with increased gene expression of SREBP-I, a transcription factor for biosynthesis of triglyceride, and decreased expression of PPAR-alpha, a transcription factor for fatty acid oxidation.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Shinozaki K: "Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta"Diabetes. 48. 2437-2445 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shinozaki K: "Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats"Circ Res. 87. 566-573 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kashiwagi A: "Free radical production in endothelial cells as a pathogenetic factor for vascular dysfunction in the insulin resistance state"Diabetes Res Clin Pract. 45. 199-203 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kashiwagi A: "Endothelium-specific activation of NAD(P)H oxidase in aortas of exogenously hyperinsulinemic rats"Am J Physiol. 277. E976-E983 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shinozaki K: "Evaluation of endothelial free radical release by vascular tension responses in insulin-resistant rat aorta"Eur J Pharmacol. 394. 295-299 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shinozaki K: "Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteri dine metabolism and vascular oxidative stress"J Am Coll Cardiol. 38. 1821-1828 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nagai Y: "Amelioration of high fructose-induced metabolic derangement by activation of PPAR-alpha"Am J Physiol Endocrinology and Metabolism. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shinozaki K., Kashiwagi A.. Nishio Y., Okamura T., YoshidaY., Masada M., Toda N., Kikkawa R.: "Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta"Diabetes. 48. 2437-2445 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shinozaki K. ,Nishio Y., Okamura T., Yoshida Y., Maegawa H., Kojima H., Masada M., Toda N., Kikkawa R., Kashiwagi A.: "Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin resistant rats"Circ Res.. 87. 566-573 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kashiwagi A., Shinozaki K., Nishio Y., Okamura T., Toda N., Kikkawa R.: "Free radical production in endothelial cells as a pathogenetic factor for vascular dysfunction in the insulin resistance state"Diabetes Res Clin. Pract.. 45. 199-203 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kashiwagi A., Shinozaki K., Nishio Y., Maegawa H., Maeno Y., Kanazawa A., Kojima H., Haneda M., Hidaka H., Yasuda H., Kikkawa R.: "Endothelium-specific activation of NAD(P)H oxidase in aortas of exogenously hyperinsiilinemic rats"Am J. Physiol.. E976-E983 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shinozaki K., Okamura T., Nishio Y., Kashiwagi A., Kikkawa R., Toda N.: "Evaluation of endothelial free radical release by vascular tension responses in insulin-resistant rat aorta"Eur J. Pharmacol. 394. 295-299 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sinozaki K., Hirayama A., Nishio Y., Yoshida Y., Ohtani T,. Okamura T., Masada M., Kikkawa R., Kodama K., Kashiwagi A.: "Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress"J Am Coll Cardiol.. 38. 1821-1828 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nagai Y., Nishio Y., Nakamura T., Maegawa H., Kikkawa R., Kashiwagi A.: "Amelioration of high fructose-induced metabolic derangement by activation of PPAR-alpha"Am J Physiol Endocrinology and Metabolism. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shinozaki K: "Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta"Diabetes. 48. 2437-2445 (1999)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shinozaki K: "Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats"Circ Res. 87. 566-573 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kashiwagi A: "Free radical production in endothelial cells as a pathogenetic factor for vascular dysfunction in the insulin resistance state"Diabetes Res Clin Pract. 45. 199-203 (1999)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kashiwagi A: "Endothelium-specific activation of NAD(P)H oxidase in aortas of exogenously hyperinsulinemic rats"Am J Physiol. 277. E976-E983 (1999)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shinozaki K: "Evaluation of endothelial free radical release by vascular tension responses in insulin-resistant rat aorta"Eur J Pharmacol. 394. 295-299 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shinozaki K: "Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteri dine metabolism and vascular oxidative stress"J Am Coll Cardiol. 38. 1821-1828 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagai Y: "Amelioration of high fructose-induced metabolic derangement by activation of PPAR-alpha"Am J Physiol Endocrinology and Metabolism. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Morino K,Maegawa H,Fujita T,Takahara N,Egawa K,Kashiwagi A.and Kikkawa R.: "Insulin-induced JNK activation is negatively regulated by protein kinase C delta"Endocrinology. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Obata T,Yaffe M.B,Leparc G G,Piro E T,Maegawa H,Kashiwagi A,Kikkawa R,and Cantley L C.: "Use of peptide and protein library screening to define optimal substrate motifs for AKT/PKB"J.Biol.Chem. 275. 36108-36115 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Egawa K,Nagashima N,Shrma PM,Maegawa H,Nagai Y,Kashiwagi A,Kikkawa R,and Olefsky JM.: "Persistent activation of phosphatidlylinositol 3-kinase cause insulin resistance due to accelerated insulin-induced IRS-1 degradation in 3T3-L1 adipocytes."Endocrinology. 141. 1930-1935, (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shinozaki K,Nishio Y,Okamura T,Yoshida Y,Maegawa H,Kojima H,Masada M,Toda N,Kikkawa R,and Kashiwagi A.: "Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats."Circ Res. 87. 566-573 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koya D.,Haneda M,Nakagawa H,Isshiki K,Sato H,Maeda S,Sugimoto T,Yasuda H,Kashiwagi A,Way DR,King GL,Kikkawa R.: "Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC β inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes."FASEB. 14. 439-447 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shinozaki K,Okamura T,Nishio Y,Kashiwagi,A Kikkawa R,Toda N.: "Evaluation of endothelial free radical release by vascular tension responses in insulin-resistant rat aorta."Eur J Pharmacol. 394. 295-299 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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