2001 Fiscal Year Final Research Report Summary
Molecular Mechanisms of Vascular Oxidative Stress in the Insulin Resistant State
| Project/Area Number |
12671108
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | SHIGA UNIVERSITY OF MEDICAL SCIENCE |
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Principal Investigator |
KASHIWAGI Atsunori DEPARTMEN OF MEDICINE,SHIGA UNIVERSITY OF MEDICAL SCIENCE, PROFESSOR, 医学部, 教授 (20127210)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Insulin resistance / Oxidative stress / Nitric oxide (NO) / Endothelial NO synthase (eNOS) / Tetrahydrobioputerin (BH4) / NAD(P) Hoxidase / Vasospastic angina / High fructose diet |
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| 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.
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[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
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