| Project/Area Number |
05670854
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | SHIGA UNIVERSITY OF MEDICAL SCIENCE |
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Principal Investigator |
KASHIWAGI Atsunori THIRD DEPARTMENT OF MEDICINE,SHIGA UNIVERSITY OF MEDICAL SCIENCE,ASSISTANT PROFESSOR, 医学部, 講師 (20127210)
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| Co-Investigator(Kenkyū-buntansha) |
MAEGAWA Hiroshi THIRD DEPARTMENT OF MEDICINE,SHIGA UNIVERSITY OF MEDICAL SCIENCE,INSTRUCTOR, 医学部, 助手 (00209363)
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| Project Period (FY) |
1993 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1994: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1993: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | Diabetes mellitus / Aging / Hyperglycemia / Endothelial cells / Oxidative stress / ICAM-1 / Oxidative LDL / Glutathione redox cycle / 糖尿病性血管障害 / 遺伝子発現 / 活性酸素 / ペントース燐酸経路 / ラジカルスカベンジャー / 動脈硬化症 |
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| Research Abstract |
It has been well known that abnormal production and degradation of active oxygen radicals in vascular cells are major factors which can induce accelerated atherosclerosis in aging and diabetes mellitus. Particularly, we have shown that radical scavenger function is impaired in cultured endothelial cells exposed to high glucose condition. Furthermore, the increased oxidative stress in high glucose condition can induce activation of endothelial cell gene expression. The following vascular endothelial cell dysfunction was studied in the present study.
1) Impaired activation of pentose phosphate pathway and dysfunction of glutathione redox (GR) cycle in endothelial cells exposed to high glucose medium.
We reported that GR cycle was dccreased by 50% in endothelial cells exposed to high glucose medium (Kashiwagi et al Diabetes 1992, Kashiwagi et al. Diabetologia 1994, Asahina et al. Diabetes 1995). These abnormal GR cycle was also found in acidosis (Ikebuchi et al Metabolism, 1993) and was rev
… More
ersed by the treatment of either radical scavenger (Kashiwagi et al. Diabetes 1991,1991) or pyruvate to endothelial cells (Kashiwagi et al. Am J Physiol. in submission).
2) Endothelial cell activation in high glucose condition
Specific ICAM-1 expression in endothelial cells was induced as high glucose-specific and concentration-dependent manners and resulted in increased adhesion of monocytes to endothelial cells (Taki et al. Atheroscleresis in submission). The activation of endothelial cell function in high glucose condition was mediated via hyperosmolar effect and was not mediated by oxidative stress.
3) Oxidized LDL and Lysophosphatidylcholine and endothelial cell gene expression
Oxidized LDL and a main component lysophosphatidylcholine (LPC) can induce MCP-1 gene expression in endothelial cells (Takahara et al, Metabolism, in submission). This effect was mediated by activation of PKC.
[In summary] Metabolic abnormalities in diabetes (hyperglycemia, hyperosmolarity, acidosis, lipid oxidation) can induce profound effects on various gene expression of endothelial cells which indicate activation of endothelial cells resulting in accelerated interaction between monocytes and endothelial cells. The interaction may be an initial event of early atherogenesis in diabetes. To prevent aging of vascular tissue and atherosclerosis, clinical studies to prevent in vivo oxidative stress in diabetes using antioxidant drugs will be the future projects. Less
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