| Project/Area Number |
10671061
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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 | NAGOYA UNIVERSITY |
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Principal Investigator |
KUZUYA Masafumi MEDICINE, NAGOYA UNIVERSITY, ASSISTANT PROFESSOR, 医学部, 講師 (10283441)
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| Co-Investigator(Kenkyū-buntansha) |
KOIKE Teruhiko MEDICINE, NAGOYA UNIVERSITY, MEDICAL STAFF, 医学部, 医員
IGUCHI Akihisa MEDICINE, NAGOYA UNIVERSITY, PROFESSOR, 医学部, 教授 (20109763)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1998: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | atherosclerosis / vascular endothelial cell / vascular endothelial growth factor / oxidized low density lipoprotein / macrophage / VEGF receptor / glutathione / angiogenesis / 変性低比重リポ蛋白 |
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| Research Abstract |
Immunohistochemical studies showed that human early atherosclerotic lesions exhibited intensive vascular endothelial growth factor (VEGF) immunoreactivity in subendothelial macrophage-rich regions of thickened intima. In atherosclerotic plaques, VEGF staining was also observed in foam cell-rich regions adjacent to lipid core or neovascularized basal regions of plaque consisting predominantly of smooth muscle cells. High powered field observation revealed that VEGF was localized in extracellular space as well as macrophage cell surface. These observations suggest the possible involvement of oxidized loe density lipoprtein (Ox-LDL) in the development of human atherosclerosis through VEGF induction in macrophages. We also demonstrated that Ox-LDL upregulated VEGF mRNA expression in RAW 264 cells, monocytic cell line, in a time and concentration dependent manner, and that Ox-LDL stimulated the VEGF protein secretion from the cells.
We hypothesized that VEGF in subendothelial macrophage-rich
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regions adjacent to endothelial cells at the luminal surface may participate in the maintenance and repair of the lumen endothelium. To test our hypothesis we examined whether VEGF protects the toxicity of Ox-LDL to cultured endothelial cells derived from bovine aorta (BAECs). BAECs preincubation with VEGF prevented Ox-LDL toxicity in a preincubation time- and VEGF concentration-dependent manner. Incubation of BAECs with VEGF increased intracellular glutathione (GSH) in a time-dependent manner. Combined addition of VEGF and L-buthionine sulfoximine, a GSH synthesis inhibitor, reversed GSH level and the protective effect of VEGF on Ox-LDL-induced cytotoxicity. Placenta growth factor, which ligates to VEGF Fit-1 receptor but not KDR/Flk-1, failed to prevent Ox-LDL toxicity and had no effect on intracellular GSH level. Anti- KDR/Flk-1 antibody completely blocked these activities of VEGF.These results suggest that VEGF prevents Ox-LDL-induced endothelial cell damage via intracellular GSH-dependent mechanism through KDR/Flk-1 receptor. Less
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