| Project/Area Number |
18590283
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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 |
Pathological medical chemistry
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| Research Institution | Hirosaki University |
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Principal Investigator |
ITOH Ken Hirosaki University, Hirosaki University, Graduate School of Medicine, Professor (10323289)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Nrf2 / atherosclerosis / macrophage / endothelial cell / 酸化ストレス |
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| Research Abstract |
Previous in vitro study demonstrated that Nrf2 mediates expression of anti-inflammatory genes in endothelial cells, whereas Nrf2 induces scavenger receptor CD36 in macrophages that mediates uptake of oxidized low-density lipoproteins (oxLDLs). CD36 reportedly plays a key role in the pathogenesis of atherosclerosis by promoting foam cell formation. Therefore, the overall in vivo role of Nrf2 in atherosclerosis is not clear at present. To clarify the role of Nrf2 in atherosclerosis, we generated Nrf2-ApoE double null mice and examined the severity of atherosclerosis in aorta. The mice were fed a high-fat diet for 12 weeks and aortic lesions were examined by lipid staining with Oil Red O. We found that atherosclerotic lesions were markedly diminished in Nrf2-ApoE double null mice compared to that in ApoE knockout mice. Therefore, absence of Nrf2 was protective against atherosclerosis. Apoptosis inhibitor expressed by macrophage (AIM) is a critical factor that protects macrophages from apoptosis initiated by oxidized lipids. We found that Nrf2 inducer diethyl maleate (DEM) induce AIM expression in mouse macrophage cell line. Therefore, we surmise that Nrf2 may upregulate oxLDL uptake through CD36 and protect from oxLDL-induced apoptosis by AIM induction in macrophages. We are currently undergoing bone marrow transplantation experiments to test the above-mentioned hypothesis. In summary, our analysis suggested that macrophage Nrf2 plays a crucial role in the development of atherosclerosis.
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