2006 Fiscal Year Final Research Report Summary
Analysis of Angiopoietin-related growth factor (AGF) as a potential target for the pharmacological drugs to treat atherosclerotic disease
| Project/Area Number |
17590762
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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 |
Circulatory organs internal medicine
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| Research Institution | KEIO UNIVERSITY |
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Principal Investigator |
OIKE Yuichi Keio University, School of Medicine, Associate Proffesor, 医学部, 助教授 (90312321)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Angiogenesis / Metabolic Syndrome / Atherosclerosis / 0besity |
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| Research Abstract |
We previously reported that transgenic mice overexpressing angiopoietin-related growth factor (AGF) exhibit enhanced angiogenesis through AGF-activated migration of endothelial cells, suggesting that AGF might be an attractive drug target in ischemic disease. Here we determine whether AGF induces angiogenesis and ameliorates blood flow in a mouse hind-limb ischemia model and define molecular mechanisms underlying AGF signaling in endothelial cells. Intramuscular injection of adenovirus expressing AGF into the ischemic limb increased AGF production, angiogenesis, and blood flow compared to control mice receiving GFP-expressing adenovirus, decreasing the necessity for limb amputation. In vitro analysis showed that exposure of human venous endothelial cells (HUVECs) to AGF increased NO production by activating the ERK1/2-eNOS signaling pathway. Furthermore, AGF-stimulated phosphorylation of eNOS, production of NO, and chemotactic activity of endothelial cells was abolished by specific MEK
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I/2 inhibitors (U0126 and PD98059). Finally, AGF did not increase blood flow in a hind-limb ischemia model in eNOS knockout mice, indicating that eNOS activity is required for AGF-mediated NO upregulation. Overall this study identifies a signaling mechanism whereby AGF stimulates angiogenesis. This pathway may prove pharmacologically promising for therapeutic interventions for patients with ischemic disease. Furthermore, we show that most (>80%) of the AGF deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity due to increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance, and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a novel hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance. Less
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Research Products
(6 results)
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[Journal Article] Angiopoietin-related growth factor (AGF) antagonizes obesity and related insulin resistance2005
Author(s)
Oike, Y., Akao, M., Yasunaga, K., Yamauchi, T., Morisada, T., Ito, Y., Urano, T., Kimura, Y., Kubota, Y., Maekawa, H., Miyamoto, T., Miyata, K., Matsumoto, S., Sakai, J., Nakagata, N., Takeya, M., Koseki, H., Ogawa, Y., Kadowaki, T., Suda, T.
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Journal Title
Nat Med 11
Pages: 400-408
Description
「研究成果報告書概要(欧文)」より
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