Analysis of Angiopoietin-related growth factor (AGF) as a potential target for the pharmacological drugs to treat atherosclerotic disease

• Project/Area Number: 17590762
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: KEIO UNIVERSITY
• Principal Investigator: OIKE Yuichi Keio University, School of Medicine, Associate Proffesor, 医学部, 助教授 (90312321)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,800,000 (Direct Cost: ¥3,800,000); Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2005: ¥2,700,000 (Direct Cost: ¥2,700,000)
• Keywords: Angiogenesis / Metabolic Syndrome / Atherosclerosis / 0besity / ERK / MAPK / NO / 生活習慣病 / メタボリック症候群 / インスリン抵抗性

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 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.

Research Products

• [Journal Article] Angiopoietins and Angiopoietin-like proteins in angiogenesis (2006)
  • Author(s): Morisada T et al.
  • Journal Title: Endothelium 13 Pages: 71-79
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Angiopoietins and Angiopoietin-like proteins in angiogenesis (2006)
  • Author(s): Morisada, T., Kubota, Y., Urano, T., Suda, T., Oike, Y.
  • Journal Title: Endothelium 13 Pages: 71-79
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiopoietins and Angiopoietin-like proteins in angiogenesis (2006)
  • Author(s): Morisada, T. et al.
  • Journal Title: Endothelium 13・2 Pages: 71-79
• [Journal Article] Angiopoietins and Angiopoietin-like proteinsin angiogenesis (2006)
  • Author(s): Morisada T.et al.
  • Journal Title: Endothelium (印刷中)
• [Journal Article] Oncogenic transcript ionfactor Evi-1 regulates hematopoietic stem cell proliferation through GATA-2 expression (2006)
  • Author(s): Yuasa H.et al.
  • Journal Title: EMBO J 24・11 Pages: 1976-1987
• [Journal Article] Angiopoietin-related growth factor (AGF) antagonizes obesity and related insulin resistance (2005)
  • Author(s): Oike Y et al.
  • Journal Title: Nat Med 11 Pages: 400-408
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Angiopoietin-like proteins : potential newtargets for metabolic syndrome therapy (2005)
  • Author(s): Oike Y et al.
  • Journal Title: Trends Mol Med 11 Pages: 473-479
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Angiopoietin-related growth factor (AGF) antagonizes obesity and related insulin resistance (2005)
  • 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.
  • Journal Title: Nat Med 11 Pages: 400-408
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiopoietin-like proteins : potential new targets for metabolic syndrome therapy (2005)
  • Author(s): Oike, Y., Akao, M., Kubota, Y., Suda, T.
  • Journal Title: Trends Mol Med 11 Pages: 473-479
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiopoietin-related growth factor (AGF) antagonizes obesity and related insulin resistance (2005)
  • Author(s): Oike Y.et al.
  • Journal Title: Nature Medicine 11・4 Pages: 400-408
• [Journal Article] Angiopoietin-like proteins : potential new targets for metabolic syndrome therapy (2005)
  • Author(s): Oike Y.et al.
  • Journal Title: Trends Mol Med 11・10 Pages: 473-479
• [Journal Article] Cooperative interaction of Angiopoietin-like proteins1 and 2 in zebrafish vascular development (2005)
  • Author(s): Kubota Y.et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA 102・38 Pages: 13502-13507
• [Journal Article] Isolation and Expression Patterns of Genes for Three Angiopoietin-like Proteins, Angptl1, 2 and 6 (2005)
  • Author(s): Kubota Y.et al.
  • Journal Title: Gene Expr Patterns 5・5 Pages: 679-685
• [Book] 宮園浩平, 佐藤靖史編 急速進展する血管研究 分担「アンジオポエチンとアンジオポエチン様因子」 (2006)
  • Author(s): 浦野貴之, 尾池雄一
  • Total Pages: 225
  • Publisher: 羊土社
• [Book] 糖尿病学2006分担:アンジオポエチン様増殖因子(Angiopoietin-relate Growth Factr ; AGF):抗肥満、抗インスリン抵抗性の新規治療標的分子 (2006)
  • Author(s): 尾池尾池
  • Publisher: 診断と治療社(印刷中)