Anti-atherosclerotic factors induced by Smad signaling in vascular cells

• Project/Area Number: 18590976
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Chiba University
• Principal Investigator: YOKOTE Koutaro Chiba University, Graduate School of Medicine, Associate professor (20312944)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Atherosclerosis / TGF-beta / macrophage / Smad3 / MCP-1 / inflammation / Smad / 細胞内シグナル伝達 / プラーク / 骨髄移植

Research Abstract

Aim: To investigate the molecular basis of TGF-beta signaling involved in its anti-atherosclerotic effect.
Methods and Results: Double knockout mice for ApoE and Smad3, a major intracellular signaling molecule for TGF-beta, were generated, and subjected to in vivo and in vitro analyses. The double knockout mice developed significantly larger atheromatous lesions in the aorta compared with the control apoE knockout mice. The aortic lesions of double knockout mice were rich in macrophages, scarce in collagen deposition, and highly expressed monocyte chemoattractant protein-1 (MCP-1). Inhibitory effect of TGF-beta on MCP-1 gene expression was lost in the peritoneal macrophages derived from Smad3 knockout mice. The Smad3 knockout macrophages were also resistant to growth inhibitory effect of TGF beta.
Conclusion: Our results suggest that endogenous Smad3 in macrophage has inhibitory effects on progression of atherosclerosis via modulation of inflammatory gene expression and cell growth.

Research Products

• [Journal Article] Development and characterization of IL-21-producing CD4+Tcells. (2008)
  • Author(s): Suto A et. al.
  • Journal Title: J Exp Med (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Development and characterization of IL-21-producing CD4+ T cells (2008)
  • Author(s): Suto A, Kashiwakuma D, Kagami S, Hirose K, Watanabe N, Yokote K, Saito Y, Grusby MJ, Iwamoto I, Nakajima H.
  • Journal Title: J Exp Med (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Development and characterization of IL-21-producing CD4+ T cells (2008)
  • Author(s): Suto A, et. al.
  • Journal Title: Journal of Experimental Medicine (印刷中)
  • Peer Reviewed
• [Journal Article] Early amelioration of insulin resistance and reduction of interleukin-6 in Werner syndrome using pioglitazone (2007)
  • Author(s): Honjo S, Yokote K, et. al.
  • Journal Title: J Am Geriatr Soc 56 Pages: 173-174
  • Peer Reviewed
• [Journal Article] 動脈硬化研究におけるPDGFとTGF-β (2007)
  • Author(s): 横手 幸太郎
  • Journal Title: 医学のあゆみ 221 Pages: 1179-1183
• [Journal Article] Role of TGF-β/Smad3 signaling in response to vascular injury. (2006)
  • Author(s): Yokote K et. al.
  • Journal Title: Trends. Cardiovasc. Med. 16 Pages: 240-245
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Influence of C-peptide on Early Glomerular Changes in Diabetic Mice. (2006)
  • Author(s): Maezawa Y, Yokote K et. al.
  • Journal Title: Diabetes Metab. Res. Rev. 22 Pages: 313-322
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Role of TGF-β/Smad3 signaling in response to vascular injury (2006)
  • Author(s): Yokote, K, Kobayashi, K. and Saito, Y.
  • Journal Title: Trends. Cardiovasc. Med 16 Pages: 240-245
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Influence of C-peptide on Early Glomerular Changes in Diabetic Mice (2006)
  • Author(s): Maezawa, Y., Yokote, K., Sonezaki, K., Fujimoto, M., Kobayashi, K., Kawamura, H., Tokuyama, T., Takemoto, M., Ueda S, Kuwaki, T., Mori, S., Wahren, J., Saito, Y.
  • Journal Title: Diabetes Metab. Res. Rev 22 Pages: 313-322
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of TGF-β/Smad3 signaling in response to vascular injury. (2006)
  • Author(s): Yokote, K, Kobayashi, K., Saito, Y.
  • Journal Title: Trends. Cardiovasc. Med. 16 Pages: 240-245
• [Journal Article] Influence of C-peptide on Early Glomerular Changes in Diabetic Mice. (2006)
  • Author(s): Maezawa, Y., Yokote, K et al.
  • Journal Title: Diabetes Metab. Res. Rev. 22 Pages: 313-322
• [Journal Article] Werner syndrome and adiponectin gene mutation. (2006)
  • Author(s): Hashimoto, N., Hatanaka, S., Yokote, K et al.
  • Journal Title: Diabetes Res Clin Pract. 75 Pages: 27-29
• [Journal Article] 大小血管障害の形成におけるTGF-β/Smad3経路の役割の解明。 (2006)
  • Author(s): 横手 幸太郎
  • Journal Title: 糖尿病合併症 20 Pages: 112-118
• [Journal Article] メタボリックシンドロームにおける動脈硬化性疾患発症とその予防対策 (2006)
  • Author(s): 横手幸太郎, 齋藤康
  • Journal Title: 日本臨床 64 Pages: 30-36
• [Journal Article] 血管石灰化の予防と治療 (2006)
  • Author(s): 本城聡, 横手幸太郎, 齋藤康
  • Journal Title: 日本病院薬剤師会雑誌 42 Pages: 1433-1435
• [Presentation] 血管平滑筋細胞の傷害に対する血管防御反応 (2007)
  • Author(s): 横手 幸太郎
  • Organizer: 第39回に本動脈硬化学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2007-07-13
• [Book] 今日の治療指針2007 (2006)
  • Author(s): 山口徹, 北原光夫, 福井次矢総編集
  • Total Pages: 1668
  • Publisher: 医学書院