Development of new drug therapy for atherosclerosis

动脉粥样硬化新药治疗的开发

• 批准号: 06557058
• 负责人: KAWATA Sumio
• 金额: $ 4.86万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06557058/
• 关键词: Atherosclerosis; Vascular smooth muscle cells; Ras p21; Farnesyl ; protein transferase; manumycin; Rasp21; ファネルシルトランスフェラーゼ; 酵素阻害剤; HPLC; 血管平滑筋細胞; 増殖抑制

Migration and proliferation of vascular smooth muscle cells (VSMC) play important roles in development of atherosclerosis. The migration and proliferation of VSMC are known to be stimulated by growth factors. Ras p21 is a key component in intracellular signal transduction pathway for cell growth via growth factor receptors.Farnesylation of C-terminal of Ras p21 is required for its function as signal transducer. This farnesylation Ras p21 is catalyzed by farnesyl : protein transferase.In this project, we examined inhibitory effects of manumycin, a potent farnesyl : protein transferase inhibitor, on VSMC growth in vitro and in vivo. Manumycin inhibited VSMC proliferation in vitro. Then, we administered manumycin to rats with balloon injury in carotid arteries. As a result, this inhibitor significantly suppressed intimal thickening in injured carotid arteries.

血管平滑肌细胞（VSMC）的迁移和增殖在动脉粥样硬化的发生发展中起着重要作用。已知VSMC的迁移和增殖受到生长因子的刺激。Ras p21是通过生长因子受体介导细胞生长的胞内信号转导途径中的关键组分，其C端的法尼基化是其发挥信号转导功能所必需的。本课题研究了法尼基蛋白转移酶抑制剂manumycin在体外和体内对VSMC生长的抑制作用。Manumycin在体外抑制VSMC增殖。然后，我们给大鼠颈动脉球囊损伤manumycin。结果，这种抑制剂显著抑制损伤的颈动脉内膜增厚。

项目成果

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H.Ishiguro,et al.: "High-performance liquid chrom,atographic assay for farnesyl:protein transferase activity with dabsylates peptide." J.Chromatogr.B. 663. 35-42 (1995)

H.Ishiguro 等人：“法呢基的高效液相色谱测定：用达磺酸盐肽进行蛋白质转移酶活性。”

K.Fukuda, S.Kawata, et al.: "Increased mitogenic response to heparin-binding epidermal growth factor-like growth facotr in vascular smooth muscle cells of diabetic rats." Arterioscr.Thromb.Vasc.Biol.15. 1680-1687 (1995)

K.Fukuda、S.Kawata 等人：“糖尿病大鼠血管平滑肌细胞中对肝素结合表皮生长因子样生长因子的促有丝分裂反应增加。”

T. Nagase,S. Kawata,et al.: "Inhibition of cell growth of human hepatoma cell line (Hep G2) by a farnesyl : protein transferase inhibitor : a preferential suppression of Ras farnasylation." Int. J. Cancer. (in press). (1996)

T.长濑，S.

K. Fukuda,S. Kawata,et al.: "Increased mitogenic response to heparin-binding epidermal growth factor-like growth factor in vascular smooth muscle cells of diabetic rats." Arterioscler. Thromb. Vasc. Biol.15. 1680-1687 (1995)

K.福田，S。