Development of new drug therapy for atherosclerosis

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。VSMC的迁移和增殖受生长因子的刺激。Ras p21是通过生长因子受体介导的细胞内信号转导途径中的关键成分，其C端需要法尼基修饰才能发挥信号转导作用。Ras p21的这种法尼化是由法尼基：蛋白转移酶催化的。在这个项目中，我们研究了一种有效的法尼基：蛋白转移酶抑制剂甘露霉素在体外和体内对VSMC生长的抑制作用。曼努霉素在体外对VSMC增殖有抑制作用。然后，我们给颈动脉球囊损伤的大鼠注射曼纽霉素。结果，这种抑制剂显著抑制了受损颈动脉内膜的增厚。

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.