Cho Chung-Hyun, Kammerer Richard A, Lee Hyuek Jong, Yasunaga Kunio, Kim Kyung-Tae, Choi Han-Ho, Kim Won, Kim Sung Hyun, Park Sung Kwang, Lee Gyun Min, Koh Gou Young
Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5553-8. doi: 10.1073/pnas.0307575101. Epub 2004 Apr 1.
Radiation therapy is a widely used cancer treatment, but it causes side effects even when localized radiotherapy is used. Extensive apoptosis of microvascular endothelial cells of the lamina propria is the primary lesion initiating intestinal radiation damage after abdominal radiation therapy. Many in vitro studies suggest that angiopoietin-1 (Ang1) has potential therapeutic applications in enhancing endothelial cell survival. For in vivo use, we developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. COMP-Ang1 is more potent than native Ang1 in phosphorylating the Tie2 receptor in lung endothelial cells in vivo. Interestingly, COMP-Ang1 administered i.v. was mainly localized to microvascular endothelial cells of the intestinal villi and lung but not to microvascular endothelial cells of the liver. In irradiated mice, i.v. COMP-Ang1 protected against radiation-induced apoptosis in microcapillary endothelial cells of the intestinal villi and prolonged survival. Thus, COMP-Ang1 could be used as a therapeutic protein for specific protection against endothelial cell injury.
放射治疗是一种广泛应用的癌症治疗方法，但即使使用局部放射治疗也会产生副作用。腹部放射治疗后，固有层微血管内皮细胞的广泛凋亡是引发肠道放射损伤的主要病变。许多体外研究表明，血管生成素-1（Ang1）在提高内皮细胞存活率方面具有潜在的治疗应用价值。为了用于体内，我们开发了一种可溶性、稳定且高效的Ang1变体，即COMP-Ang1。COMP-Ang1在体内使肺内皮细胞中的Tie2受体磷酸化方面比天然Ang1更有效。有趣的是，静脉注射的COMP-Ang1主要定位于肠绒毛和肺的微血管内皮细胞，而不是肝脏的微血管内皮细胞。在受辐射的小鼠中，静脉注射COMP-Ang1可保护肠绒毛微毛细血管内皮细胞免受辐射诱导的凋亡，并延长生存期。因此，COMP-Ang1可作为一种治疗性蛋白，用于特异性保护内皮细胞免受损伤。
