Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis.
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.
Cho
Chung-Hyun
CH
Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Kammerer
Richard A
RA
Lee
Hyuek Jong
HJ
Yasunaga
Kunio
K
Kim
Kyung-Tae
KT
Choi
Han-Ho
HH
Kim
Won
W
Kim
Sung Hyun
SH
Park
Sung Kwang
SK
Lee
Gyun Min
GM
Koh
Gou Young
GY
D042683:Angiopoietin-1 / Q000235:genetics* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D064235:Matrilin Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation; D011832:Radiation Injuries / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D016019:Survival Analysis; D014018:Tissue Distribution
D042683:Angiopoietin-1; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D042787:Receptor, TIE-2