title: PAI-1-dependent endothelial cell death determines severity of radiation-induced intestinal injury.
abstract: Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1) was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 -/- mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs) death was investigated. The level of apoptotic ECs is lower in PAI-1 -/- compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 -/- mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 -/- mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.
authors.affiliation: Laboratory of Radiopathology and Experimental Therapeutics, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France.
authors.forename: Rym
authors.initials: R
authors.lastname: Abderrahmani
authors.forename: Agnes
authors.initials: A
authors.lastname: François
authors.forename: Valerie
authors.initials: V
authors.lastname: Buard
authors.forename: Georges
authors.initials: G
authors.lastname: Tarlet
authors.forename: Karl
authors.initials: K
authors.lastname: Blirando
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hneino
authors.forename: Aurelie
authors.initials: A
authors.lastname: Vaurijoux
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000528:radiation effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007422:Intestines / Q000293:injuries* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse