Intra- and extracellular plasminogen activator inhibitor-1 regulate effect of vitronectin against radiation-induced endothelial cell death
| Autor: | Takeshi Yasuda, Takaya Goto, Masaharu Hazawa, Katsushi Tajima, Ai Saotome-Nakamura, Kenichi Tomiyama, Chizuka Obara |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Endothelium Physiology 03 medical and health sciences chemistry.chemical_compound Plasminogen Activator Inhibitor 1 medicine Extracellular Humans Vitronectin Radiation Injuries Furin Pharmacology biology Cell Death Endothelial Cells Hep G2 Cells Molecular biology Cell biology Endothelial stem cell 030104 developmental biology medicine.anatomical_structure HEK293 Cells chemistry Plasminogen activator inhibitor-1 Mutation biology.protein Molecular Medicine Plasminogen activator Intracellular |
| Zdroj: | Vascular pharmacology. 87 |
| ISSN: | 1879-3649 |
| Popis: | Plasminogen activator inhibitor-1 (PAI-1) is induced by radiation resulting in endothelial cell impairment, potentially leading to multiple organ failure. Vitronectin (VN) is a 75-kDa glycoprotein (VN75) cleaved into two forms (VN75 or VN65/10) by furin, which is regulated by intracellular PAI-1. VN protects against radiation-induced endothelial cell death, but the mechanisms involved in VN processing and its interactions with intra- and extracellular PAI-1 remain unclear. We examined these processes in cells in vitro using recombinant proteins or overexpression of VN and PAI-1 genes, including furin-susceptible (T381) and furin-resistant VN (A381). VN processing was analyzed using a mutant PAI-1 with relatively weaker binding to VN. VN function was evaluated by survival of radiation-damaged endothelial cells. Wild-type, but not mutant PAI-1 inhibited furin-dependent VN processing. Gene transfer revealed that furin-susceptible VN was processed more than the furin-resistant form, but processing of both was inhibited by PAI-1 overexpression. Intracellular PAI-1 formed a complex with VN75 (T381) in cells and media, and the VN75 form was secreted preferentially. Only VN75 protected against radiation-induced endothelial cell death, in which its effect was abolished by wild-type but not mutant PAI-1. These findings indicate that intracellular PAI-1 inhibits VN processing and protects against radiation-induced endothelial cell death. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect