Intra- and extracellular plasminogen activator inhibitor-1 regulate effect of vitronectin against radiation-induced endothelial cell death.
Vascul Pharmacol
; 87: 150-158, 2016 12.
Article
in En
| MEDLINE
| ID: mdl-27650166
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Radiation Injuries
/
Plasminogen Activator Inhibitor 1
/
Vitronectin
/
Endothelial Cells
Limits:
Humans
Language:
En
Journal:
Vascul Pharmacol
Journal subject:
ANGIOLOGIA
/
FARMACOLOGIA
Year:
2016
Document type:
Article
Affiliation country:
Japan