A small molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration.
Arterioscler Thromb Vasc Biol
; 33(5): 935-42, 2013 May.
Article
in En
| MEDLINE
| ID: mdl-23471233
ABSTRACT
OBJECTIVE:
Macrophage (MÏ) migration rests on the adhesion/detachment between MÏ surface components and extracellular matrixes, and the contribution of numerous inflammatory disorders. Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, influences MÏ motility through an action distinct from its classical modulation of the plasmin-based fibrinolytic process. We rely here on a small molecule PAI-1 inhibitor (TM5275) to investigate the role of PAI-1 in MÏ migration in the pathogenesis of renal injury. APPROACH ANDRESULTS:
MÏ migration was inhibited both in vitro and in vivo by TM5275. It was also reduced in T-cell-deficient nude mice, but not in PAI-1-deficient mice. MÏ migration hinged on the interaction of PAI-1 with low-density lipoprotein receptor-related protein, an interaction prevented by TM5275, but not with vitronectin, urokinase-type plasminogen activator, or tissue-type plasminogen activator. Fed to rats with anti-Thy-1-induced nephritis, TM5275 significantly decreased MÏ accumulation and ameliorated the progression of renal injury.CONCLUSIONS:
These findings suggest that a small molecule PAI-1 inhibitor represents a novel class of anti-inflammatory agents targeting MÏ migration by the inhibition of the interaction of PAI-1 with low-density lipoprotein receptor-related protein.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperazines
/
Plasminogen Activator Inhibitor 1
/
Para-Aminobenzoates
/
Macrophages
Limits:
Animals
Language:
En
Journal:
Arterioscler Thromb Vasc Biol
Journal subject:
ANGIOLOGIA
Year:
2013
Document type:
Article
Affiliation country:
Japan