A Small Molecule Inhibitor to Plasminogen Activator Inhibitor 1 Inhibits Macrophage Migration
Objective—Macrophage (Mφ) migration rests on the adhesion/detachment between Mφ surface components and extracellular matrixes, and the contribution of numerous inflammatory disorders. Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, influences Mφ 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 Mφ migration in the pathogenesis of renal injury.
Approach and Results—Mφ 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. Mφ 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 Mφ 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 Mφ migration by the inhibition of the interaction of PAI-1 with low-density lipoprotein receptor–related protein.
- low-density lipoprotein receptor–related protein
- macrophage migration
- plasminogen activator inhibitor 1
- Thy-1 nephritis
- Received October 11, 2012.
- Accepted February 20, 2013.
- © 2013 American Heart Association, Inc.