A small molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration

Abstract

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. © 2013 American Heart Association, Inc.