TY - JOUR
T1 - A small molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration
AU - Ichimura, Atsuhiko
AU - Matsumoto, Sachiko
AU - Suzuki, Shinobu
AU - Dan, Takashi
AU - Yamaki, Satoshi
AU - Sato, Yayoi
AU - Kiyomoto, Hideyasu
AU - Ishii, Naoto
AU - Okada, Kiyotaka
AU - Matsuo, Osamu
AU - Hou, Fan Fan
AU - Vaughan, Douglas E.
AU - Van Ypersele De Strihou, Charles
AU - Miyata, Toshio
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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.
KW - Thy-1 nephritis
KW - inflammation
KW - low-density lipoprotein receptor-related protein
KW - macrophage migration
KW - plasminogen activator inhibitor 1
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U2 - 10.1161/ATVBAHA.113.301224
DO - 10.1161/ATVBAHA.113.301224
M3 - Article
C2 - 23471233
AN - SCOPUS:84876291882
SN - 1079-5642
VL - 33
SP - 935
EP - 942
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 5
ER -