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

Atsuhiko Ichimura, Sachiko Matsumoto, Shinobu Suzuki, Takashi Dan, Satoshi Yamaki, Yayoi Sato, Hideyasu Kiyomoto, Naoto Ishii, Kiyotaka Okada, Osamu Matsuo, Fan Fan Hou, Douglas E. Vaughan, Charles Van Ypersele De Strihou, Toshio Miyata*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)935-942
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • Thy-1 nephritis
  • inflammation
  • low-density lipoprotein receptor-related protein
  • macrophage migration
  • plasminogen activator inhibitor 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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