Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor γ for monocyte recruitment and endothelial regeneration

Tokuji Tanaka, Yasutomo Fukunaga, Hiroshi Itoh, Kentaro Doi, Jun Yamashita, Tae Hwa Chun, Mayumi Inoue, Ken Masatsugu, Takatoshi Saito, Naoki Sawada, Satsuki Sakaguchi, Hiroshi Arai, Kazuwa Nakao

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Abstract

Thiazolidinediones, a new class of antidiabetic drugs that increase insulin sensitivity, have been shown to be ligands for peroxisome proliferator- activated receptor γ (PPARγ). Recent studies demonstrating that PPARγ occurs in macrophages have focused attention on its role in macrophage functions. In this study, we investigated the effect of thiazolidinediones on monocyte proliferation and migration in vitro and the mechanisms involved. In addition, we examined the therapeutic potentials of thiazolidinediones for injured atherosclerotic lesions. Troglitazone and pioglitazone, the two thiazolidinediones, as well as 15-deoxy-Δ12,14- prostaglandin J2 inhibited in a dose-dependent manner the serum-induced proliferation of THP-1 (human monocytic leukemia cells) and of U937 (human monoblastic leukemia cells), which permanently express PPARγ. These ligands for PPARγ also significantly inhibited migration of THP-1 induced by monocyte chemoattractant protein-1 (MCP-1). Troglitazone and 15-deoxy-Δ12,14-prostaglandin J2 significantly suppressed the mRNA expression of the MCP family-specific receptor CCR2 (chemokine CCR2 receptor) in THP-1 at the transcriptional level. Furthermore, troglitazone significantly inhibited MCP-1 binding to THP-1. Oral administration of troglitazone to Watanabe heritable hyperlipidemic (WHHL) rabbits after balloon injury suppressed acute recruitment of monocytes/macrophages and accelerated re- endothelialization. These results suggest that thiazolidinediones have therapeutic potential for the treatment of diabetic vascular complications.

Original languageEnglish
Pages (from-to)255-265
Number of pages11
JournalEuropean journal of pharmacology
Volume508
Issue number1-3
DOIs
Publication statusPublished - 2005 Jan 31

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Keywords

  • CCR2
  • Insulin resistance
  • MCP-1
  • Macrophage
  • PPARγ
  • Thiazolidinedione

ASJC Scopus subject areas

  • Pharmacology

Cite this

Tanaka, T., Fukunaga, Y., Itoh, H., Doi, K., Yamashita, J., Chun, T. H., Inoue, M., Masatsugu, K., Saito, T., Sawada, N., Sakaguchi, S., Arai, H., & Nakao, K. (2005). Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor γ for monocyte recruitment and endothelial regeneration. European journal of pharmacology, 508(1-3), 255-265. https://doi.org/10.1016/j.ejphar.2004.10.056