Background and Aims: Local macrophage proliferation in the atherosclerotic plaque is linked to the enhanced atherosclerosis progression. Although we reported that troglitazone, a thiazolidinedione (TZD), suppressed oxidized low-density lipoprotein (Ox-LDL)-induced macrophage proliferation, its mechanisms have been unclear. We therefore investigated the mechanism(s) of the inhibitory effect of macrophage proliferation by another TZD, pioglitazone.

Methods: High-fat diet (HFD)-fed, apolipoprotein E-deficient (ApoE KO) mice were treated orally with pioglitazone (10 mg/kg/day). After 8 weeks of treatment, the whole aorta or frozen sections of the aortic sinus were stained with Oil red O. To identify macrophage proliferation and apoptosis, we performed Ki67/Iba-1 double immunohistochemical staining and TUNEL method, respectively.

Results: Atherosclerosis progression was suppressed in aortic sinuses of pioglitazone-treated ApoE KO mice, and they showed fewer proliferating macrophages in the plaques. Pioglitazone suppressed Ox-LDL-induced macrophage proliferation in a dose-dependent manner, which was ameliorated by peroxisome proliferator-activated receptor-γ (PPARγ) siRNA. Low concentrations (less than 100 µM) of pioglitazone, which can suppress macrophage proliferation, activated PPARγ in macrophages, but did not induce macrophage apoptosis. Pioglitazone did not induce TUNEL-positive cells in atherosclerotic plaques in ApoE KO mice.

Conclusions: Pioglitazone suppresses macrophage proliferation through PPARγ without inducing macrophage apoptosis. These findings imply that pioglitazone could prevent macrovascular complications in diabetics.


S. Murakami-Nishida: None. T. Matsumura: None. S. Nishida: None. T. Senokuchi: None. N. Ishii: None. S. Yamada: None. Y. Morita: None. T. Wada: None. H. Motoshima: None. T. Kondo: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi.

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