Troglitazone inhibits oxidized low-density lipoprotein-induced macrophage proliferation: Impact of the suppression of nuclear translocation of ERK1/2

Abstract 

Thiazolidinediones (TZDs), which were known as novel insulin-sensitizing antidiabetic agents, have been reported to inhibit the acceleration of atherosclerotic lesions. Macrophages play important roles in the development of atherosclerosis. We previously reported that oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation through ERK1/2-dependent GM-CSF production. In the present study, we investigated the effects of two TZDs, troglitazone and ciglitazone on Ox-LDL-induced macrophage proliferation. Troglitazone significantly inhibited Ox-LDL-induced increases in [³H]thymidine incorporation into and proliferation of mouse peritoneal macrophages, whereas ciglitazone had no effects. Troglitazone and ciglitazone both significantly induced PPARγ activity, suggesting that the inhibitory effect of troglitazone was not mediated by PPARγ. Ox-LDL-induced production of GM-CSF was significantly inhibited by troglitazone, but not by ciglitazone. Troglitazone inhibited Ox-LDL-induced production of intracellular reactive oxygen species, whereas ciglitazone had no effect. The antioxidant reagents NAC and NMPG each inhibited phosphorylation of ERK1/2, whereas troglitazone and ciglitazone had no effects. However, troglitazone, NAC and NMPG all inhibited nuclear translocation of ERK1/2. In conclusion, troglitazone inhibited Ox-LDL-induced GM-CSF production by suppressing nuclear translocation of ERK1/2, thereby inhibiting macrophage proliferation. This suppression of macrophage proliferation by troglitazone may, at least in part, explain its antiatherogenic effects.

Abbreviations: 15d-PGJ₂, 15-deoxy-Δ^12,14-prostaglandin J₂, DAPI, 4′,6-diamidino-2-phenylindole dihydrochloride, ERK1/2, extracellular-signal regulated kinase 1/2, GM-CSF, granulocyte/macrophage colony-stimulating factor, LDL, low-density lipoprotein, NAC, N-acetylcysteine (NAC), NMPG, N-(2-mercapto-procinyl)-glycine, Ox-LDL, oxidized low-density lipoprotein, PPARγ, peroxisome proliferator-activated receptor γ, ROS, reactive oxygen species, TZDs, thiazolidinediones, VSMCs, vascular smooth muscle cells

Keywords: Thiazolidinedione, Ox-LDL, Atherosclerosis, Macrophage, Growth factor