Troglitazone inhibits oxidized low-density lipoprotein-induced macrophage proliferation: impact of the suppression of nuclear translocation of ERK1/2.
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 [(3)H]thymidine incorporation into and proliferation of mouse peritoneal macrophages, whereas ciglitazone had no effects. Troglitazone and ciglitazone both significantly induced PPARgamma activity, suggesting that the inhibitory effect of troglitazone was not mediated by PPARgamma. 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.
Yano
Miyuki
M
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Matsumura
Takeshi
T
Senokuchi
Takafumi
T
Ishii
Norio
N
Motoshima
Hiroyuki
H
Taguchi
Tetsuya
T
Matsuo
Tomoko
T
Sonoda
Kazuhiro
K
Kukidome
Daisuke
D
Sakai
Masakazu
M
Kawada
Teruo
T
Nishikawa
Takeshi
T
Araki
Eiichi
E
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D045162:Thiazolidinediones; C099252:oxidized low density lipoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077288:Troglitazone; C039671:ciglitazone