Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway
| Autor: | Koujiroh Imoto, Tomoko Matsuo, Eiichi Araki, Masakazu Sakai, Daisuke Kukidome, Miyuki Yano, Tetsuya Taguchi, Takeshi Matsumura, Takeshi Nishikawa, Shokei Kim-Mitsuyama, Kazuhiro Sonoda, Takafumi Senokuchi, Yoh Takuwa |
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| Rok vydání: | 2005 |
| Předmět: |
Male
MAPK/ERK pathway Simvastatin Geranylgeranyl Transferase RHOA Geranylgeranyl pyrophosphate Pyridines Farnesyl pyrophosphate p38 Mitogen-Activated Protein Kinases Biochemistry Mice chemistry.chemical_compound medicine Animals Molecular Biology Cell Proliferation Monomeric GTP-Binding Proteins Mice Inbred C3H biology Farnesyl Transferase Inhibitor Granulocyte-Macrophage Colony-Stimulating Factor Cerivastatin Cell Biology Lipoproteins LDL chemistry Macrophages Peritoneal biology.protein Cancer research lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors rhoA GTP-Binding Protein Macrophage proliferation Signal Transduction medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 280:6627-6633 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m412531200 |
| Popis: | Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) ameliorate atherosclerotic diseases. Macrophages play an important role in the development and subsequent stability of atherosclerotic plaques. We reported previously that oxidized low density lipoprotein (Ox-LDL) induced macrophage proliferation through the secretion of granulocyte/macrophage colony-stimulating factor (GM-CSF) and the consequent activation of p38 MAPK. The present study was designed to elucidate the mechanism of the inhibitory effect of statins on macrophage proliferation. Mouse peritoneal macrophages were used in our study. Cerivastatin and simvastatin each inhibited Ox-LDL-induced [(3)H]thymidine incorporation into macrophages. Statins did not inhibit Ox-LDL-induced GM-CSF production, but inhibited GM-CSF-induced p38 MAPK activation. Farnesyl transferase inhibitor and geranylgeranyl transferase inhibitor inhibited GM-CSF-induced macrophage proliferation, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the effect of statins. GM-CSF-induced p38 MAPK phosphorylation was also inhibited by farnesyl transferase inhibitor or geranylgeranyl transferase inhibitor, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the suppression of GM-CSF-induced p38 MAPK phosphorylation by statins. Furthermore, we found that statin significantly inhibited the membrane translocation of the small G protein family members Ras and Rho. GM-CSF-induced p38 MAPK activation and macrophage proliferation was partially inhibited by overexpression of dominant negative Ras and completely by that of RhoA. In conclusion, statins inhibited GM-CSF-induced Ras- or RhoA-p38 MAPK signal cascades, thereby suppressing Ox-LDL-induced macrophage proliferation. The significant inhibition of macrophage proliferation by statins may also explain, at least in part, their anti-atherogenic action. |
| Databáze: | OpenAIRE |
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