title: Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small G protein-p38 MAPK pathway.
abstract: 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.
authors.affiliation: Departments of Metabolic Medicine and Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Senokuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sakai
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yano
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Taguchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Matsuo
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sonoda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kukidome
authors.forename: Koujiroh
authors.initials: K
authors.lastname: Imoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
authors.forename: Eiichi
authors.initials: E
authors.lastname: Araki
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011725:Pyridines; C099252:oxidized low density lipoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019821:Simvastatin; C086276:cerivastatin; D048051:p38 Mitogen-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein