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J. Biol. Chem., Vol. 280, Issue 8, 6627-6633, February 25, 2005

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Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway^*

Takafumi Senokuchi, Takeshi Matsumura, Masakazu Sakai¶, Miyuki Yano, Tetsuya Taguchi, Tomoko Matsuo, Kazuhiro Sonoda, Daisuke Kukidome, Koujiroh Imoto, Takeshi Nishikawa, Shokei Kim-Mitsuyama||, Yoh Takuwa**, and Eiichi Araki

From the Departments of Metabolic Medicine and ^||Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan and the ^**Department of Physiology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan

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 [³H]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.

Received for publication, November 5, 2004 , and in revised form, December 14, 2004.

^* This work was supported by Grant-in-Aid for Scientific Research 16046219 from the Japan Society for the Promotion of Science (to E. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: Dept. of Internal Medicine, Nishi-Kumamoto Hospital, Kumamoto 861-4157, Japan.

To whom correspondence should be addressed: Dept. of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Tel.: 81-96-373-5169; Fax: 81-96-366-8397; E-mail: takeshim{at}gpo.kumamoto-u.ac.jp.

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