Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway*
Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway*
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DOI：
10.1074/jbc.m412531200
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发表时间：
2005-02
影响因子：
4.8
通讯作者：
Takafumi Senokuchi;T. Matsumura;M. Sakai;M. Yano;T. Taguchi;T. Matsuo;Kazuhiro Sonoda;D. Kukidome;Koujiroh Imoto;T. Nishikawa;S. Kim‐Mitsuyama;Y. Takuwa;E. Araki
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文献类型：
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作者：
Takafumi Senokuchi;T. Matsumura;M. Sakai;M. Yano;T. Taguchi;T. Matsuo;Kazuhiro Sonoda;D. Kukidome;Koujiroh Imoto;T. Nishikawa;S. Kim‐Mitsuyama;Y. Takuwa;E. Araki
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）可改善动脉粥样硬化性疾病。巨噬细胞在动脉粥样硬化斑块的发展和随后的稳定性中起重要作用。我们以前报道过氧化低密度脂蛋白（Ox-LDL）通过分泌粒细胞/巨噬细胞集落刺激因子（GM-CSF）和随后激活p38 MAPK来诱导巨噬细胞增殖。本研究旨在阐明他汀类药物抑制巨噬细胞增殖的机制。在我们的研究中使用小鼠腹腔巨噬细胞。西立伐他汀和辛伐他汀均抑制Ox-LDL诱导的[3 H]胸苷掺入巨噬细胞。他汀类药物不抑制Ox-LDL诱导的GM-CSF产生，但抑制GM-CSF诱导的p38 MAPK活化。法呢基转移酶抑制剂和香叶基香叶基转移酶抑制剂抑制GM-CSF诱导的巨噬细胞增殖，法呢基焦磷酸和香叶基香叶基焦磷酸阻止他汀类药物的作用。法呢基转移酶抑制剂或香叶基香叶基转移酶抑制剂也能抑制GM-CSF诱导的p38 MAPK磷酸化，法呢基焦磷酸和香叶基香叶基焦磷酸可阻止他汀类药物对GM-CSF诱导的p38 MAPK磷酸化的抑制。此外，我们发现他汀类药物显着抑制小G蛋白家族成员Ras和Rho的膜转位。GM-CSF诱导的p38 MAPK活化和巨噬细胞增殖被显性负性Ras的过表达部分抑制，而被RhoA的过表达完全抑制。总之，他汀类药物抑制GM-CSF诱导的Ras或RhoA-p38 MAPK信号级联，从而抑制Ox-LDL诱导的巨噬细胞增殖。他汀类药物对巨噬细胞增殖的显著抑制也可以解释，至少部分解释其抗动脉粥样硬化作用。
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.