Loike J D, Shabtai D Y, Neuhut R, Malitzky S, Lu E, Husemann J, Goldberg I J, Silverstein S C
Department of Physiology, Columbia University College of Physician and Surgeons, 630 W 168th St, New York, NY 10032, USA.
Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2051-6. doi: 10.1161/01.ATV.0000143858.15909.29. Epub 2004 Sep 2.
An inflammatory response to altered lipoproteins that accumulate in the arterial wall is a major component of the pathogenesis of atherosclerosis. Statins reduce plasma levels of low-density lipoprotein (LDL) and are effective treatments for atherosclerosis. It is hypothesized that they also modulate inflammation. The aim of this study was to examine whether lovastatin inhibits macrophage inflammatory processes and clarify its mechanism of action.
We examined the effects of statins on phagocytosis of antibody-coated red blood cells by cultured human monocytes and mouse peritoneal macrophages. Lovastatin, simvastatin, and zaragozic acid, a squalene synthase inhibitor, blocked Fc receptor-mediated phagocytosis by cultured human monocytes and mouse peritoneal macrophages. The inhibitory effect of lovastatin on Fc receptor-mediated phagocytosis was prevented completely by addition of mevalonate, farnesyl pyrophosphate, LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic acid was reversed by addition of LDL, but not by the addition of geranylgeranyl pyrophosphate, to the medium. In addition, the effect of lovastatin on phagocytosis is a function of cell activation because treatment of cells with tumor necrosis factor-alpha or lipopolysaccharide prevented inhibition of phagocytosis by lovastatin.
The inhibition of Fc receptor-mediated phagocytosis of lovastatin is related to its effect on cholesterol biosynthesis rather than its effect on the formation of isoprenoids.
对积聚在动脉壁中的脂蛋白改变产生的炎症反应是动脉粥样硬化发病机制的主要组成部分。他汀类药物可降低血浆低密度脂蛋白（LDL）水平，是治疗动脉粥样硬化的有效药物。据推测，它们还可调节炎症。本研究的目的是检验洛伐他汀是否抑制巨噬细胞炎症过程并阐明其作用机制。
我们研究了他汀类药物对培养的人单核细胞和小鼠腹腔巨噬细胞吞噬抗体包被红细胞的影响。洛伐他汀、辛伐他汀和角鲨烯合酶抑制剂扎戈泽酸可阻断培养的人单核细胞和小鼠腹腔巨噬细胞的Fc受体介导的吞噬作用。向培养基中添加甲羟戊酸、法尼基焦磷酸、LDL或胆固醇可完全阻止洛伐他汀对Fc受体介导的吞噬作用的抑制效果。向培养基中添加LDL可逆转扎戈泽酸的抑制效果，但添加香叶基香叶基焦磷酸则不能。此外，洛伐他汀对吞噬作用的影响是细胞活化的函数，因为用肿瘤坏死因子-α或脂多糖处理细胞可防止洛伐他汀对吞噬作用的抑制。
洛伐他汀对Fc受体介导的吞噬作用的抑制与其对胆固醇生物合成的影响有关，而非其对类异戊二烯形成的影响。
