HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7.
HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7.
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DOI：
10.1016/j.atherosclerosis.2011.06.031
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发表时间：
2011-08
期刊：
影响因子：
5.3
通讯作者：
Yokoyama, Shinji
中科院分区：
文献类型：
--
作者：
Tanaka, Nobukiyo;Abe-Dohmae, Sumiko;Iwamoto, Noriyuki;Fitzgerald, Michael L.;Yokoyama, Shinji
我们最近报道了内源性atp结合盒转运体（ABC） A7与吞噬作用密切相关，受固醇调节元件结合蛋白2的调节。因此，我们通过SREBP-ABCA7检测了他汀类药物对体外和体内吞噬的影响。发现普伐他汀、瑞舒伐他汀、辛伐他汀和环dextrin可增强J774巨噬细胞的吞噬功能，降低细胞胆固醇水平，调节胆固醇相关基因的表达，包括ABCA7 mRNA的升高和ABCA1 mRNA的降低。相反，通过siRNA敲低ABCA7表达会减弱他汀类药物对吞噬的增强作用。在体内，普伐他汀增强了野生型小鼠的吞噬能力，但对abca7基因敲除小鼠没有作用。因此，我们得出结论，他汀类药物通过SREBP-ABCA7途径增强吞噬作用。这些发现为他汀类药物增强宿主防御系统提供了分子基础，表明他汀类药物的“多效性”效应之一实际上是通过对主要靶点的反应实现的。
We recently reported that the endogenous ATP-binding cassette transporter (ABC) A7 strongly associates with phagocytosis, being regulated by sterol regulatory element binding protein 2. We therefore examined the effect of statins on phagocytosis in vitro and in vivo through the SREBP-ABCA7. Phagocytosis was found to be enhanced by pravastatin, rosuvastatin and simvastatin and cyclodextrin in J774 macrophages, as cellular cholesterol was reduced and expressions of the cholesterol-related genes were modulated, including an increase of ABCA7 mRNA and decrease of ABCA1 mRNA. Conversely, knock-down of ABCA7 expression by siRNA ablated enhancement of phagocytosis by statins. In vivo, pravastatin enhanced phagocytosis in wild-type mice, but not in ABCA7-knockout mice. We thus concluded that statins enhance phagocytosis through the SREBP-ABCA7 pathway. These findings provide a molecular basis for enhancement of the host-defense system by statins showing that one of their “pleiotropic” effects is in fact achieved through their reaction to a primary target.
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