Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis
Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis
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DOI：
10.1161/atvbaha.108.182303
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发表时间：
2009-04-01
影响因子：
8.7
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
--
作者：
Brunham, Liam R.;Singaraja, Roshni R.;Hayden, Michael R.
目的：ATP结合盒转运蛋白亚家族A成员1（ABCA 1）在高密度脂蛋白胆固醇代谢中起关键作用。然而，ABCA 1在调制动脉粥样硬化的易感性的作用是有争议的。方法和结果-我们研究了ABCA 1在动脉粥样硬化中的作用，使用过表达和选择性缺失模型的组合。首先，我们研究了在存在或不存在内源性小鼠Abca 1基因的情况下，转基因过表达全长含人ABCA 1的细菌人工染色体（BAC）的效果。在动脉粥样硬化易感的Ldlr（-/-）背景下，ABCA 1过表达在存在和不存在小鼠Abca 1的情况下都显著降低了动脉粥样硬化的发展。接下来，我们使用Abca 1组织特异性失活的小鼠来剖析Abca 1在不同组织中对动脉粥样硬化易感性的不同作用。在Apoe（-/-）背景下，缺乏肝脏Abca 1的小鼠显著降低HDL胆固醇并加速动脉粥样硬化，表明肝脏是Abca 1发挥抗动脉粥样硬化作用的重要部位。与此相反，小鼠巨噬细胞特异性灭活Abca 1的Ldlr（-/-）背景显示动脉粥样硬化病变area.Conclusions没有变化-这些数据表明，生理表达的Abca 1调节动脉粥样硬化的易感性，并建立肝Abca 1表达作为一个重要的网站动脉粥样硬化保护。相反，我们发现选择性删除巨噬细胞Abca 1并不能显著调节动脉粥样硬化的形成。（Arterioscler Thromb Vasc Biol.2009;29：548-554.）
Objective - The ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial.Methods and Results - We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1-containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr(-/-) background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1. Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe(-/-) background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr(-/-) background displayed no change in atherosclerotic lesion area.Conclusions - These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis. (Arterioscler Thromb Vasc Biol. 2009;29:548-554.)