Increased ABCA1 activity protects against atherosclerosis
Increased ABCA1 activity protects against atherosclerosis
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DOI：
10.1172/jci200215748
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发表时间：
2002-07-01
影响因子：
15.9
通讯作者：
Hayden, MR
中科院分区：
文献类型：
--
作者：
Singaraja, RR;Fievet, C;Hayden, MR
ABC转运蛋白ABCA 1通过介导脂质从巨噬细胞流出，在胆固醇反向转运途径的第一步中起关键作用。先前，已经证明，在转基因小鼠中体内人ABCA 1过表达导致血浆HDL水平的轻度升高和胆固醇从巨噬细胞的流出增加。在这项研究中，我们确定了ABCA 1过表达对动脉粥样硬化发展的影响。人类ABCA 1转基因小鼠（BAC（+））与ApoE（-/-）小鼠杂交，ApoE（-/-）小鼠是一种自发发展动脉粥样硬化病变的品系。BAC（+）ApoE（-/-）小鼠与ApoE（-/-）小鼠相比，病变明显更小，更不复杂。此外，从BAC-ApoE（-/-）小鼠分离的巨噬细胞中的胆固醇流出增加。虽然血浆HDL胆固醇水平的增加很小，但来自BAC（+）ApoE（-/-）小鼠的HDL颗粒是胆固醇的明显更好的受体。BAC（+）ApoE（-/-）小鼠HDL颗粒的脂质分析显示磷脂水平增加，这与其增强胆固醇流出的能力显著相关。我们的结论是，提高ABCA 1活性在体内的结果显着保护动脉粥样硬化。
The ABC transporter ABCA1 plays a key role in the first steps of the reverse cholesterol transport pathway by mediating lipid efflux from macrophages. Previously, it was demonstrated that human ABCA1 overexpression in vivo in transgenic mice results in a mild elevation of plasma HDL levels and increased efflux of cholesterol from macrophages. In this study, we determined the effect of overexpression of ABCA1 on atherosclerosis development. Human ABCA1 transgenic mice (BAC(+)) were crossed with ApoE(-/-) mice, a strain that spontaneously develop atherosclerotic lesions. BAC(+)ApoE(-/-) mice developed dramatically smaller, less-complex lesions as compared with their ApoE(-/-) counterparts. In addition, there was increased efflux of cholesterol from macrophages isolated from the BAC-ApoE(-/-) mice. Although the increase in plasma HDL cholesterol levels was small, HDL particles from BAC(+)ApoE(-/-) mice were significantly better acceptors of cholesterol. Lipid analysis of HDL particles from BAC(+)ApoE(-/-) mice revealed an increase in phospholipid levels, which was correlated significantly with their ability to enhance cholesterol efflux. We conclude that raising ABCA1 activity in vivo results in significant protection against atherosclerosis.