Influence of Apolipoprotein A-I Domain Structure on Macrophage Reverse Cholesterol Transport in Mice

被引:25
作者
Alexander, Eric T.
Vedhachalam, Charulatha
Sankaranarayanan, Sandhya
de la Llera-Moya, Margarita
Rothblat, George H.
Rader, Daniel J. [2 ]
Phillips, Michael C. [1 ]
机构
[1] Childrens Hosp Philadelphia, Abramson Res Ctr, Lipid Res Grp, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
apolipoproteins; cardiovascular disease prevention; lipoproteins; DENSITY-LIPOPROTEIN PARTICLES; APOA-I; SR-BI; ACYLTRANSFERASE ACTIVITY; BIDIRECTIONAL FLUX; LIPID INTERACTION; LECITHIN; VIVO; EFFLUX; BINDING;
D O I
10.1161/ATVBAHA.110.216226
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective-The goal of this study was to determine the influence of apolipoprotein A-I (apoA-I) tertiary structure domain properties on the antiatherogenic properties of the protein. Two chimeric hybrids with the N-terminal domains swapped (human-mouse apoA-I and mouse-human apoA-I) were expressed in apoA-I-null mice with adeno-associated virus (AAV) and used to study macrophage reverse cholesterol transport (RCT) in vivo. Methods and Results-The different apoA-I variants were expressed in apoA-I-null mice that were injected with [H-3]cholesterol-labeled J774 mouse macrophages to measure RCT. Significantly more cholesterol was removed from the macrophages and deposited in the feces via the RCT pathway in mice expressing mouse-H apoA-I compared with all other groups. Analysis of the individual components of the RCT pathway demonstrated that mouse-H apoA-I promoted ATP-binding cassette transporter A1-mediated cholesterol efflux more efficiently than all other variants, as well as increasing the rate of cholesterol uptake into liver cells. Conclusion-The structural domain properties of apoA-I affect the ability of the protein to mediate macrophage RCT. Replacement of the N-terminal helix bundle domain in the human apoA-I with the mouse apoA-I counterpart causes a gain of function with respect to macrophage RCT, suggesting that engineering some destabilization into the N-terminal helix bundle domain or increasing the hydrophobicity of the C-terminal domain of human apoA-I would enhance the antiatherogenic properties of the protein. (Arterioscler Thromb Vasc Biol. 2011;31:320-327.)
引用
收藏
页码:320 / U217
页数:28
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