Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
Cardiovasc Res. 2010 Nov 1;88(2):376-85. doi: 10.1093/cvr/cvq204. Epub 2010 Jun 18.
The ATP-binding cassette transporter A1 (ABCA1) lipidates apolipoprotein (apo) A-I. The hypothesis that hepatocyte-specific ABCA1 overexpression results in high-density lipoprotein (HDL) dysfunction was evaluated by comparing the effects of murine ABCA1 (AdABCA1) and human apo A-I (AdA-I) transfer on lipoprotein profile, HDL function, and progression of atherosclerosis.
Gene transfer in male and female C57BL/6 apo E(-/-) mice was performed at the age of 3 months with E1E3E4-deleted adenoviral vectors containing hepatocyte-specific expression cassettes. Atherosclerosis was quantified at baseline and 56 days later in AdABCA1, AdA-I, and control mice. HDL cholesterol after AdA-I transfer was 1.7-fold (P < 0.001) and 1.8-fold (P < 0.001) higher in male and female mice, respectively, and potently inhibited atherosclerosis progression compared with respective controls. Notwithstanding a 1.4-fold (P < 0.01) and a 1.7-fold (P < 0.01) increase of HDL cholesterol in male and female mice, respectively, after AdABCA1 transfer, the intima was 2.2-fold (P < 0.001) larger in male and 1.3-fold (P = NS) larger in female mice compared with respective controls. HDL isolated from control and AdA-I mice but not from AdABCA1 mice enhanced endothelial progenitor cell (EPC) migration in vitro and reduced endothelial cell death in vitro after serum and growth factor withdrawal. Scavenger receptor class B type I (SR-BI) protein level in the liver was significantly lower in AdABCA1 mice than in control and AdA-I mice.
Hepatocyte-specific ABCA1 transfer decreases SR-BI protein level in the liver and abrogates beneficial effects of HDL on EPCs and endothelial cells. Decreased HDL function may underlie accelerated atherosclerosis in AdABCA1 apo E(-/-)mice.
三磷酸腺苷结合盒转运子 A1（ABCA1）使载脂蛋白（apo）A-I 脂质化。通过比较鼠源 ABCA1（AdABCA1）和人源 apo A-I（AdA-I）转染对脂蛋白谱、高密度脂蛋白（HDL）功能和动脉粥样硬化进展的影响，评估了肝细胞特异性 ABCA1 过表达导致 HDL 功能障碍的假说。
在雄性和雌性 C57BL/6 apo E（-/-）小鼠 3 个月大时，用含有肝细胞特异性表达盒的 E1E3E4 缺失腺病毒载体进行基因转染。在 AdABCA1、AdA-I 和对照小鼠中，在基线和 56 天后定量测定动脉粥样硬化。AdA-I 转染后雄性和雌性小鼠的 HDL 胆固醇分别增加 1.7 倍（P < 0.001）和 1.8 倍（P < 0.001），并与各自的对照相比强力抑制动脉粥样硬化进展。尽管 AdABCA1 转染后雄性和雌性小鼠的 HDL 胆固醇分别增加 1.4 倍（P < 0.01）和 1.7 倍（P < 0.01），但雄性小鼠的内膜比各自的对照大 2.2 倍（P < 0.001），而雌性小鼠的内膜比各自的对照大 1.3 倍（P = NS）。与对照和 AdA-I 小鼠的 HDL 相比，从 AdABCA1 小鼠分离的 HDL 体外增强内皮祖细胞（EPC）迁移，并减少血清和生长因子耗尽后内皮细胞死亡。与对照和 AdA-I 小鼠相比，AdABCA1 小鼠肝脏中的清道夫受体 B 型 I（SR-BI）蛋白水平显著降低。
肝细胞特异性 ABCA1 转染降低了肝脏中的 SR-BI 蛋白水平，并消除了 HDL 对 EPC 和内皮细胞的有益作用。HDL 功能降低可能是 AdABCA1 apo E（-/-）小鼠动脉粥样硬化加速的基础。
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