Tangirala R K, Praticó D, FitzGerald G A, Chun S, Tsukamoto K, Maugeais C, Usher D C, Puré E, Rader D J
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 2001 Jan 5;276(1):261-6. doi: 10.1074/jbc.M003324200.
Apolipoprotein E is a multifunctional protein synthesized by hepatocytes and macrophages. Plasma apoE is largely liver-derived and known to regulate lipoprotein metabolism. Macrophage-derived apoE has been shown to reduce the progression of atherosclerosis in mice. We tested the hypothesis that liver-derived apoE could directly induce regression of pre-existing advanced atherosclerotic lesions without reducing plasma cholesterol levels. Aged low density lipoprotein (LDL) receptor-deficient (LDLR(-/-)) mice were fed a western-type diet for 14 weeks to induce advanced atherosclerotic lesions. One group of mice was sacrificed for evaluation of atherosclerosis at base line, and two other groups were injected with a second generation adenoviruses encoding human apoE3 or a control empty virus. Hepatic apoE gene transfer increased plasma apoE levels by 4-fold at 1 week, and apoE levels remained at least 2-fold higher than controls at 6 weeks. There were no significant changes in plasma total cholesterol levels or lipoprotein composition induced by expression of apoE. The liver-derived human apoE gained access to and was retained in arterial wall. Compared with base-line mice, the control group demonstrated progression of atherosclerosis; in contrast, hepatic apoE expression induced highly significant regression of advanced atherosclerotic lesions. Regression of lesions was accompanied by the loss of macrophage-derived foam cells and a trend toward increase in extracellular matrix of lesions. As an index of in vivo oxidant stress, we quantitated the isoprostane iPF(2 alpha)-VI and found that expression of apoE markedly reduced urinary, LDL-associated, and arterial wall iPF(2 alpha)-VI levels. In summary, these results demonstrate that liver-derived apoE directly induced regression of advanced atherosclerosis and has anti-oxidant properties in vivo that may contribute to its anti-atherogenic effects.
载脂蛋白E是一种由肝细胞和巨噬细胞合成的多功能蛋白质。血浆载脂蛋白E主要来源于肝脏，已知其可调节脂蛋白代谢。巨噬细胞源性载脂蛋白E已被证明可减缓小鼠动脉粥样硬化的进展。我们检验了这样一个假说，即肝脏源性载脂蛋白E可直接促使已存在的晚期动脉粥样硬化病变消退，而不降低血浆胆固醇水平。将老年低密度脂蛋白（LDL）受体缺陷（LDLR(-/-)）小鼠喂食西式饮食14周以诱导晚期动脉粥样硬化病变。一组小鼠在基线时被处死以评估动脉粥样硬化情况，另外两组分别注射编码人载脂蛋白E3的第二代腺病毒或对照空病毒。肝脏载脂蛋白E基因转移在1周时使血浆载脂蛋白E水平升高了4倍，在6周时载脂蛋白E水平仍比对照组至少高2倍。载脂蛋白E表达未引起血浆总胆固醇水平或脂蛋白组成的显著变化。肝脏源性人载脂蛋白E进入并保留在动脉壁中。与基线小鼠相比，对照组的动脉粥样硬化有所进展；相反，肝脏载脂蛋白E表达促使晚期动脉粥样硬化病变高度显著消退。病变的消退伴随着巨噬细胞源性泡沫细胞的减少以及病变细胞外基质增加的趋势。作为体内氧化应激的指标，我们对异前列腺素iPF(2α)-VI进行了定量，发现载脂蛋白E的表达显著降低了尿液、LDL相关及动脉壁中的iPF(2α)-VI水平。总之，这些结果表明肝脏源性载脂蛋白E可直接促使晚期动脉粥样硬化消退，且在体内具有抗氧化特性，这可能有助于其抗动脉粥样硬化作用。
