Reduction of isoprostanes and regression of advanced atherosclerosis by apolipoprotein E

被引:96
作者
Tangirala, RK
Praticó, D
FitzGerald, GA
Chun, S
Tsukamoto, K
Maugeais, C
Usher, DC
Puré, E
Rader, DJ
机构
[1] Univ Penn, Med Ctr, Sch Med, Dept Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Ctr Expt Therapeut, Philadelphia, PA 19104 USA
[3] Univ Delaware, Newark, DE 19711 USA
[4] Wistar Inst, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.M003324200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 S-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 anal 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.
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收藏
页码:261 / 266
页数:6
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