Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation
Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation
复制标题
DOI：
10.1161/01.res.0000185320.82962.f7
复制
发表时间：
2005-10-14
影响因子：
20.1
通讯作者：
Rader, DJ
中科院分区：
文献类型：
--
作者：
Moore, RE;Navab, M;Rader, DJ
为了验证载脂蛋白A-I（apoA-I）通过促进胆固醇逆向转运和HDL-胆固醇（HDL-C）功能而特异性抑制动脉粥样硬化的假说，我们建立了载脂蛋白A-I缺乏的小鼠动脉粥样硬化模型，其中HDL-C水平维持良好。将ApoA-I-/-小鼠与动脉粥样硬化易感低密度脂蛋白受体（-/-）/apobec（-/-）（LA）小鼠杂交，以产生具有apoA-I-/-、apoA-I+/+和apoA-I-/-基因型的LA小鼠。不同apoA-I基因型之间血浆中非HDL-C和HDL-C含量无显著差异。然而，在雌性和雄性小鼠中，apoA-I基因剂量与动脉粥样硬化之间观察到显著的负相关。与LA-apoA-I-/-小鼠相比，来自LA-apoA-I-/-小鼠的血清具有作为ABCA 1和SR-BI介导的细胞胆固醇流出的受体的功能的显著降低的能力，并且还具有显著降低的卵磷脂胆固醇酰基转移酶活性。此外，LA-apoA-I-/-小鼠体内巨噬细胞衍生的胆固醇酯化和胆固醇逆向转运显著减少。与LA-apoA-I-/-小鼠相比，LA-apoA-I-/-小鼠血浆中对氧磷酶（PON-1）活性显著降低，HDL血管内皮功能受损，单核细胞趋化蛋白-1基础水平升高。在LA-apoA-I-/-小鼠中，响应于腹腔内注射脂多糖，也存在比LA-apoA-I-/-小鼠更大的一些但不是全部的炎性细胞因子和趋化因子的诱导。我们的结论是，apoA-I抑制动脉粥样硬化，促进巨噬细胞胆固醇逆向转运和HDL胆固醇的功能，这些抗动脉粥样硬化的apoA-I的功能在很大程度上是独立的血浆中的HDL-C在这个小鼠模型。
To test the hypothesis that apolipoprotein A-I ( apoA-I) functions specifically to inhibit atherosclerosis independent of the level of high-density lipoprotein cholesterol ( HDL-C) by promoting both reverse cholesterol transport and HDL antiinflammatory function in vivo, we established a murine atherosclerosis model of apoA-I deficiency in which the level of HDL-C is well maintained. ApoA-I-/- mice were crossed with atherosclerosis susceptible low-density lipoprotein receptor(-/-)/apobec(-/-) ( LA) mice to generate LA mice with apoA-I-/-, apoA-I+/+,and apoA-I-/- genotypes. There were no major differences in the amounts of non-HDL-C and HDL-C in the plasma between different apoA-I genotypes. A significant inverse relationship was observed, however, between apoA-I gene dose and atherosclerosis in both female and male mice. Compared with LA-apoA-I-/- mice, serum from LA-apoA-I-/- mice had a significantly reduced capacity to function as an acceptor of ABCA1- and SR-BI-mediated cellular cholesterol efflux, and also had markedly reduced lecithin cholesterol acyltransferase activity. In addition, LA-apoA-I-/- mice had significantly reduced macrophage-derived cholesterol esterification and reverse cholesterol transport in vivo. There was significantly reduced plasma paraoxonase ( PON-1) activity, impaired HDL vascular antiinflammatory function, and increased basal levels of monocyte chemotactic protein-1 in the plasma of LA-apoA-I-/- mice compared with LA-apoA-I-/- mice. In LA-apoA-I-/- mice, there was also greater induction of some, but not all, inflammatory cytokines and chemokines in response to intraperitoneal injection of lipopolysaccharide than in LA-apoA-I-/- mice. We conclude that apoA-I inhibits atherosclerosis by promoting both macrophage reverse cholesterol transport and HDL antiinflammatory function, and that these anti-atherogenic functions of apoA-I are largely independent of the plasma level of HDL-C in this mouse model.