Overexpression of apolipoprotein all in transgenic mice converts high density lipoproteins to proinflammatory particles
Overexpression of apolipoprotein all in transgenic mice converts high density lipoproteins to proinflammatory particles
复制标题
DOI：
10.1172/jci119554
复制
发表时间：
1997-07-15
影响因子：
15.9
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
--
作者：
Castellani, LW;Navab, M;Lusis, AJ
先前的研究表明，过表达载脂蛋白Al（apoAI）或载脂蛋白AII（apoAII）（HDL的主要蛋白质）的转基因小鼠表现出HDL胆固醇水平升高，但是，尽管apoAI转基因小鼠免受动脉粥样硬化，apoAII转基因小鼠的病变发展增加，我们现在研究这种惊人的功能异质性的基础，来自apoAI转基因的HDL表现出增强的促进巨噬细胞胆固醇流出的能力，但来自apoAII转基因和非转基因的HDL在流出研究中没有明显的不同，与来自非转基因和apoAI转基因的HDL相反，在动脉壁的共培养模型中，来自apoAII转基因小鼠的HDL不能保护免于LDL氧化。此外，从apoAII转基因小鼠获得的HDL，而不是从apoAII转基因小鼠或非转基因同窝对照小鼠获得的HDL，其本身刺激动脉壁细胞中脂质氢过氧化物的形成，并诱导单核细胞迁移，表明apoAII转基因HDL实际上是促炎性的。apoAII转基因HDL作为抗氧化剂/抗氧化剂的能力的这种丧失与对氧磷酶（一种保护免受LDL氧化的酶）含量的降低有关。用纯化的对氧磷酶重建apoAII转基因HDL恢复了对氧磷酶活性和保护免受LDL氧化的能力，我们的结论是过度表达apoAII将HDL从抗炎症颗粒转化为促炎症颗粒，对氧磷酶在这种转化中起作用。
Previous studies showed that transgenic mice overexpressing either apolipoprotein Al (apoAI) or apolipoprotein AII (apoAII), the major proteins of HDL, exhibited elevated levels of HDL cholesterol, but, whereas the apoAI-transgenic mice were protected against atherosclerosis, the apoAII-transgenic mice had increased lesion development, We now examine the basis for this striking functional heterogeneity, HDL from apoAI transgenics exhibited an enhanced ability to promote cholesterol efflux from macrophages, but HDL from apoAII transgenics and nontransgenics were not discernibly different in efflux studies, In contrast with HDL from nontransgenics and apoAI transgenics, HDL from the apoAII transgenics were unable to protect against LDL oxidation in a coculture model of the artery wall, Furthermore, HDL taken from apoAII-transgenic mice, but not HDL taken from either the apoAI transgenics or nontransgenic littermate controls, by itself stimulated lipid hydroperoxide formation in artery wall cells and induced monocyte transmigration, indicating that the apoAII-transgenic HDL were in fact proinflammatory. This loss in the ability of the apoAII-transgenic HDL to function as an antioxidant/antiinflammatory agent was associated with a decreased content of paraoxonase, an enzyme that protects against LDL oxidation, Reconstitution of the apoAII transgenic HDL with purified paraoxonase restored both paraoxonase activity and the ability to protect against LDL oxidation, We conclude that overexpression of apoAII converts HDL from an anti- to a proinflammatory particle and that paraoxonase plays a role in this transformation.