Apolipoprotein E4 Domain Interaction Accelerates Diet-Induced Atherosclerosis in Hypomorphic Arg-61 Apoe Mice
Apolipoprotein E4 Domain Interaction Accelerates Diet-Induced Atherosclerosis in Hypomorphic Arg-61 Apoe Mice
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DOI：
10.1161/atvbaha.112.246389
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发表时间：
2012-05-01
影响因子：
8.7
通讯作者：
Raffai, Robert L.
中科院分区：
文献类型：
--
作者：
Eberle, Delphine;Kim, Roy Y.;Raffai, Robert L.
载脂蛋白E4是动脉粥样硬化的一个确定的危险因素，但这种关联的结构成分仍不清楚。ApoE 4具有两个生物物理特性：结构域相互作用和熔融球状态。替代Arg-61的Thr-61在小鼠apoE引入域相互作用没有熔融球状态，使我们能够描绘潜在的proatherogenic影响域的相互作用invivo.Methods和结果-我们研究了动脉粥样硬化易感性的hypomorphic ApoE小鼠表达Thr-61或Arg-61 apoE（ApoeT（h/h）或ApoeR（h/h）小鼠）。在普通饲料中，两种小鼠模型的血脂正常，血浆apoE和脂蛋白水平相似。然而，与ApoeT（h/h）小鼠相比，在高胆固醇饮食下，ApoeR（h/h）小鼠显示出血浆总胆固醇和极低密度脂蛋白水平升高，以及主动脉根部、弓部和降主动脉中的动脉粥样硬化斑块更大。此外，细胞功能障碍的证据被确定在腹膜ApoeR（h/h）巨噬细胞释放较低的载脂蛋白E在培养基中，并显示增加表达的主要组织相容性复合物II类molecules. Conclusions，这些数据表明，域相互作用介导的促动脉粥样硬化的影响apoE 4的部分通过调节脂蛋白代谢和巨噬细胞生物学。药物靶向域相互作用可能导致新的治疗apoE 4个体动脉粥样硬化。（Arterioscler Thromb Vasc Biol.2012; 32：1116-1123.）
Objectives-Apolipoprotein (apo) E4 is an established risk factor for atherosclerosis, but the structural components underlying this association remain unclear. ApoE4 is characterized by 2 biophysical properties: domain interaction and molten globule state. Substituting Arg-61 for Thr-61 in mouse apoE introduces domain interaction without molten globule state, allowing us to delineate potential proatherogenic effects of domain interaction in vivo.Methods and Results-We studied atherosclerosis susceptibility of hypomorphic Apoe mice expressing either Thr-61 or Arg-61 apoE (ApoeT(h/h) or ApoeR(h/h) mice). On a chow diet, both mouse models were normolipidemic with similar levels of plasma apoE and lipoproteins. However, on a high-cholesterol diet, ApoeR(h/h) mice displayed increased levels of total plasma cholesterol and very-low-density lipoprotein as well as larger atherosclerotic plaques in the aortic root, arch, and descending aorta compared with ApoeT(h/h) mice. In addition, evidence of cellular dysfunction was identified in peritoneal ApoeR(h/h) macrophages which released lower amounts of apoE in culture medium and displayed increased expression of major histocompatibility complex class II molecules.Conclusions-These data indicate that domain interaction mediates proatherogenic effects of apoE4 in part by modulating lipoprotein metabolism and macrophage biology. Pharmaceutical targeting of domain interaction could lead to new treatments for atherosclerosis in apoE4 individuals. (Arterioscler Thromb Vasc Biol. 2012; 32: 1116-1123.)