Deficiency of Cholesteryl Ester Transfer Protein Protects Against Atherosclerosis in Rabbits.
Deficiency of Cholesteryl Ester Transfer Protein Protects Against Atherosclerosis in Rabbits.
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DOI：
10.1161/atvbaha.117.309114
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Chen YE
中科院分区：
文献类型：
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作者：
Zhang J;Niimi M;Yang D;Liang J;Xu J;Kimura T;Mathew AV;Guo Y;Fan Y;Zhu T;Song J;Ackermann R;Koike Y;Schwendeman A;Lai L;Pennathur S;Garcia-Barrio M;Fan J;Chen YE
胆固醇酯转运蛋白（CETP）在脂蛋白代谢中起重要作用，但抑制CETP活性是否能预防心血管疾病仍存在争议。我们通过锌指核酸酶基因编辑产生了CETP敲除（KO）兔，并将其对胆固醇饮食诱导的动脉粥样硬化的易感性与野生型（WT）兔进行了比较。在普通饲料中，KO兔的血浆HDL-C水平高于WT对照组，KO兔的HDL颗粒基本上富含apoAI和apoE含量。当用富含胆固醇的饮食挑战18周时，KO兔不仅具有更高的HDL-C水平，而且总胆固醇水平低于WT兔。血浆脂蛋白分析显示，KO兔血浆总胆固醇降低归因于含apoB颗粒减少，而HDL仍高于WT兔。与WT兔相比，KO兔的主动脉和冠状动脉粥样硬化均显著减少。从CETP KO兔分离的ApoB耗尽血浆显示出比WT兔显著更高的胆固醇从巨噬细胞流出的能力。此外，从CETP KO兔中分离的HDL抑制TNFα诱导的培养内皮细胞中VCAM-1和E-选择素的表达。这些结果提供了证据表明，基因消融CETP活性保护胆固醇饮食诱导的动脉粥样硬化兔。
Cholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial. We generated CETP knockout (KO) rabbits by zinc finger nuclease gene editing and compared their susceptibility to cholesterol diet-induced atherosclerosis to that of wild-type (WT) rabbits. On a chow diet, KO rabbits showed higher plasma levels of HDL-C than WT controls, and HDL particles of KO rabbits were essentially rich in apoAI and apoE contents. When challenged with a cholesterol-rich diet for 18 weeks, KO rabbits not only had higher HDL-C levels but also lower total cholesterol levels than WT rabbits. Analysis of plasma lipoproteins revealed that reduced plasma total cholesterol in KO rabbits was attributable to decreased apoB-containing particles while HDLs remained higher than that in WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared to WT rabbits. ApoB-depleted plasma isolated from CETP KO rabbits showed significantly higher capacity for cholesterol efflux from macrophages than that from WT rabbits. Furthermore, HDLs isolated from CETP KO rabbits suppressed TNFα-induced VCAM-1 and E-selectin expression in cultured endothelial cells. These results provide evidence that genetic ablation of CETP activity protects against cholesterol diet-induced atherosclerosis in rabbits.