APOLIPOPROTEIN-E DEFICIENCY IN MICE - GENE REPLACEMENT AND PREVENTION OF ATHEROSCLEROSIS USING ADENOVIRUS VECTORS
APOLIPOPROTEIN-E DEFICIENCY IN MICE - GENE REPLACEMENT AND PREVENTION OF ATHEROSCLEROSIS USING ADENOVIRUS VECTORS
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DOI：
10.1172/jci118200
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发表时间：
1995-09-01
影响因子：
15.9
通讯作者：
BREWER, HB
中科院分区：
文献类型：
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作者：
KASHYAP, VS;SANTAMARINAFOJO, S;BREWER, HB
载脂蛋白 E (apoE) 缺陷小鼠会出现明显的高脂血症和动脉粥样硬化，因此是评估人类遗传性异常脂蛋白血症基因治疗潜力的绝佳动物模型。 产生含有人 apoE (rAdv.apoE) 或报告基因荧光素酶 (rAdv.luc) 的重组腺病毒，并静脉注射到 apoE 缺陷小鼠中，输注前血浆总胆固醇为644+/-149 mg/dl 和富含胆固醇的 VLDL/IDL。单次输注 rAdv.apoE 后，人 apoE 血浆浓度达到 1.5 至 650 mg/dl，腺病毒介导的 apoE 替代导致脂肪酸脂蛋白谱正常化，总胆固醇 (103+/-18 mg/dl)、VLDL、IDL 和 LDL 显着降低，HDL 增加，腺病毒输注后 1 个月主动脉粥样硬化的测量与输注 rAdv.luc 的对照小鼠 (161+/-19 x 10(3) mu m(2); P < 0.0001) 相比，输注 rAdv.apoE 的小鼠的平均病变面积显着减少 (58+/-8 x 10(3) mu m(2))，因此，4 周的 apoE 表达足以显着减少动脉粥样硬化，证明了基因治疗纠正动脉粥样硬化的可行性。腺病毒载体和apoE缺陷小鼠的联合使用代表了一种新的体内方法，可以快速筛选预防动脉粥样硬化的候选基因。
Apolipoprotein E (apoE)-deficient mice develop marked hyperlipidemia as well as atherosclerosis and thus are an excellent animal model for evaluating the potential for gene therapy in human genetic dyslipoproteinemias, Recombinant adenovirus containing either human apoE (rAdv.apoE) or the reporter gene luciferase (rAdv.luc) were generated and infused intravenously in apoE-deficient mice with preinfusion plasma total cholesterol of 644+/-149 mg/dl and cholesterol rich VLDL/IDL. After a single infusion of rAdv.apoE, plasma concentrations of human apoE ranging from 1.5 to 650 mg/dl were achieved, Adenovirus-mediated apoE replacement resulted in normalization of the lipid acid lipoprotein profile with markedly decreased total cholesterol (103+/-18 mg/dl), VLDL, IDL, and LDL, as well as increased HDL, Measurement of aortic atherosclerosis 1 mo after adenoviral infusion demonstrated a marked reduction in the mean lesion area of mice infused with rAdv.apoE (58+/-8 x 10(3) mu m(2)) when compared with control mice infused with rAdv.luc (161+/-19 x 10(3) mu m(2); P < 0.0001), Thus, apoE expression for 4 wk was sufficient to markedly reduce atherosclerosis, demonstrating the feasibility of gene therapy for correction of genetic hyperlipidemias resulting in atherosclerosis, The combined use of adenovirus vectors and the apoE-deficient mouse represents a new in vivo approach that will permit rapid screening of candidate genes for the prevention of atherosclerosis.