Lebherz Corinna, Sanmiguel Julio, Wilson James M, Rader Daniel J
Department of Pathology and Laboratory Medicine, Gene Therapy Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Cardiovasc Diabetol. 2007 May 2;6:15. doi: 10.1186/1475-2840-6-15.
The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-IM) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice--a model which is most adequately mimicking the clinical setting.
Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-IM or green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic en face analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-IM by 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.
Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-IM each significantly reduced atherosclerosis progression to a similar extent.
载脂蛋白A-I（野生型载脂蛋白A-I，wtApoA-I）或天然存在的突变型载脂蛋白A-I米兰型（ApoA-IM）的全身递送的抗动脉粥样硬化作用已在动物和人体试验中得到证实，但评估ApoA-I或ApoA-I米兰型基因敲入小鼠或选择性转导了ApoA-I或ApoA-I米兰型的巨噬细胞的骨髓移植动物的表型的直接比较研究，对于两者中哪一种表现更优给出了相互矛盾的结果。因此，我们试图在高胆固醇血症小鼠中使用肝脏定向体细胞基因转移来比较这两种形式的载脂蛋白A-I，该模型最能充分模拟临床情况。
构建了基于血清型8腺相关病毒（AAV2.8）的载体，其编码wtApoA-I、ApoA-IM或绿色荧光蛋白（GFP）作为对照。给低密度脂蛋白受体缺陷小鼠喂食西式饮食。8周后注射AAV载体，6周后通过主动脉面分析确定动脉粥样硬化病变大小。与对照组相比，wtApoA-I的表达使动脉粥样硬化进展降低了32%（p = 0.02），ApoA-IM使动脉粥样硬化进展降低了24%（p = 0.04）。两种形式的ApoA-I在抑制动脉粥样硬化进展方面没有显著差异。
肝脏定向AAV2.8介导的wtApoA-I和ApoA-IM基因转移均显著降低了动脉粥样硬化进展，且程度相似。
