Adeno-associated virus-mediated expression of acid sphingomyelinase decreases atherosclerotic lesion formation in apolipoprotein E-/- mice
Adeno-associated virus-mediated expression of acid sphingomyelinase decreases atherosclerotic lesion formation in apolipoprotein E-/- mice
复制标题
DOI：
10.1002/jgm.1575
复制
发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Yew, Nelson S.
中科院分区：
文献类型：
--
作者：
Leger, Andrew J.;Mosquea, Leocadia M.;Yew, Nelson S.
背景酸性鞘磷脂酶（ASM）的分泌形式被认为通过将脂蛋白中的鞘磷脂转化为神经酰胺，在脂蛋白在动脉壁内皮下空间的滞留和聚集中起关键作用。本研究旨在确定循环ASM活性水平是否影响动脉粥样硬化小鼠模型的病变发展。ApoE（-/-）小鼠静脉注射重组腺相关病毒（AAV8-ASM）结果血浆鞘磷脂水平在给药后早期降低，但在给药后较晚的时间点没有降低。在一些实施方案中，尽管持续升高的循环ASM，但施用AAV 8-ASM。未观察到血清脂蛋白水平的变化。AAV 8-ASM给药后13周或17周，主动脉窦中斑块形成的量与对照AAV治疗的小鼠相当。结论出乎意料的是，AAV 8-ASM病毒治疗组中整个主动脉的病变面积显著减少。在ApoE（-/-）小鼠中，肝脏表达和ASM分泌到循环中不会加速或加剧病变形成，而是减少病变形成。因此，血浆ASM活性似乎并不是动脉粥样硬化形成过程中斑块形成的速率限制。版权所有（C）2011约翰威利父子有限公司
Background The secretory form of acid sphingomyelinase (ASM) is postulated to play a key role in the retention and aggregation of lipoproteins in the subendothelial space of the arterial wall by converting sphingomyelin in lipoproteins into ceramide. The present study aimed to determine whether the level of circulating ASM activity affects lesion development in mouse model of atherosclerosis.Methods Apolipoprotein E deficient (ApoE(-/-)) mice were injected intravenously with a recombinant adeno-associated virus (AAV8-ASM) that constitutively expressed high levels of human ASM in liver and plasma.Results Plasma sphingomyelin levels were reduced at early but not later time points after the administration of AAV8-ASM despite persistently elevated circulating ASM. No change in serum lipoprotein levels was observed. Thirteen or 17 weeks after the administration of AAV8-ASM, the amount of plaque formation in the aortic sinus was comparable to that of mice treated with a control AAV.Conclusions Unexpectedly, the lesion area of the entire aorta was reduced significantly in the AAV8-ASM virus-treated group. Hepatic expression and secretion of ASM into the circulation did not accelerate or exacerbate, but rather decreased, lesion formation in ApoE(-/-) mice. Thus, plasma ASM activity does not appear to be rate limiting for plaque formation during atherogenesis. Copyright (C) 2011 John Wiley & Sons, Ltd.