Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression.
Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression.
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DOI：
10.1161/atvbaha.108.173344
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Tabas I
中科院分区：
文献类型：
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作者：
Devlin CM;Leventhal AR;Kuriakose G;Schuchman EH;Williams KJ;Tabas I
动脉粥样硬化形成的关键起始步骤是含载脂蛋白B的脂蛋白的内皮下滞留。酸性鞘磷脂酶（酸性SMase）是一种存在于动脉壁细胞外的酶，可强烈增强体外模型系统中的脂蛋白保留，并且人斑块中保留的脂蛋白富含神经酰胺（SMase产物）。我们现在试图测试酸性SMase在体内脂蛋白保留和动脉粥样硬化形成中的直接因果作用。我们研究了Apoe−/−和Ldlr−/−背景下Asm−/−与Asm+/+小鼠的动脉粥样硬化形成和脂蛋白潴留。Asm−/−;与Asm+/+;Apoe −/−小鼠相比，Apoe −/−小鼠的早期泡沫细胞主动脉根部病变面积减少约40-50%（P<0.05），尽管血浆胆固醇或脂蛋白没有差异。为了测定体内脂蛋白的保留，两组小鼠注射了荧光标记的Apoe−/−脂蛋白。与Asm +/+;Apoe−/−病变相比，Asm−/−; Apoe −/−的早期泡沫细胞病变显示脂蛋白捕获显著减少87%（P<0.0001）。Ldlr−/−小鼠也获得了类似的结果，包括与Asm +/+;Ldlr−/−病变相比，Asm−/−; Ldlr −/−病变内的脂蛋白滞留减少了81%（P<0.0005）。这些发现支持了酸性SMase在脂蛋白滞留和病变进展中的因果作用，并为动脉粥样硬化形成的反应-滞留模型提供了进一步的支持。
The key initial step in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Acid sphingomyelinase (acid SMase), an enzyme present extracellularly within the arterial wall, strongly enhances lipoprotein retention in model systems in vitro, and retained lipoproteins in human plaques are enriched in ceramide, an SMase product. We now sought to test a direct, causative role for acid SMase in lipoprotein retention and atherogenesis in vivo. We studied atherogenesis and lipoprotein retention in Asm−/− vs. Asm+/+ mice on the Apoe−/− and Ldlr−/− backgrounds. Asm−/−;Apoe−/− mice had a ~40–50% decrease in early foam cell aortic root lesion area compared with Asm+/+;Apoe−/− mice (P<0.05) despite no difference in plasma cholesterol or lipoproteins. To assay lipoprotein retention in vivo, the two groups of mice were injected with fluorescently labeled Apoe−/− lipoproteins. Early foam cell lesions of Asm−/−;Apoe−/− showed a striking 87% reduction in lipoprotein trapping (P<0.0001) compared with Asm+/+;Apoe−/− lesions. Similar results were obtained with Ldlr−/− mice, including an 81% reduction in lipoprotein retention within Asm−/−;Ldlr−/− lesions compared with Asm+/+;Ldlr−/− lesions (P<0.0005). These findings support a causal role for acid SMase in lipoprotein retention and lesion progression and provides further support for the response-to-retention model of atherogenesis.