Subendothelial retention of atherogenic lipoproteins in early atherosclerosis
Subendothelial retention of atherogenic lipoproteins in early atherosclerosis
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DOI：
10.1038/nature00804
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发表时间：
2002-06-13
期刊：
影响因子：
64.8
通讯作者：
Borén, J
中科院分区：
文献类型：
--
作者：
Skålén, K;Gustafsson, M;Borén, J
动脉粥样硬化的并发症是西方社会最常见的死亡原因（1）。在流行病学研究确定的许多风险因素中，即使在没有其他风险因素的情况下，只有含载脂蛋白（apo）B的脂蛋白水平升高才能驱动人类和实验动物动脉粥样硬化的发展（2）。然而，导致动脉粥样硬化的机制仍然知之甚少。我们检验了这样一个假设，即动脉粥样硬化形成的起始事件是内皮下含有载脂蛋白B的脂蛋白的滞留（3）。内皮下的细胞外基质，特别是蛋白多糖，被认为在致动脉粥样硬化脂蛋白的滞留中起主要作用（4）。致动脉粥样硬化脂蛋白和蛋白聚糖之间的相互作用涉及apoB100中碱性氨基酸和蛋白聚糖上带负电荷的硫酸基团之间的离子相互作用（5）。在这里，我们提出了直接的实验证据表明，含载脂蛋白B的低密度脂蛋白（LDL）的致动脉粥样硬化性与它们对动脉壁蛋白多糖的亲和力有关。与表达野生型对照LDL的小鼠相比，表达蛋白聚糖结合缺陷型LDL的小鼠发生动脉粥样硬化的情况明显较少。我们的结论是，内皮下的载脂蛋白B100的保留是动脉粥样硬化形成的早期步骤。
Complications of atherosclerosis are the most common cause of death in Western societies(1). Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors(2). However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis(3). The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins(4). The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans(5). Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.