Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein - Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins
Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein - Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins
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DOI：
10.1172/jci118934
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发表时间：
1996-09-15
影响因子：
15.9
通讯作者：
Tabas, I
中科院分区：
文献类型：
--
作者：
Schissel, SL;TweedieHardman, J;Tabas, I
LDL在动脉壁的聚集和滞留是动脉粥样硬化形成的关键事件，但体内机制尚不清楚。我们实验室以前的工作表明，在体外将LDL暴露于细菌鞘磷脂酶（SMase）会导致形成LDL聚集体，这些聚集体可以被细胞外基质保留，并能够刺激巨噬细胞泡沫细胞形成。我们现在提供的证据表明，保留LDL是水解的动脉壁SMase活动。首先，我们证明了SMase诱导的聚集是由颗粒神经酰胺含量增加引起的，即使在存在过量鞘磷脂（SM）的情况下也是如此。这一发现与以前的数据相一致，表明病变LDL富含SM，尽管其神经酰胺含量以前没有报道过。为了解决这一关键的组成问题，测定了损伤LDL的神经酰胺含量，并且显著地发现与血浆LDL神经酰胺相比富集10-50倍。此外，仅在聚集的损伤LDL中发现神经酰胺;占损伤物质20-25%的未聚集的损伤LDL仍然缺乏神经酰胺。当[H-3]SM-LDL与离体兔主动脉条孵育时，一部分LDL被保留，这部分的[H-3]SM被非溶酶体动脉水解酶水解为[H-3]神经酰胺，而非未保留的LDL。总之，动脉壁SMase对动脉粥样硬化病变中的LDL起作用，可能参与LDL聚集和动脉粥样硬化形成过程中可能的其他SMase介导的过程。
Aggregation and retention of LDL in the arterial wall are key events in atherogenesis, but the mechanisms in vivo are not known. Previous work from our laboratories has shown that exposure of LDL to bacterial sphingomyelinase (SMase) in vitro leads to the formation of LDL aggregates that can be retained by extracellular matrix and that are able to stimulate macrophage foam cell formation. We now provide evidence that retained LDL is hydrolyzed by an arterial-wall SMase activity. First, we demonstrated that SMase-induced aggregation is caused by an increase in particle ceramide content, even in the presence of excess sphingomyelin (SM). This finding is compatible with previous data showing that lesional LDL is enriched in SM, though its ceramide content has not previously been reported. To address this critical compositional issue, the ceramide content of lesional LDL was assayed and, remarkably, found to be 10-50-fold enriched compared with plasma LDL ceramide. Furthermore, the ceramide was found exclusively in lesional LDL that was aggregated; unaggregated lesional LDL, which accounted for 20-25% of the lesional material, remained ceramide poor. When [H-3]SM-LDL was incubated with strips of rabbit aorta ex vivo, a portion of the LDL was retained, and the [H-3]SM of this portion, but not that of unretained LDL, was hydrolyzed to [H-3]ceramide by a nonlysosomal arterial hydrolase. In summary, LDL retained in atherosclerotic lesions is acted upon by an arterial-wall SMase, which may participate in LDL aggregation and possibly other SMase-mediated processes during atherogenesis.