Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis
Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis
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DOI：
10.1073/pnas.1732494100
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发表时间：
2003-09-02
影响因子：
11.1
通讯作者：
Tabas, I
中科院分区：
文献类型：
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作者：
Feng, B;Zhang, DJ;Tabas, I
晚期动脉粥样硬化病变中的巨噬细胞死亡导致病变坏死，并可能促进斑块不稳定，这是急性血管事件的前兆。晚期病变中的巨噬细胞积累大量未酯化胆固醇，这是巨噬细胞凋亡的有效诱导剂。我们最近发现，诱导培养的巨噬细胞凋亡需要胆固醇运输到内质网（ER）。此外，来自胆固醇运输蛋白Npc 1中具有杂合突变的小鼠的巨噬细胞在胆固醇运输到ER中具有选择性缺陷，并且被保护免于胆固醇诱导的细胞凋亡。本研究的目的是通过比较Npc 1（+/+）;Apoe（-/-）和Npc 1（+/-）;Apoe（-/-）小鼠的病变形态，检测细胞内胆固醇运输在动脉粥样硬化病变巨噬细胞死亡中的重要性。尽管Npc 1（+/+）;Apoe（-/-）小鼠的晚期病变具有广泛的非细胞区域，富含未酯化胆固醇和巨噬细胞碎片，但Npc 1（+/-）;Apoe（-/-）小鼠的病变实质上细胞更多，坏死较少。此外，与Npc 1（+/-）;Apoe（-/-）病变相比，Npc 1（+/+）;Apoe（-/-）病变在坏死区域周围有更多数量的大的TUNEL（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）阳性区域，表明巨噬细胞凋亡。尽管两组小鼠的总病变面积和血浆脂质水平相似，但仍观察到这些差异。这些数据提供了体内证据，完整的细胞内胆固醇运输是重要的巨噬细胞凋亡在先进的动脉粥样硬化病变和ER为基础的模型胆固醇诱导的细胞毒性是生理相关的。此外，通过显示病变坏死可以通过细胞内运输的细微缺陷来减少，这些发现提示了稳定动脉粥样硬化斑块的治疗策略。
Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis and likely promotes plaque instability, a precursor of acute vascular events. Macrophages in advanced lesions accumulate large amounts of unesterified cholesterol, which is a potent inducer of macrophage apoptosis. We have shown recently that induction of apoptosis in cultured macrophages requires cholesterol trafficking to the endoplasmic reticulum (ER). Moreover, macrophages from mice with a heterozygous mutation in the cholesterol-trafficking protein Npc1 have a selective defect in cholesterol trafficking to the ER and are protected from cholesterol-induced apoptosis. The goal of the present study was to test the importance of intracellular cholesterol trafficking in atherosclerotic lesional macrophage death by comparing lesion morphology in Npc1(+/+);Apoe(-/-) and Npc1(+/-);Apoe(-/-)mice. Although advanced lesions in Npc1(+/+);Apoe(-/-) mice had extensive acellular areas that were rich in unesterified cholesterol and macrophage debris, the lesions of Npc1(+/-);Apoe(-/-) mice were substantially more cellular and less necrotic. Moreover, compared with Npcl(+/-);Apoe(-/-) lesions, Npc1(+/+);Apoe(-/-) lesions had a greater number of large, TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling)-positive areas surrounding necrotic areas, indicative of macrophage apoptosis. These differences were observed despite similar total lesion area and similar plasma lipid levels in the two groups of mice. These data provide in vivo evidence that intact intracellular cholesterol trafficking is important for macrophage apoptosis in advanced atherosclerotic lesions and that the ER-based model of cholesterol-induced cytotoxicity is physiologically relevant. Moreover, by showing that lesional necrosis can be diminished by a subtle defect in intracellular trafficking, these findings suggest therapeutic strategies to stabilize atherosclerotic plaques.