In atherosclerotic lesions, vascular smooth muscle cells (VSMCs) represent half of the foam cell population, which is characterized by an aberrant accumulation of undigested lipids within lysosomes. Loss of lysosome function impacts VSMC homeostasis and disease progression. Understanding the molecular mechanisms underlying lysosome dysfunction in these cells is, therefore, crucial. We identify cholesteryl hemiazelate (ChA), a stable oxidation end-product of cholesteryl-polyunsaturated fatty acid esters, as an inducer of lysosome malfunction in VSMCs. ChA-treated VSMCs acquire a foam-cell-like phenotype, characterized by enlarged lysosomes full of ChA and neutral lipids. The lysosomes are perinuclear and exhibit degradative capacity and cargo exit defects. Lysosome luminal pH is also altered. Even though the transcriptional response machinery and autophagy are not activated by ChA, the addition of recombinant lysosomal acid lipase (LAL) is able to rescue lysosome dysfunction. ChA significantly affects VSMC proliferation and migration, impacting atherosclerosis. In summary, this work shows that ChA is sufficient to induce lysosomal dysfunction in VSMCs, that, in ChA-treated VSMCs, neither lysosome biogenesis nor autophagy are triggered, and, finally, that recombinant LAL can be a therapeutic approach for lysosomal dysfunction.

中文翻译：

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Cholesteryl hemiazelate 导致溶酶体功能障碍影响血管平滑肌细胞稳态。

在动脉粥样硬化病变中，血管平滑肌细胞 (VSMC) 占泡沫细胞群的一半，其特征是溶酶体内未消化的脂质异常积累。溶酶体功能的丧失会影响 VSMC 稳态和疾病进展。因此，了解这些细胞中溶酶体功能障碍的分子机制至关重要。我们确定了胆固醇半壬二酸酯 (ChA)，一种胆固醇-多不饱和脂肪酸酯的稳定氧化终产物，作为 VSMC 中溶酶体功能障碍的诱导剂。ChA 处理的 VSMC 获得泡沫细胞样表型，其特征是溶酶体增大，充满 ChA 和中性脂质。溶酶体是核周的，表现出降解能力和货物出口缺陷。溶酶体腔内的 pH 值也发生了改变。尽管 ChA 不激活转录反应机制和自噬，但添加重组溶酶体酸性脂肪酶 (LAL) 能够挽救溶酶体功能障碍。ChA 显着影响 VSMC 增殖和迁移，影响动脉粥样硬化。总之，这项工作表明，ChA 足以在 VSMC 中诱导溶酶体功能障碍，即在 ChA 处理的 VSMC 中，既不会触发溶酶体生物发生，也不会触发自噬，最后，重组 LAL 可以成为溶酶体功能障碍的治疗方法。