AIMS SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage. METHODS AND RESULTS We generated mice deficient for SR-B1 in monocytes/macrophages (Lysm-Cre × SR-B1f/f) and transplanted their BM into Ldlr-/- mice. Fed a cholesterol-rich diet, these mice displayed accelerated aortic atherosclerosis characterized by larger macrophage-rich areas and decreased macrophage apoptosis compared with SR-B1f/f transplanted controls. These findings were reproduced in BM transfer studies using another atherogenic mouse recipient (SR-B1 KOliver × Cholesteryl Ester Transfer Protein). Haematopoietic reconstitution with SR-B1-/- BM conducted in parallel generated similar results to those obtained with Lysm-Cre × SR-B1f/f BM; thus suggesting that among haematopoietic-derived cells, SR-B1 exerts its atheroprotective role primarily in monocytes/macrophages. Consistent with our in vivo data, free cholesterol (FC)-induced apoptosis of macrophages was diminished in the absence of SR-B1. This effect could not be attributed to differential cellular cholesterol loading. However, we observed that expression of apoptosis inhibitor of macrophage (AIM) was induced in SR-B1-deficient macrophages, and notably upon FC-loading. Furthermore, we demonstrated that macrophages were protected from FC-induced apoptosis by AIM. Finally, AIM protein was found more present within the macrophage-rich area of the atherosclerotic lesions of SR-B1-deficient macrophages than controls. CONCLUSION Our findings suggest that macrophage SR-B1 plays a role in plaque growth by controlling macrophage apoptosis in an AIM-dependent manner.

中文翻译：

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巨噬细胞中SR-B1的靶向无效可减少巨噬细胞凋亡并加速动脉粥样硬化。

AIMS SR-B1是一种胆固醇转运蛋白，可在小鼠的肝脏和周围组织中发挥抗动脉粥样硬化特性。骨髓（BM）转移研究表明，造血起源细胞具有抗动脉粥样硬化作用。在这里，我们解决了单核细胞/巨噬细胞中SR-B1的特定贡献。方法和结果我们产生了单核细胞/巨噬细胞中SR-B1缺陷的小鼠（Lysm-Cre×SR-B1f / f），并将其BM移植到Ldlr-/-小鼠中。饲喂富含胆固醇的饮食，这些小鼠表现出加速的主动脉粥样硬化，其特征是与SR-B1f / f移植的对照组相比，富含巨噬细胞的区域更大，巨噬细胞凋亡减少。这些发现在使用另一位致动脉粥样硬化小鼠（SR-B1 KOliver×胆固醇酯转移蛋白）的BM转移研究中得以重现。用SR-B1-/-BM并行进行的造血重建产生的结果与用Lysm-Cre×SR-B1f / f BM获得的结果相似。因此表明在造血细胞中，SR-B1主要在单核细胞/巨噬细胞中发挥其抗动脉粥样硬化作用。与我们的体内数据一致，在没有SR-B1的情况下，游离胆固醇（FC）诱导的巨噬细胞凋亡减少了。这种作用不能归因于不同的细胞胆固醇负荷。但是，我们观察到，在缺乏SR-B1的巨噬细胞中诱导了巨噬细胞凋亡抑制剂（AIM）的表达，特别是在FC加载时。此外，我们证明了巨噬细胞被AIM保护免受FC诱导的细胞凋亡。最后，发现AIM蛋白比缺乏SR-B1的巨噬细胞的动脉粥样硬化病变的巨噬细胞富集区域更多。结论我们的发现表明，巨噬细胞SR-B1通过以AIM依赖性方式控制巨噬细胞凋亡而在噬菌斑生长中发挥作用。