Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo
Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo
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DOI：
10.1093/eurheartj/eht532
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发表时间：
2014-10-21
影响因子：
39.3
通讯作者：
Luescher, Thomas F.
中科院分区：
文献类型：
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作者：
Akhmedov, Alexander;Rozenberg, Izabela;Luescher, Thomas F.
目的凝集素样oxLDL受体-1 （LOX-1）介导内皮细胞和巨噬细胞对氧化低密度脂蛋白（oxLDL）的摄取。然而，lox -1介导的内皮细胞和巨噬细胞摄取oxLDL的不同致动脉粥样硬化潜能仍不清楚。本研究旨在探讨内皮细胞LOX-1在动脉粥样硬化发生中的体内作用。方法和结果利用Tie2启动子（LOX-1TG）制备内皮特异性LOX-1转基因小鼠。氧化低密度脂蛋白摄取在培养的内皮细胞中增强，但在LOX-1TG小鼠的巨噬细胞中没有增强。6周龄雄性LOX-1TG和野生型（WT）小鼠饲喂高胆固醇饮食（HCD） 30周。与WT幼崽相比，LOX-1TG小鼠的活性氧生成增加，内皮一氧化氮合酶活性受损，内皮功能障碍。LOX-1过表达导致p38磷酸化，核因子κ B活性增加，随后血管细胞粘附分子-1上调，从而有利于巨噬细胞积聚和主动脉脂肪条纹。一致地，与ApoE（-/-）对照相比，hcd喂养的双突变LOX-1TG/ApoE（-/-）表现出氧化应激和血管炎症，主动脉斑块增加。最后，骨髓移植实验表明内皮细胞LOX-1足以促进体内动脉粥样硬化的发展。结论内皮特异性LOX-1过表达可增强主动脉oxLDL水平，从而促进内皮功能障碍、血管炎症和斑块形成。因此，LOX-1可能成为动脉粥样硬化的新治疗靶点。
Aims Lectin-like oxLDL receptor-1 (LOX-1) mediates the uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells and macrophages. However, the different atherogenic potential of LOX-1-mediated endothelial and macrophage oxLDL uptake remains unclear. The present study was designed to investigate the in vivo role of endothelial LOX-1 in atherogenesis.Methods and results Endothelial-specific LOX-1 transgenic mice were generated using the Tie2 promoter (LOX-1TG). Oxidized low-density lipoprotein uptake was enhanced in cultured endothelial cells, but not in macrophages of LOX-1TG mice. Six-week-old male LOX-1TG and wild-type (WT) mice were fed a high-cholesterol diet (HCD) for 30 weeks. Increased reactive oxygen species production, impaired endothelial nitric oxide synthase activity and endothelial dysfunction were observed in LOX-1TG mice as compared with WT littermates. LOX-1 overexpression led to p38 phosphorylation, increased nuclear factor kappa B activity and subsequent up-regulation of vascular cell adhesion molecule-1, thereby favouring macrophage accumulation and aortic fatty streaks. Consistently, HCD-fed double-mutant LOX-1TG/ApoE(-/-) displayed oxidative stress and vascular inflammation with higher aortic plaques than ApoE(-/-) controls. Finally, bone marrow transplantation experiments showed that endothelial LOX-1 was sufficient for atherosclerosis development in vivo.Conclusions Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favouring endothelial dysfunction, vascular inflammation and plaque formation. Thus, LOX-1 may serve as a novel therapeutic target for atherosclerosis.