Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis
Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis
复制标题
DOI：
10.1161/atvbaha.115.305777
复制
发表时间：
2015-11-01
影响因子：
8.7
通讯作者：
Rye, Kerry-Anne
中科院分区：
文献类型：
--
作者：
Bisoendial, Radjesh;Tabet, Fatiha;Rye, Kerry-Anne
目的淋巴内皮功能障碍是许多慢性炎性疾病的发病机制。促炎细胞因子肿瘤坏死因子（TNF）因其在破坏淋巴血管功能中的作用而闻名。本研究探讨载脂蛋白（apo） A-I（高密度脂蛋白的主要载脂蛋白）在TNF处理淋巴内皮细胞后维持正常功能的能力。方法和结果TNF降低淋巴内皮细胞形成管状结构的能力。用apoA-I预孵育淋巴内皮细胞以浓度依赖的方式减弱tnf介导的管形成抑制。此外，apoA-I逆转了tnf介导的胸导管环淋巴内皮细胞迁移和淋巴生长的抑制。ApoA-I还通过atp结合盒转运体a1依赖的方式消除了TNF对淋巴新生血管的负面影响。在分子水平上，这涉及TNF受体-1的下调和繁荣相关同源盒基因-1表达的保存，繁荣相关同源盒基因-1是淋巴管生成的主要调节因子。ApoA-I还重建了人TNF转基因小鼠膈膜淋巴网络的正常表型。结论在tnf介导的炎症中，ApoA-I可恢复淋巴系统的新生血管能力。本研究提供了一个概念证明，高密度脂蛋白为基础的治疗策略可能通过其对淋巴血管的作用来减轻慢性炎症。
Objective Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF.Approach and Results TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice.Conclusions ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature.